Patent Publication Number: US-2021187011-A1

Title: Method of treating acid-base disorders

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application is a U.S. National Phase Application of International Application PCT Application No. PCT/US18/59093 filed on Nov. 3, 2018, which claims benefit of U.S. Provisional Patent Application Ser. No. 62/748,363, filed on Oct. 19, 2018, and U.S. Provisional Patent Application Ser. No. 62/581,448, filed on Nov. 3, 2017, which applications are incorporated by reference herein in their entireties. 
    
    
     The present invention generally relates to methods of treating acid-base disorders that may be used, for example, in the treatment of metabolic acidosis. 
     Metabolic acidosis is the result of metabolic and dietary processes that in various disease states create a condition in which non-volatile acids accumulate in the body, causing a net addition of protons (H + ) or the loss of bicarbonate (HCO 3   − ). Metabolic acidosis occurs when the body accumulates acid from metabolic and dietary processes and the excess acid is not completely removed from the body by the kidneys. Chronic kidney disease is often accompanied by metabolic acidosis due to the reduced capacity of the kidney to excrete hydrogen ions secondary to an inability to reclaim filtered bicarbonate (HCO 3   − ), synthesize ammonia (ammoniagenesis), and excrete titratable acids. Clinical practice guidelines recommend initiation of alkali therapy in patients with non-dialysis-dependent chronic kidney disease (CKD) when the serum bicarbonate level is &lt;22 mEq/L to prevent or treat complications of metabolic acidosis. (Clinical practice guidelines for nutrition in chronic renal failure, K/DOQI, National Kidney Foundation, Am. J. Kidney Dis. 2000; 35:S1-140; Raphael, K L, Zhang, Y, Wei, G, et al. 2013, Serum bicarbonate and mortality in adults in NHANES III, Nephrol. Dial. Transplant 28: 1207-1213). These complications include malnutrition and growth retardation in children, exacerbation of bone disease, increased muscle degradation, reduced albumin synthesis, and increased inflammation. (Leman, J, Litzow, J R, Lennon, E J. 1966. The effects of chronic acid loads in normal man: further evidence for the participation of bone mineral in the defense against chronic metabolic acidosis, J. Clin. Invest. 45: 1608-1614; Franch H A, Mitch W E, 1998, Catabolism in uremia: the impact of metabolic acidosis, J. Am. Soc. Nephrol. 9: S78-81; Ballmer, P E, McNurlan, M A, Hulter, H N, et al., 1995, Chronic metabolic acidosis decreases albumin synthesis and induces negative nitrogen balance in humans, J. Clin. Invest. 95: 39-45; Farwell, W R, Taylor, E N, 2010, Serum anion gap, bicarbonate and biomarkers of inflammation in healthy individuals in a national survey, CMAJ 182:137-141). Overt metabolic acidosis is present in a large proportion of patients when the estimated glomerular filtration rate is below 30 ml/min/1.73 m 2 . (KDOQI bone guidelines: American Journal of Kidney Diseases (2003) 42:S1-S201. (suppl); Widmer B, Gerhardt R E, Harrington J T, Cohen J J, Serum electrolyte and acid base composition: The influence of graded degrees of chronic renal failure, Arch Intern Med 139:1099-1102, 1979; Dobre M, Yang, W, Chen J, et. al., Association of serum bicarbonate with risk of renal and cardiovascular outcomes in CKD: a report from the chronic renal insufficiency cohort (CRIC) study. Am. J. Kidney Dis. 62: 670-678, 2013; Yaqoob, M M. Acidosis and progression of chronic kidney disease. Curr. Opin. Nephrol. Hypertens. 19: 489-492, 2010). 
     Metabolic acidosis, regardless of etiology, lowers extracellular fluid bicarbonate and, thus, decreases extracellular pH. The relationship between serum pH and serum bicarbonate is described by the Henderson-Hasselbalch equation 
       pH=pK′+log[HCO 3   − ]/[(0.03×PaCO 2 )]
 
     where 0.03 is the physical solubility coefficient for CO 2 , [HCO 3   −  ] and P a CO 2  are the concentrations of bicarbonate and the partial pressure of carbon dioxide, respectively. 
     There are several laboratory tests that can be used to define metabolic acidosis. The tests fundamentally measure either bicarbonate (HCO 3   − ) or proton (H + ) concentration in various biological samples, including venous or arterial blood. These tests can measure either bicarbonate (HCO 3   − ) or proton (H + ) concentration by enzymatic methodology, by ion selective electrodes or by blood gas analysis. In both the enzymatic and ion selective electrode methods, bicarbonate is “measured.” Using blood gas analysis, bicarbonate level can be calculated using the Henderson-Hasselbalch equation. 
     Arterial blood gas (ABG) analysis is commonly performed for clinical evaluation, but the procedure has certain limitations in the form of reduced patient acceptability because of painful procedure and the potential to cause complications such as arterial injury, thrombosis with distal ischaemia, haemorrhage, aneurysm formation, median nerve damage and reflex sympathetic dystrophy. Venous blood gas (VBG) analysis is a relatively safer procedure as fewer punctures are required thus reducing the risk of needle stick injury to the health care workers. Therefore, as set out below, when the invention requires assessment of metabolic acidosis, it is preferred to complete this assessment using VBG analysis. Any measurements specified herein are preferably achieved by VBG analysis where possible, for example measurements of blood or serum bicarbonate levels. 
     The most useful measurements for the determination of acidosis rely on a measurement of the venous plasma bicarbonate (or total carbon dioxide [tCO 2 ]), or arterial plasma bicarbonate (or total carbon dioxide [tCO 2 ]), serum electrolytes C, K + , and Na + , and a determination of the anion gap. In the clinical laboratory, measurement of venous plasma or serum electrolytes includes an estimation of the tCO 2 . This measurement reflects the sum of circulating CO 2  [i.e., the total CO 2  represented by bicarbonate (HCO 3   − ), carbonic acid, (H 2 CO 3 ) and dissolved CO 2  (0.03×PCO 2 )]. tCO 2  can also be related to HCO 3   −  by using a simplified and standardized form of the Henderson-Hasselbalch equation: tCO 2 ═HCO 3   − +0.03 PCO 2 , where PCO 2  is the measured partial pressure of CO 2 . Since HCO 3   −  concentration is greater than 90% of the tCO 2 , and there are small amounts of H 2 CO 3 , then venous tCO 2  is often used as a reasonable approximation of the venous HCO 3   −  concentration in the blood. Especially during chronic kidney disease, an abnormal plasma HCO 3   −  value &lt;22 mEq/L generally indicates metabolic acidosis. 
     Changes in serum Cl −  concentration can provide additional insights into possible acid-base disorders, particularly when they are disproportionate to changes in serum Na +  concentration. When this occurs, the changes in serum C concentration are typically associated with reciprocal changes in serum bicarbonate. Thus, in metabolic acidosis with normal anion gap, serum Cl −  increases &gt;105 mEq/L as serum bicarbonate decreases &lt;22 mEq/L. 
     Calculation of the anion gap [defined as the serum Na + —(Cl − +HCO 3   − )] is an important aspect of the diagnosis of metabolic acidosis. Metabolic acidosis may be present with a normal or an elevated anion gap. However, an elevated anion gap commonly signifies the presence of metabolic acidosis, regardless of the change in serum HCO 3   − . An anion gap greater than 20 mEq/L (normal anion gap is 8 to 12 mEq/L) is a typical feature of metabolic acidosis. 
     Arterial blood gases are used to identify the type of an acid-base disorder and to determine if there are mixed disturbances. In general, the result of arterial blood gas measures should be coordinated with history, physical exam and the routine laboratory data listed above. An arterial blood gas measures the arterial carbon dioxide tension (P a CO 2 ), acidity (pH), and the oxygen tension (P a O 2 ). The HCO 3  concentration is calculated from the pH and the P a CO 2 . Hallmarks of metabolic acidosis are a pH&lt;7.35, P a CO 2 &lt;35 mm Hg and HCO 3 &lt;22 mEq/L. The value of P a O 2  (normal 80-95 mmHg) is not used in making the diagnosis of metabolic acidosis but may be helpful in determining the cause. Acid-base disturbance are first classified as respiratory or metabolic. Respiratory disturbances are those caused by abnormal pulmonary elimination of CO 2 , producing an excess (acidosis) or deficit (alkalosis) of CO 2  (carbon dioxide) in the extracellular fluid. In respiratory acid-base disorders, changes in serum bicarbonate (HCO 3   − ) are initially a direct consequence of the change in PCO 2  with a greater increase in PCO 2  resulting in an increase in HCO 3   − . (Adrogue H J, Madias N E, 2003, Respiratory acidosis, respiratory alkalosis, and mixed disorders, in Johnson R J, Feehally J (eds): Comprehensive Clinical Nephrology. London, C V Mosby, pp. 167-182). Metabolic disturbances are those caused by excessive intake of, or metabolic production or losses of, nonvolatile acids or bases in the extracellular fluid. These changes are reflected by changes in the concentration of bicarbonate anion (HCO 3 ) in the blood adaptation in this case involves both buffering (immediate), respiratory (hours to days) and renal (days) mechanisms. (DuBose T D, MacDonald G A: renal tubular acidosis, 2002, in DuBose T D, Hamm L L (eds): Acid-base and electrolyte disorders: A companion to Brenners and Rector&#39;s the Kidney, Philadelphia, W B Saunders, pp. 189-206). 
     The overall hydrogen ion concentration in the blood is defined by the ratio of two quantities, the serum HCO 3   −  content (regulated by the kidneys) and the PCO 2  content (regulated by the lungs) and is expressed as follows: 
       [H + ]∝(PCO 2 /[HCO 3   − ])
 
     The consequence of an increase in the overall hydrogen ion concentration is a decline in the major extracellular buffer, bicarbonate. Normal blood pH is between 7.38 and 7.42, corresponding to a hydrogen ion (H + ) concentration of 42 to 38 nmol/L (Goldberg M: Approach to Acid-Base Disorders. 2005. In Greenberg A, Cheung A K (eds) Primer on Kidney Diseases, National Kidney Foundation, Philadelphia, Elsevier-Saunders, pp. 104-109.). Bicarbonate (HCO 3   − ) is an anion that acts to buffer against pH disturbances in the body, and normal levels of plasma bicarbonate range from 22-26 mEq/L (Szerlip H M: Metabolic Acidosis, 2005, in Greenberg A, Cheung A K (eds) Primer on Kidney Diseases, National Kidney Foundation, Philadelphia, Elsevier-Saunders, pp. 74-89.). Acidosis is the process which causes a reduction in blood pH (acidemia) and reflects the accumulation of hydrogen ion (H + ) and its consequent buffering by bicarbonate ion (HCO 3   − ) resulting in a decrease in serum bicarbonate. Metabolic acidosis can be represented as follows: 
     
       
         
         
             
             
         
       
     
     (Clinical practice guidelines for nutrition in chronic renal failure. K/DOQI, National Kidney Foundation. Am. J. Kidney Dis. 2000; 35:S1-140). Using this balance equation, the loss of one HCO 3   −  is equivalent to the addition of one H +  and conversely, the gain of one HCO 3   −  is equivalent to the loss of one H + . Thus, changes in blood pH, particularly increases in H +  (lower pH, acidosis) can be corrected by increasing serum HCO 3   −  or, equivalently, by decreasing serum H + . 
     In order to maintain extracellular pH within the normal range, the daily production of acid must be excreted from the body. Acid production in the body results from the metabolism of dietary carbohydrates, fats and amino acids. Complete oxidation of these metabolic substrates produces water and CO 2 . The carbon dioxide generated by this oxidation (˜20,000 mmol/day) is efficiently exhaled by the lungs, and represents the volatile acid component of acid-base balance. 
     In contrast, nonvolatile acids (˜50-100 mEq/day) are produced by the metabolism of sulfate- and phosphate-containing amino acids and nucleic acids. Additional nonvolatile acids (lactic acid, butyric acid, acetic acid, other organic acids) arise from the incomplete oxidation of fats and carbohydrates, and from carbohydrate metabolism in the colon, where bacteria residing in the colon lumen convert the substrates into small organic acids that are then absorbed into the bloodstream. The impact of short chain fatty acids on acidosis is somewhat minimized by anabolism, for example into long-chain fatty acids, or catabolism to water and CO 2 . 
     The kidneys maintain pH balance in the blood through two mechanisms: reclaiming filtered HCO 3   −  to prevent overall bicarbonate depletion and the elimination of nonvolatile acids in the urine. Both mechanisms are necessary to prevent bicarbonate depletion and acidosis. 
     In the first mechanism, the kidneys reclaim HCO 3   −  that is filtered by the glomerulus. This reclamation occurs in the proximal tubule and accounts for ˜4500 mEq/day of reclaimed HCO 3 . This mechanism prevents HCO 3   −  from being lost in the urine, thus preventing metabolic acidosis. In the second mechanism, the kidneys eliminate enough H +  to equal the daily nonvolatile acid production through metabolism and oxidation of protein, fats and carbohydrates. Elimination of this acid load is accomplished by two distinct routes in the kidney, comprising active secretion of H +  ion and ammoniagenesis. The net result of these two interconnected processes is the elimination of the 50-100 mEq/day of nonvolatile acid generated by normal metabolism. 
     Thus, normal renal function is needed to maintain acid-base balance. During chronic kidney disease, filtration and reclamation of HCO 3   −  is impaired as is generation and secretion of ammonia. These deficits rapidly lead to chronic metabolic acidosis which is, itself, a potent antecedent to end-stage renal disease. With continued acid production from metabolism, a reduction in acid elimination will disturb the H + /HCO 3   −  balance such that blood pH falls below the normal value of pH=7.38-7.42. 
     Treatment of metabolic acidosis by alkali therapy is usually indicated to raise and maintain the plasma pH to greater than 7.20. Sodium bicarbonate (NaHCO 3 ) is the agent most commonly used to correct metabolic acidosis. NaHCO 3  can be administered intravenously to raise the serum HCO 3   −  level adequately to increase the pH to greater than 7.20. Further correction depends on the individual situation and may not be indicated if the underlying process is treatable or the patient is asymptomatic. This is especially true in certain forms of metabolic acidosis. For example, in high-anion gap (AG) acidosis secondary to accumulation of organic acids, lactic acid, and ketones, the cognate anions are eventually metabolized to HCO 3 . When the underlying disorder is treated, the serum pH corrects; thus, caution should be exercised in these patients when providing alkali to raise the pH much higher than 7.20, to prevent an increase in bicarbonate above the normal range (&gt;26 mEq/L). 
     Citrate is an appropriate alkali therapy to be given orally or IV, either as the potassium or sodium salt, as it is metabolized by the liver and results in the formation of three moles of bicarbonate for each mole of citrate. Potassium citrate administered IV should be used cautiously in the presence of renal impairment and closely monitored to avoid hyperkalemia. 
     Intravenous sodium bicarbonate (NaHCO 3 ) solution can be administered if the metabolic acidosis is severe or if correction is unlikely to occur without exogenous alkali administration. Oral alkali administration is the preferred route of therapy in persons with chronic metabolic acidosis. The most common alkali forms for oral therapy include NaHCO 3  tablets where 1 g of NaHCO 3  is equal to 11.9 mEq of HCO 3   − . However, the oral form of NaHCO 3  is not approved for medical use and the package insert of the intravenous sodium bicarbonate solution includes the following contraindications, warnings and precautions (Hospira label for NDC 0409-3486-16):
         Contraindications: Sodium Bicarbonate Injection, USP is contraindicated in patients who are losing chloride by vomiting or from continuous gastrointestinal suction, and in patients receiving diuretics known to produce a hypochloremic alkalosis.   Warnings: Solutions containing sodium ions should be used with great care, if at all, in patients with congestive heart failure, severe renal insufficiency and in clinical states in which there exists edema with sodium retention. In patients with diminished renal function, administration of solutions containing sodium ions may result in sodium retention. The intravenous administration of these solutions can cause fluid and/or solute overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema.   Precautions: [ . . . ] The potentially large loads of sodium given with bicarbonate require that caution be exercise in the use of sodium bicarbonate in patients with congestive heart failure or other edematous or sodium-retaining states, as well as in patients with oliguria or anuria.       

     Acid-base disorders are common in chronic kidney disease and heart failure patients. Chronic kidney disease (CKD) progressively impairs renal excretion of the approximately 1 mmol/kg body weight of hydrogen ions generated in healthy adults (Yaqoob, M M. 2010, Acidosis and progression of chronic kidney disease, Curr. Opin. Nephrol. Hyperten. 19:489-492.). Metabolic acidosis, resulting from the accumulation of acid (H + ) or depletion of base (HCO 3 ) in the body, is a common complication of patients with CKD, particularly when the glomerular filtration rate (GFR, a measure of renal function) falls below 30 ml/min/1.73 m 2 . Metabolic acidosis has profound long term effects on protein and muscle metabolism, bone turnover and the development of renal osteodystrophy. In addition, metabolic acidosis influences a variety of paracrine and endocrine functions, again with long term consequences such as increased inflammatory mediators, reduced leptin, insulin resistance, and increased corticosteroid and parathyroid hormone production (Mitch W E, 1997, Influence of metabolic acidosis on nutrition, Am. J. Kidney Dis. 29:46-48.). The net effect of sustained metabolic acidosis in the CKD patient is loss of bone and muscle mass, a negative nitrogen balance, and the acceleration of chronic renal failure due to hormonal and cellular abnormalities (De Brito-Ashurst I, Varagunam M, Raftery M J, et al, 2009, Bicarbonate supplementation slows progression of CKD and improves nutritional status, J. Am. Soc. Nephrol. 20: 2075-2084). Conversely, the potential concerns with alkali therapy in CKD patients include expansion of extracellular fluid volume associated with sodium ingestion, resulting in the development or aggravation of hypertension, facilitation of vascular calcification, and the decompensation of existing heart failure. CKD patients of moderate degree (GFR at 20-25% of normal) first develop hyperchloremic acidosis with a normal anion gap due to the inability to reclaim filtered bicarbonate and excrete proton and ammonium cations. As they progress toward the advanced stages of CKD the anion gap increases, reflective of the continuing degradation of the kidney&#39;s ability to excrete the anions that were associated with the unexcreted protons. Serum bicarbonate in these patients rarely goes below 15 mmol/L with a maximum elevated anion gap of approximately 20 mmol/L. The non-metabolizable anions that accumulate in CKD are buffered by alkaline salts from bone (Lemann J Jr, Bushinsky D A, Hamm L L Bone buffering of acid and base in humans. Am. J. Physiol Renal Physiol. 2003 November, 285(5):F811-32). 
     The majority of patients with chronic kidney disease have underlying diabetes (diabetic nephropathy) and hypertension, leading to deterioration of renal function. In almost all patients with hypertension a high sodium intake will worsen the hypertension. Accordingly, kidney, heart failure, diabetes and hypertensive guidelines strictly limit sodium intake in these patients to less than 1.5 g or 65 mEq per day (HFSA 2010 guidelines, Lindenfeld 2010, J Cardiac Failure V16 No 6 P475). Chronic anti-hypertensive therapies often induce sodium excretion (diuretics) or modify the kidney&#39;s ability to excrete sodium and water (such as, for example, Renin Angiotensin Aldosterone System inhibiting “RAASi” drugs). However, as kidney function deteriorates, diuretics become less effective due to an inability of the tubule to respond. The RAASi drugs induce life-threatening hyperkalemia as they inhibit renal potassium excretion. Given the additional sodium load, chronically treating metabolic acidosis patients with amounts of sodium-containing base that often exceed the total daily recommended sodium intake is not a reasonable practice. As a consequence, oral sodium bicarbonate is not commonly prescribed chronically in these diabetic nephropathy patients. Potassium bicarbonate is also not acceptable as patients with CKD are unable to readily excrete potassium, leading to severe hyperkalemia. 
     Despite these shortcomings, the role of oral sodium bicarbonate has been studied in the small subpopulation of non-hypertensive CKD patients. As part of the Kidney Research National Dialogue, alkali therapy was identified as having the potential to slow the progression of CKD, as well as to correct metabolic acidosis. The annual age-related decline in glomerular filtration rate (GFR) after the age of 40 is 0.75-1.0 ml/min/1.73 m 2  in normal individuals. In CKD patients with fast progression, a steeper decline of &gt;4 ml/min/1.73 m 2  annually can be seen. Glomerular filtration rate or estimated glomerular filtration rate is typically used to characterize kidney function and the stage of chronic kidney disease. The five stages of chronic kidney disease and the GFR for each stage is as follows:
         Stage 1 with normal or high GFR (GFR&gt;90 mL/min/1.73 m 2 )   Stage 2 Mild CKD (GFR=60-89 mL/min/1.73 m 2 )   Stage 3A Moderate CKD (GFR=45-59 mL/min/1.73 m 2 )   Stage 3B Moderate CKD (GFR=30-44 mL/min/1.73 m 2 )   Stage 4 Severe CKD (GFR=15-29 mL/min/1.73 m 2 )   Stage 5 End Stage CKD (GFR&lt;15 mL/min/1.73 m 2 ).       

     In one outcome study, De Brito-Ashurst et al showed that bicarbonate supplementation preserves renal function in CKD (De Brito-Ashurst I, Varagunam M, Raftery M J, et al, 2009, Bicarbonate supplementation slows progression of CKD and improves nutritional status, J. Am. Soc. Nephrol. 20: 2075-2084). The study randomly assigned 134 adult patients with CKD (creatinine clearance [CrCl] 15 to 30 ml/min per 1.73 m 2 ) and serum bicarbonate 16 to 20 mmol/L to either supplementation with oral sodium bicarbonate or standard of care for 2 years. The average dose of bicarbonate in this study was 1.82 g/day, which provides 22 mEq of bicarbonate per day. The primary end points were rate of CrCl decline, the proportion of patients with rapid decline of CrCl (&gt;3 ml/min per 1.73 m 2 /yr), and end-stage renal disease (“ESRD”) (CrCl&lt;10 ml/min). Compared with the control group, decline in CrCl was slower with bicarbonate supplementation (decrease of 1.88 ml/min per 1.73 m 2  for patients receiving bicarbonate versus a decrease of 5.93 ml/min per 1.73 m 2  for control group; P&lt;0.0001). Patients supplemented with bicarbonate were significantly less likely to experience rapid progression (9% versus 45%; relative risk 0.15; 95% confidence interval 0.06 to 0.40; P&lt;0.0001). Similarly, fewer patients supplemented with bicarbonate developed ESRD (6.5% versus 33%; relative risk 0.13; 95% confidence interval 0.04 to 0.40; P&lt;0.001). 
     Hyperphosphatemia is a common co-morbidity inpatients with CKD, particularly in those with advanced or end-stage renal disease. Sevelamer hydrochloride is a commonly used ion-exchange resin that reduces serum phosphate concentration. However, reported drawbacks of this agent include metabolic acidosis apparently due to the net absorption of HCl in the process of binding phosphate in the small intestine. Several studies in patients with CKD and hyperphosphatemia who received hemodialysis or peritoneal dialysis found decreases in serum bicarbonate concentrations with the use of sevelamer hydrochloride (Brezina, 2004 Kidney Int. V66 S90 (2004) S39-S45; Fan, 2009 Nephrol Dial Transplant (2009) 24:3794). 
     Among the various aspects of the present disclosure, the following is a useful guide for one method for treating metabolic acidosis (without wishing to be bound by theory). When an H +  is pumped into the stomach a HCO 3   −  enters the systemic circulation and raises the serum bicarbonate concentration. The initial binding of gastric H +  to a nonabsorbable composition as described herein results in HCO 3   −  entering the systemic circulation and raising the serum bicarbonate concentration. The more H +  bound the greater the increase in systemic HCO 3   − . The binding of Cl −  the nonabsorbable composition prevents subsequent exchange of luminal Cl −  for HCO 3  which would counteract the initial rise in HCO 3   − . The analogous clinical situation to administering the composition is vomiting. Administration of the composition is essentially causing the loss of gastric HCl as in vomiting. If a person vomits they lose gastric HCl and have an increase in serum bicarbonate. The increase in serum bicarbonate persists only if they are not given a lot of oral Cl − , for example as NaCl, which would allow subsequent exchange of intestinal Cl −  for HCO 3   −  and dissipate the increase in serum bicarbonate concentration. The disclosure is not limited by these requirements, and instead they are set out in full below. 
     Among the various aspects of the present disclosure may be noted a method of treating an individual afflicted with a chronic acid/base disorder characterized by a baseline serum bicarbonate value of less than 22 mEq/l. The method comprises oral administration of a pharmaceutical composition comprising a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system and increase the individual&#39;s serum bicarbonate value to at least 24 mEq/l but less than 30 mEq/l. 
     Among the various aspects of the present disclosure may be noted a method of treating an individual afflicted with a chronic acid/base disorder characterized by a baseline serum bicarbonate value of less than 22 mEq/l. The method comprises oral administration of a pharmaceutical composition comprising a nonabsorbable composition having the capacity to bind a target species selected from the group consisting of protons, a conjugate base of a strong acid, and a strong acid as it transits the digestive system and increase the individual&#39;s serum bicarbonate value to at least 24 mEq/l but not greater than 29 mEq/l. 
     Another aspect of the present disclosure is a method of treating an individual afflicted with an acid-base disorder characterized by a baseline serum bicarbonate value of less than 22 mEq/l, the method comprising oral administration of a daily dose of a pharmaceutical composition having the capacity to remove at least 5 meq of a target species as it transits the digestive system to increase the individual&#39;s serum bicarbonate value to at least 24 mEq/l but not greater than 29 mEq/l from baseline within a treatment period not greater than 1 month. The target species is selected from the group consisting of protons, strong acids, and conjugate bases of strong acids. 
     Another aspect of the present disclosure is a composition for use in a method of treating metabolic acidosis in an adult human patient by increasing that patient&#39;s serum bicarbonate value by at least 1 mEq/L over 15 days of treatment (i.e., within 15 days of treatment), said composition being a nonabsorbable composition having the capacity to remove protons from the patient. In this aspect, the composition may be administered orally, and so would be an orally administered nonabsorbable composition as defined herein. 
     In certain embodiments, the orally administered nonabsorbable composition comprises cations (such as Na + , K + , Mg 2+ , Ca 2+  Li + , or a combination thereof) that are exchanged for protons as the nonabsorbable composition transits the digestive system, and the protons are then excreted from the body along with the nonabsorbable composition upon defecation. The net effect is reduction in protons in the body, in exchange for an increase in one or more cations. In this embodiment, the pharmaceutical composition may also optionally comprise a pharmaceutically acceptable carrier, diluent or excipient, or a combination thereof that does not significantly interfere with the proton-binding characteristics of the nonabsorbable composition in vivo. Optionally, the pharmaceutical composition may also comprise an additional therapeutic agent. 
     In certain embodiments, the orally administered nonabsorbable composition comprises anions that are exchanged for chloride ions and if the anion comprised by the orally administered nonabsorbable composition is a stronger base (e.g., OH − ) than the removed base (e.g., Cl − , HSO 4   − , or SO 4   2− ), the net effect is the removal of a strong acid from the body (e.g., HCl or H 2 SO 4 ) in exchange for a weak acid (e.g., H 2 O). In this embodiment, the pharmaceutical composition may also optionally comprise a pharmaceutically acceptable carrier, diluent or excipient, or a combination thereof that does not significantly interfere with the chloride-binding characteristics of the nonabsorbable composition in vivo. Optionally, the pharmaceutical composition may also comprise an additional therapeutic agent. 
     In certain embodiments, the orally administered nonabsorbable composition is a neutral composition having the capacity to bind and remove a strong acid, such as HCl or H 2 SO 4 , from the body upon oral administration. The nonabsorbable composition may, but does not necessarily, introduce (i.e., by ion exchange) counterbalancing cations or anions in the process of removing the acid. In this embodiment, binding of both ionic species of HCl (H +  and Cl − ) may be achieved through favorable surface energy of the bulk material, which can include hydrogen bonding and other interactions as well as ionic interactions. Complexation of HCl can occur on functional groups that are dehydrated and upon administration in an acidic aqueous medium, result in the hydrochloride salt of the functional group. 
     Among the various aspects of the present disclosure may further be noted a method of treating an individual afflicted with a chronic acid/base disorder comprising oral administration of a pharmaceutical composition containing a nonabsorbable composition having the capacity to bind protons and chloride ions as it transits the digestive system and remove the bound protons and chloride ions from the individual&#39;s digestive system via defecation. In each of these embodiments, the pharmaceutical composition may also optionally comprise a pharmaceutically acceptable carrier, diluent or excipient, or a combination thereof that does not significantly interfere with the chloride-binding characteristics of the nonabsorbable composition in vivo. Optionally, the pharmaceutical composition may also comprise an additional therapeutic agent. 
     In one embodiment, any of the methods of treating an individual afflicted with an acid-base disorder disclosed in this application comprise: i) the individual having a diet regimen, or ii) the method including, specifying, prescribing or recommending a diet regimen. In one embodiment, said diet regimen is an alkaline diet regimen. In one embodiment, said diet regimen is a conventional low-protein diet regimen (&lt;0.6 g/kg per day). In one embodiment, said diet regimen is a very low-protein diet regimen (0.3-0.4 g/kg per day). In one embodiment, said diet regimen is a vegetarian diet regimen. In one embodiment, said diet regimen is a vegetarian diet regimen supplemented with either essential amino acids or a mixture of essential amino acids and nitrogen-free ketoanalogues (keto diet regimen). In one embodiment, said diet regimen is ketoanalogue-supplemented vegetarian very low-protein diet. In one embodiment, said diet regimen is a vegan diet regimen. In one embodiment, said diet regimen is a casein diet regimen. In one embodiment, said diet regimen is an adenine-containing diet regimen. In one embodiment, said diet regimen comprises one or more base-producing vegetables (e.g. carrots, cauliflower, eggplant, lettuce, potatoes, spinach, tomatoes, or zucchini, or a combination thereof). In one embodiment, said diet regimen comprises one or more base-producing fruits (e.g. apple, apricot, oranges, peaches, pears, raisins, or strawberries, or a combination thereof). In one embodiment, said diet regimen does not comprise acid-producing meat. 
     In one embodiment the diet commences one year before administering the nonabsorbable composition. In another embodiment the diet commences six months before administering the nonabsorbable composition. In another embodiment the diet commences one month before administering the nonabsorbable composition. In another embodiment the diet regimen commences when the administering of the nonabsorbable composition commences. In another embodiment the diet commences one month after administering the nonabsorbable composition. In another embodiment the diet commences six months after administering the nonabsorbable composition. In another embodiment the diet commences one year after administering the nonabsorbable composition. 
     De Brito-Ashurst et al. is one of six published prospective randomized, controlled clinical studies of alkali supplementation and dietary intervention, which demonstrate that increasing serum bicarbonate levels results in improved renal outcomes associated with chronic metabolic acidosis. The five other studies are: Garneata L, Stancu A, Dragomir D, et al., 2016, Ketoanalogue-Supplemented Vegetarian Very Low-Protein Diet and CKD Progression, J. Am. Soc. Nephrol. 27: 2164-2176; Phisitkul S, Khanna A, Simoni J, et al., 2010, Amelioration of metabolic acidosis in patients with low GFR reduced kidney endothelin production and kidney injury, and better preserved GFR, Kidney International 77: 617-623; Goraya N, Simoni J, Jo C, Wesson D, 2013, A comparison of treating metabolic acidosis in CKD stage 4 hypertensive kidney disease with fruits and vegetables or sodium bicarbonate, Clin. J. Am. Soc. Nephrol. 8: 371-381; Goraya N, Simoni J, Jo C, Wesson D, 2014, Treatment of metabolic acidosis in patients with stage 3 chronic kidney disease with fruits and vegetables or oral bicarbonate reduces urine angiotensinogen and preserves glomerular filtration rate, Kidney International 86: 1031-1038; and Mahajan A, Simoni J, Sheather S, et al., 2010, Daily oral sodium bicarbonate preserves glomerular filtration rate by slowing its decline in early hypertensive nephropathy, Kidney International 78: 303-309. 
     Garneata et al. assessed the effects of a ketoanalogue-supplemented vegetarian very low protein diet (0.3 g/kg/day) in diet-compliant patients to those of a usual mixed-source low protein diet (0.6 g/kg/day). Baseline serum bicarbonate was similar in the two treatment groups (16.7-16.8 mEq/L), however the end of study serum bicarbonate value was significantly higher in the vegetarian very low protein diet group than the usual mixed-source low protein diet group. Efficacy of the vegetarian very low protein diet to reduce incidence of renal events was most noted in patients with initial eGFR &lt;20 mL/min·1.73 m 2 . 
     In those embodiments in which the nonabsorbable composition binds chloride ions, it is generally preferred that the nonabsorbable composition selectively bind chloride ions relative to other physiologically significant competing anions such as bicarbonate equivalent anions, phosphate anions, and the conjugate bases of bile and fatty acids that are present in the GI tract. Stated differently, it is generally preferred that the nonabsorbable composition remove more chloride ions than any other competing anion in the GI tract. 
     In those embodiments in which the nonabsorbable composition binds protons, it is generally preferred that the nonabsorbable composition bind protons without delivering sodium, potassium, calcium, magnesium, and/or other electrolytes in exchange for the protons in an amount that is physiologically detrimental. As a result, treatment with the nonabsorbable composition will not significantly contribute to edema, hypertension, hyperkalemia, hypercalcemia or a similar disorder associated with an elevated load of sodium, potassium, calcium or other electrolyte. Similarly, in those embodiments in which the nonabsorbable composition binds protons, it is generally preferred that the nonabsorbable composition bind protons without removing an amount of sodium, potassium, calcium, magnesium and/or other electrolytes along with the protons. As a result, treatment with the nonabsorbable composition will not significantly contribute to hypotension, hypokalemia, hypocalcemia or other disorder associated with a depressed serum concentration of sodium, potassium, calcium, magnesium or other electrolyte. 
     In certain embodiments, the polymers preferably bind and maintain their ability to bind proton and anions at the physiological conditions found along the gastrointestinal (GI) lumen. These conditions can change according to dietary intake (see, for example, Fordtran J, Locklear T. Ionic constituents and osmolality of gastric and small-intestinal fluids after eating. Digest Dis Sci. 1966; 11(7):503-21) and location along the GI tract (Binder, H et al. Chapters 41-45 in “Medical Physiology”, 2nd Edition, Elsevier [2011]. Boron and Boulpaep [Ed.]). Rapid binding of proton and chloride in the stomach and small intestine is desirable. High binding levels and selectivity for chloride later in the GI tract (lower small intestine and large intestine) is also desirable. In general, the polymers also preferably have a pK a  such that the majority of amines are protonated under the various pH and electrolyte conditions encountered along the GI tract and are thereby capable of removing proton, along with an appropriate counter anion (preferably chloride), from the body into the feces. 
     Since the stomach is an abundant source of HCl, and the stomach is the first site of potential HCl binding (after the mouth), and since residence time in the stomach is short (gastric residence half-life of approximately 90 minutes), compared to the rest of the GI tract (small intestine transit time of approximately 4 hours; whole gut transit time of 2-3 days; Read, N W et al. Gastroenterology [1980] 79:1276), it is desirable for the polymer of the present disclosure to demonstrate rapid kinetics of proton and chloride binding in the lumen of this organ, as well as in in vitro conditions designed to mimic the stomach lumen (e.g. SGF). Phosphate is a potential interfering anion for chloride binding in the stomach and small intestine, where phosphate is mostly absorbed (Cross, H S et al Miner Electrolyte Metab [1990] 16:115-24). Therefore rapid and preferential binding of chloride over phosphate is desirable in the small intestine and in in vitro conditions designed to mimic the small intestine lumen (e.g. SIB). Since the transit time of the colon is slow (2-3 days) relative to the small intestine, and since conditions in the colon will not be encountered by an orally administered polymer until after stomach and small intestine conditions have been encountered, kinetics of chloride binding by a polymer of the present disclosure do not have to be as rapid in the colon or in in vitro conditions designed to mimic the late small intestine/colon. It is, however, important that chloride binding and selectivity over other interfering anions is high, for example, at 24 and/or 48 hours or longer. 
     Other aspects and features will be in part apparent and in part pointed out hereinafter. 
     Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. 
       The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein. 
         FIG. 1A-1C  is a flow chart schematically depicting the mechanism of action of the polymer when passing through the gastrointestinal tract of an individual from oral ingestion/stomach ( FIG. 1A ), to the upper GI tract ( FIG. 1B ) to the lower GI tract/colon ( FIG. 1C ). 
         FIG. 2  is a graph of the effect of TRC101 on serum bicarbonate in a rat model of adenine-induced nephropathy and metabolic acidosis in Part 1 of the study described in Example 1. 
         FIGS. 3A, 3B and 3C  are graphs of the effect of TRC101 on fecal excretion of chloride ( FIG. 3A ), sulfate ( FIG. 3B ), and phosphate ( FIG. 3C ) in a rat model of adenine-induced nephropathy and metabolic acidosis in Part 1 of the study described in Example 1. 
         FIG. 4  is a graph of the effect of TRC101 on serum bicarbonate in a rat model of adenine-induced nephropathy and metabolic acidosis in Part 2 of the study described in Example 1. 
         FIGS. 5A, 5B and 5C  are graphs of the effect of TRC101 on fecal excretion of chloride ( FIG. 5A ), sulfate ( FIG. 5B ), and phosphate ( FIG. 5C ) in a rat model of adenine-induced nephropathy and metabolic acidosis in Part 2 of the study described in Example 1. 
         FIGS. 6A, 6B and 6C  are graphs of the in vivo chloride ( FIG. 6A ), sulfate ( FIG. 6B ) and phosphate ( FIG. 6C ) binding capacities of TRC101 and bixalomer in a pig with normal renal function in the study described in Example 2. 
         FIG. 7  is a line graph showing the mean change in serum bicarbonate (SBC) from baseline (BL) and standard error (SE) by treatment group over time in a human study as described more fully in Example 3 (Part 1). 
         FIG. 8  is a bar graph showing the least squares mean (LS Mean) change from baseline (CFB) to end of treatment in serum bicarbonate (SBC) by treatment group in a human study as described more fully in Example 3 (Part 1). Single asterisk (“*”) indicates statistically significant difference (p&lt;0.5) and double asterisk (“**”) indicates highly statistically significant difference (p&lt;0.0001). 
         FIG. 9  is a bar graph showing the effect on serum bicarbonate (SBC) levels and standard error (SE) at days 8 and 15 resulting from treatment (Tx=treatment) and upon withdrawal of TRC101 in a human study as described more fully in Example 3 (Part 1). 
         FIG. 10  is a line graph showing the mean change in serum bicarbonate (SBC) and standard error (SE) for the four TRC101 active arms and the two placebo arms (pooled) of the study described more fully in Example 3 (Parts 1 and 2). 
         FIG. 11  is a bar graph showing the least squares mean (LS Mean) change from baseline (CFB) in serum bicarbonate (SBC) by treatment group over time for the four TRC101 active arms and the two placebo arms (pooled) of the study described more fully in Example 3 (Parts 1 and 2). Single asterisk (“*”) indicates statistically significant difference (p&lt;0.5) and double asterisk (“**”) indicates highly statistically significant difference (p&lt;0.0001). 
         FIG. 12  is a bar graph showing the treatment effect on serum bicarbonate (SBC) levels and standard error (SE) at days 8 and 15 resulting from treatment (Tx=treatment) with and upon withdrawal of TRC101 in a human study as described more fully in Example 3 (Parts 1 and 2). 
         FIGS. 13A, 13B, 13C and 13D  are graphs showing the changes in serum bicarbonate ( FIG. 13A ), serum chloride ( FIG. 13B ), serum sodium ( FIG. 13C ) and serum potassium ( FIG. 13D ) for the four TRC101 active arms (combined) vs the two placebo arms (pooled) over time for the study described more fully in Example 3 (Parts 1 and 2). 
         FIG. 14  is a graph showing the changes in the calculated anion gap for the four TRC101 active arms (combined) vs the two placebo arms (pooled) over time for the study described more fully in Example 3 (Parts 1 and 2). 
         FIG. 15  is a dataset analysis diagram and timeline, as described in greater detail in Example 4. 
         FIG. 16  is a population analysis flow chart, as described in greater detail in Example 4. 
         FIG. 17  is an illustration of the subpopulation used in the Cox Regression Analysis, as described in greater detail in Example 4. 
         FIG. 18  is an analysis diagram and timeline for the clinical trial as described in more detail in Example 5. 
         FIG. 19A  is a graph showing the composite primary endpoint at the end of the treatment period for the clinical study described in more detail in Example 5. 
         FIG. 19B  is a graph showing the achievement of serum bicarbonate thresholds at various time points for the clinical study described in more detail in Example 5. 
         FIG. 19C  is a graph showing the change from baseline in serum bicarbonate over time at various time points for the clinical study described in more detail in Example 5. 
         FIG. 20  is a graph showing that TRC101-treated subjects experienced a statistically significant improvement in quality of life, particularly, in physical function, based on results from Question #3 of the KDQOL-SF survey for the clinical study described in more detail in Example 5. 
         FIG. 21  is a copy of Question #3 of the KDQOL-SF survey for the clinical study described in Example 5. The score conversion is as follows: 1 (limited a lot)=0; 2 (limited a little)=50; 3 (not limited)=100. Total score=sum of all 10, divided by 10. 
         FIG. 22A  is a copy of the Single Chair Stand and Repeated Chair Stand protocols, including the scoring criteria ( FIG. 22B ), as described in more detail in Example 5. 
         FIG. 23  is table showing the analysis from baseline in total score in kidney disease and quality of life (Question 3) at week 12, as described in more detail in Example 5. 
         FIG. 24  is a table showing the analysis from baseline in time (seconds) of completing repeated chair stand at the end of week 12, as described in more detail in Example 5. 
         FIG. 25  shows an overall design of a retrospective model, as described in greater detail in Example 4. 
         FIG. 26  is a graph showing time to first occurrence of DD40 endpoint, as described in greater detail in Example 4, section (B). 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Abbreviations and Definitions 
     The following definitions and methods are provided to better define the present invention and to guide those of ordinary skill in the art in the practice of the present invention. Unless otherwise noted, terms are to be understood according to conventional usage by those of ordinary skill in the relevant art. 
     The term “absorption capacity” as used herein in connection with a polymer and a swelling agent (or in the case of a mixture of swelling agents, the mixture of swelling agents) is the amount of the swelling agent (or such mixture) absorbed during a period of at least 16 hours at room temperature by a given amount of a dry polymer (e.g., in the form of a dry bead) immersed in an excess amount of the swelling agent (or such mixture). 
     The term “acrylamide” denotes a moiety having the structural formula H 2 C═CH—C(O)NR—*, where * denotes the point of attachment of the moiety to the remainder of the molecule and R is hydrogen, hydrocarbyl, or substituted hydrocarbyl. 
     The term “acrylic” denotes a moiety having the structural formula H 2 C═CH—C(O)O—*, where * denotes the point of attachment of the moiety to the remainder of the molecule. 
     The term “adult” refers to an individual over 18 years of age. 
     The term “alicyclic”, “alicyclo” or “alicyclyl” means a saturated monocyclic group of 3 to 8 carbon atoms and includes cyclopentyl, cyclohexyl, cycloheptyl, and the like. 
     The term “aliphatic” denotes saturated and non-aromatic unsaturated hydrocarbyl moieties having, for example, one to about twenty carbon atoms or, in specific embodiments, one to about twelve carbon atoms, one to about ten carbon atoms, one to about eight carbon atoms, or even one to about four carbon atoms. The aliphatic groups include, for example, alkyl moieties such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like, and alkenyl moieties of comparable chain length. 
     The term “alkanol” denotes an alkyl moiety that has been substituted with at least one hydroxyl group. In some embodiments, alkanol groups are “lower alkanol” groups comprising one to six carbon atoms, one of which is attached to an oxygen atom. In other embodiments, lower alkanol groups comprise one to three carbon atoms. 
     The term “alkenyl group” encompasses linear or branched carbon radicals having at least one carbon-carbon double bond. The term “alkenyl group” can encompass conjugated and non-conjugated carbon-carbon double bonds or combinations thereof. An alkenyl group, for example and without being limited thereto, can encompass two to about twenty carbon atoms or, in a particular embodiment, two to about twelve carbon atoms. In certain embodiments, alkenyl groups are “lower alkenyl” groups having two to about four carbon atoms. Examples of alkenyl groups include, but are not limited thereto, ethenyl, propenyl, allyl, vinyl, butenyl and 4-methylbutenyl. The terms “alkenyl group” and “lower alkenyl group”, encompass groups having “cis” or “trans” orientations, or alternatively, “E” or “Z” orientations. 
     The term “alkyl group” as used, either alone or within other terms such as “haloalkyl group,” “aminoalkyl group” and “alkylamino group”, encompasses saturated linear or branched carbon radicals having, for example, one to about twenty carbon atoms or, in specific embodiments, one to about twelve carbon atoms. In other embodiments, alkyl groups are “lower alkyl” groups having one to about six carbon atoms. Examples of such groups include, but are not limited thereto, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl and the like. In more specific embodiments, lower alkyl groups have one to four carbon atoms. 
     The term “alkylamino group” refers to amino groups directly attached to the remainder of the molecule via the nitrogen atom of the amino group and wherein the nitrogen atom of the alkylamino group is substituted by one or two alkyl groups. In some embodiments, alkylamino groups are “lower alkylamino” groups having one or two alkyl groups of one to six carbon atoms, attached to a nitrogen atom. In other embodiments, lower alkylamino groups have one to three carbon atoms. Suitable “alkylamino” groups may be mono or dialkylamino such as N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino, pentamethyleneamine and the like. 
     The term “allyl” denotes a moiety having the structural formula H 2 C═CH—CH 2 —=, where * denotes the point of attachment of the moiety to the remainder of the molecule and the point of attachment is to a heteroatom or an aromatic moiety. 
     The term “allylamine” denotes a moiety having the structural formula H 2 C═CH—CH 2 N(X 8 )(X 9 ), wherein X 8  and X are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl, or X 8  and X 9  taken together form a substituted or unsubstituted alicyclic, aryl, or heterocyclic moiety, each as defined in connection with such term, typically having from 3 to 8 atoms in the ring. 
     The term “amine” or “amino” as used alone or as part of another group, represents a group of formula —N(X 8 )(X 9 ), wherein X 8  and X 9  are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl, heteroaryl, or heterocyclo, or X 8  and X 9  taken together form a substituted or unsubstituted alicyclic, aryl, or heterocyclic moiety, each as defined in connection with such term, typically having from 3 to 8 atoms in the ring. 
     The term “aminoalkyl group” encompasses linear or branched alkyl groups having one to about ten carbon atoms, any one of which may be substituted with one or more amino groups, directly attached to the remainder of the molecule via an atom other than a nitrogen atom of the amine group(s). In some embodiments, the aminoalkyl groups are “lower aminoalkyl” groups having one to six carbon atoms and one or more amino groups. Examples of such groups include aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl. 
     The terms “anion exchange material” and “cation exchange material” take their normal meaning in the art. For example, the terms “anion exchange material” and “cation exchange material” refer to materials that exchange anions and cations, respectively. Anion and cation exchange materials are typically water-insoluble substances which can exchange some of their cations or anions, respectively, for similarly charged anions or cations contained in a medium with which they are in contact. Anion exchange materials may contain positively charged groups, which are fixed to the backbone materials and allow passage of anions but reject cations. A non-exhaustive list of such positively charged groups includes: amino group, alkyl substituted phosphine, and alkyl substituted sulphides. A non-exhaustive list of cation or anion exchange materials includes: clays (e.g., bentonite, kaolinite, and illite), vermiculite, zeolites (e.g., analcite, chabazite, sodalite, and clinoptilolite), synthetic zeolites, polybasic acid salts, hydrous oxides, metal ferrocyanides, and heteropolyacids. Cation exchange materials can contain negatively charged groups fixed to the backbone material, which allow the passage of cations but reject anions. A non-exhaustive list of such negatively charged groups includes: sulphate, carboxylate, phosphate, and benzoate. 
     The term “aromatic group” or “aryl group” means an aromatic group having one or more rings wherein such rings may be attached together in a pendent manner or may be fused. In particular embodiments, an aromatic group is one, two or three rings. Monocyclic aromatic groups may contain 5 to 10 carbon atoms, typically 5 to 7 carbon atoms, and more typically 5 to 6 carbon atoms in the ring. Typical polycyclic aromatic groups have two or three rings. Polycyclic aromatic groups having two rings typically have 8 to 12 carbon atoms, preferably 8 to 10 carbon atoms in the rings. Examples of aromatic groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. 
     The term “bead” is used to describe a crosslinked polymer that is substantially spherical in shape. 
     The term “bicarbonate equivalent” is used to describe an organic acid or anion that yields bicarbonate when metabolized. Citrate and succinate are exemplary bicarbonate equivalents. 
     The term “binds” as used herein in connection with a polymer and one or more ions, that is, a cation (e.g. “proton-binding” polymer) and an anion, is an “ion-binding” polymer and/or when it associates with the ion, generally though not necessarily in a non-covalent manner, with sufficient association strength that at least a portion of the ion remains bound under the in vitro or in vivo conditions in which the polymer is used for sufficient time to effect a removal of the ion from solution or from the body. 
     The term “ceramic material” takes its normal meaning in the art. In certain embodiments, the term “ceramic material” refers to an inorganic, nonmetallic, solid material comprising metal, nonmetal or metalloid atoms primarily held in ionic and covalent bonds. A non-exhaustive list of examples of ceramic materials includes: barium titanate, bismuth strontium calcium copper oxide, boron oxide, earthenware, ferrite, lanthanum carbonate, lead zirconate, titanate, magnesium diboride, porcelain, sialon, silicon carbide, silicon nitride, titanium carbide, yttrium barium copper oxide, zinc oxide, zirconium dioxide, and partially stabilised zirconia. In certain embodiments, the term “clinically significant increase” as used herein in connection with a treatment refers to a treatment that improves or provides a worthwhile change in an individual from a dysfunctional state back to a relatively normal functioning state, or moves the measurement of that state in the direction of normal functioning, or at least a marked improvement to untreated. A number of methods can be used to calculate clinical significance. A non-exhaustive list of methods for calculating clinical significance includes: Jacobson-Truax, Gulliksen-Lord-Novick, Edwards-Nunnally, Hageman-Arrindell, and Hierarchical Linear Modeling (HLM). 
     The term “crosslink density” denotes the average number of connections of the amine containing repeat unit to the rest of the polymer. The number of connections can be 2, 3, 4 and higher. Repeat units in linear, non-crosslinked polymers are incorporated via 2 connections. To form an insoluble gel, the number of connections should be greater than 2. Low crosslinking density materials such as sevelamer have on average about 2.1 connections between repeat units. More crosslinked systems such as bixalomer have on average about 4.6 connections between the amine-containing repeat units. “Crosslinking density” represents a semi-quantitative measure based on the ratios of the starting materials used. Limitations include the fact that it does not account for different crosslinking and polymerization methods. For example, small molecule amine systems require higher amounts of crosslinker as the crosslinker also serves as the monomer to form the polymer backbone whereas for radical polymerizations the polymer chain is formed independent from the crosslinking reaction. This can lead to inherently higher crosslinking densities under this definition for the substitution polymerization/small molecule amines as compared to radical polymerization crosslinked materials. 
     The term “crosslinker” as used, either alone or within other terms, encompasses hydrocarbyl or substituted hydrocarbyl, linear or branched molecules capable of reacting with any of the described monomers, or the infinite polymer network, as described in Formula 1, more than one time. The reactive group in the crosslinker can include, but is not limited to alkyl halide, epoxide, phosgene, anhydride, carbamate, carbonate, isocyanate, thioisocyanate, esters, activated esters, carboxylic acids and derivatives, sulfonates and derivatives, acyl halides, aziridines, α,β-unsaturated carbonyls, ketones, aldehydes, pentafluoroaryl groups, vinyl, allyl, acrylate, methacrylate, acrylamide, methacrylamide, styrenic, acrylonitriles and combinations thereof. In one exemplary embodiment, the crosslinker&#39;s reactive group will include alkyl halide, epoxide, anhydrides, isocyanates, allyl, vinyl, acrylamide, and combinations thereof. In one such embodiment, the crosslinker&#39;s reactive group will be alkyl halide, epoxide, or allyl. 
     The term “diallylamine” denotes an amino moiety having two allyl groups. 
     The terms “dry bead” and “dry polymer” refer to beads or polymers that contain no more than 5% by weight of a non-polymer swelling agent or solvent. Often the swelling agent/solvent is water remaining at the end of a purification. This is generally removed by lyophilization or oven drying before storage or further crosslinking of a preformed amine polymer. The amount of swelling agent/solvent can be measured by heating (e.g., heating to 100-200° C.) and measuring the resulting change in weight. This is referred to a “loss on drying” or “LOD.” 
     The term “estimated glomerular filtration rate” or eGFR refers to an estimate of the glomerular filtration rate and is estimated from the serum level of an endogenous filtration marker. Creatinine is a commonly used endogenous filtration marker in clinical practice and several equations have been proposed for estimating the glomerular filtration rate. As used herein, all eGFR values may be determined according to the CKD-EPI equation (Levey et al., A New Equation to Estimate Glomerular Filtration Rate. Ann Intern Med. 2009; 150:604-612): 
       GFR=41*min(Scr/κ,1) α *max(Scr/κ,1) −1.209 *0.993 Age *1.018[if female]*1.159[if black]
 
     wherein Scr is serum creatinine (mg/dL), κ is 0.7 for females and 0.9 for males, α is −0.329 for females and −0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1. 
     The term “ethereal” denotes a moiety having an oxygen bound to two separate carbon atoms as depicted the structural formula *—H x C—O—CH x *, where * denotes the point of attachment to the remainder of the moiety and x independently equals 0, 1, 2, or 3. 
     The term “gel” is used to describe a crosslinked polymer that has an irregular shape. 
     The term “glomerular filtration rate” or GFR is the volume of fluid filtered from the renal (kidney) glomerular capillaries into the Bowman&#39;s capsule per unit time. GFR cannot be measured directly; instead, it is measured indirectly (mGFR) as the clearance of an exogenous filtration marker (e.g., inulin, iothalamate, iohexol, etc.) or estimated (eGFR) using an endogenous filtration marker. 
     The term “halo” means halogens such as fluorine, chlorine, bromine or iodine atoms. 
     The term “haloalkyl group” encompasses groups wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Specifically encompassed are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups including perhaloalkyl. A monohaloalkyl group, for example, may have either an iodo, bromo, chloro or fluoro atom within the group. Dihalo and polyhaloalkyl groups may have two or more of the same halo atoms or a combination of different halo groups. “Lower haloalkyl group” encompasses groups having 1-6 carbon atoms. In some embodiments, lower haloalkyl groups have one to three carbon atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. 
     The term “heteroaliphatic” describes a chain of 1 to 25 carbon atoms, typically 1 to 12 carbon atoms, more typically 1 to 10 carbon atoms, and most typically 1 to 8 carbon atoms, and in some embodiments 1 to 4 carbon atoms that can be saturated or unsaturated (but not aromatic), containing one or more heteroatoms, such as halogen, oxygen, nitrogen, sulfur, phosphorus, or boron. A heteroatom atom may be a part of a pendant (or side) group attached to a chain of atoms (e.g., —CH(OH)— —CH(NH 2 )— where the carbon atom is a member of a chain of atoms) or it may be one of the chain atoms (e.g., —ROR— or —RNHR— where each R is aliphatic). Heteroaliphatic encompasses heteroalkyl and heterocyclo but does not encompass heteroaryl. 
     The term “heteroalkyl” describes a fully saturated heteroaliphatic moiety. 
     The term “heteroaryl” means a monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms, unless otherwise stated, where one or more, (in one embodiment, one, two, or three), ring atoms are heteroatom selected from N, O, or S, the remaining ring atoms being carbon. Representative examples include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like. As defined herein, the terms “heteroaryl” and “aryl” are mutually exclusive. “Heteroarylene” means a divalent heteroaryl radical. 
     The term “heteroatom” means an atom other than carbon and hydrogen. Typically, but not exclusively, heteroatoms are selected from the group consisting of halogen, sulfur, phosphorous, nitrogen, boron and oxygen atoms. Groups containing more than one heteroatom may contain different heteroatoms. 
     The term “heterocyclo,” “heterocyclic,” or heterocyclyl” means a saturated or unsaturated group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom such as N, O, B, P and S(O) n , where n is an integer from 0 to 2, the remaining ring atoms being carbon. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a —C(O)— group. More specifically the term heterocyclyl includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydro-pyranyl, thiomorpholino, and the like. When the heterocyclyl ring is unsaturated it can contain one or two ring double bonds provided that the ring is not aromatic. When the heterocyclyl group contains at least one nitrogen atom, it is also referred to herein as heterocycloamino and is a subset of the heterocyclyl group. 
     The term “hydrocarbon group” or “hydrocarbyl group” means a chain of 1 to 25 carbon atoms, typically 1 to 12 carbon atoms, more typically 1 to 10 carbon atoms, and most typically 1 to 8 carbon atoms. Hydrocarbon groups may have a linear or branched chain structure. Typical hydrocarbon groups have one or two branches, typically one branch. Typically, hydrocarbon groups are saturated. Unsaturated hydrocarbon groups may have one or more double bonds, one or more triple bonds, or combinations thereof. Typical unsaturated hydrocarbon groups have one or two double bonds or one triple bond; more typically unsaturated hydrocarbon groups have one double bond. 
     “Initiator” is a term used to describe a reagent that initiates a polymerization. 
     The term “measured glomerular filtration rate” or “mGFR” refers to a measurement of the glomerular filtration rate using any chemical (e.g., inulin, iothalamate, iohexol, etc.) that has a steady level in the blood, and is freely filtered but neither reabsorbed nor secreted by the kidneys according to standard technique. 
     The term “Michael acceptor” takes its normal meaning in the art. In certain embodiments the term “Michael acceptor” refers to activated olefins, such as α,β-unsaturated carbonyl compounds. A Michael acceptor can be a conjugated system with an electron withdrawing group, such as cyano, keto or ester. A non-exhaustive list of examples of Michael acceptors includes: vinyl ketones, alkyl acrylates, acrylo nitrile, and fumarates. 
     The term “molecular weight per nitrogen” or “MW/N” represents the calculated molecular weight in the polymer per nitrogen atom. It represents the average molecular weight to present one amine function within the crosslinked polymer. It is calculated by dividing the mass of a polymer sample by the moles of nitrogen present in the sample. “MW/N” is the inverse of theoretical capacity, and the calculations are based upon the feed ratio, assuming full reaction of crosslinker and monomer. The lower the molecular weight per nitrogen the higher the theoretical capacity of the crosslinked polymer. 
     The term “nonabsorbable” as used herein takes its normal meaning in the art. Therefore, if something is nonabsorbable it is not absorbed during its passage through the human GI tract. This could be measured by any appropriate means. One option known to the skilled person would be to examine faeces to see if the nonabsorbable material is recovered after passing through the GI tract. As a practical matter, the amount of a nonabsorbable material recovered in this scenario will never be 100% of the material administered. For example, about 90-99% of the material might be recovered from the faeces. Another option known to the skilled person would be to look for the presence of the material in the lymph, blood, interstitial fluid, secretions from various organs (e.g., pancreas, liver, gut, etc.) or in the body of organs (e.g., liver, kidney, lungs, etc.) as oral administration of a nonabsorbable material would not result in an increase in the amount of that material in these matrices and tissues. Nonabsorbable compositions may be particulate compositions that are essentially insoluble in the human GI tract and have a particle size that is large enough to avoid passive or active absorption through the human GI tract. As an example, nonabsorbable compositions is meant to imply that the substance does not enter the lymph, blood, interstitial fluids or organs through the main entry points of the human GI tract, namely by paracellular entry between gut epithelial cells, by endocytic uptake through gut epithelial cells, or through entry via M cells comprising the gut epithelial antigen sampling and immune surveillance system (Jung, 2000), either through active or passive transport processes. There is a known size limit for a particulate to be absorbed in the human GI tract (Jung et al., European Journal of Pharmaceutics and Biopharmaceutics 50 (2000) 147-160; Jani et al., Internation. Journal of Pharmaceutics, 84 (1992) 245-252; and Jani et al., J. Pharm. Pharmacol. 1989, 41:809-812), so the skilled person would know that materials that, when in the GI tract, have a size of at least 1 micrometers would be nonabsorbable. 
     “Optional” or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “heterocyclyl group optionally substituted with an alkyl group” means that the alkyl may but need not be present, and the description includes embodiments in which the heterocyclyl group is substituted with an alkyl group and embodiments in which the heterocyclyl group is not substituted with alkyl. 
     “Particle size” is measured by wet laser diffraction using Mie theory. Particles are dispersed in an appropriate solvent, such as water or methanol, and added to the sample chamber to achieve red channel obscuration of 10-20%. Sonication may be performed, and a dispersing agent, such as a surfactant (e.g. Tween-80), may be added in order to disrupt weak particle-particle interactions. The refractive index setting of the particles used for size distribution calculation is selected to minimize artifacts in the results and the R parameter value, determined by the laser diffraction software. The D(0.1), D(0.5), and D(0.9) values characterizing the particle size distribution by volume-basis are recorded. 
     “Pharmaceutically acceptable” as used in connection with a carrier, diluent or excipient means a carrier, diluent or an excipient, respectively, that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable for veterinary use and/or human pharmaceutical use. 
     The term “physical function” as used herein in connection with a patient afflicted with chronic kidney disease and an acid-base disorder may be assessed using (i) the Kidney Disease and Quality of Life (KDQOL) Short Form-36, Question 3 (Physical Functioning Domain) as illustrated in  FIGS. 22A &amp; 22B  and Example 5, or (iii) both the KDQOL Short Form-36 Question 3 and the standardized repeated chair stand test (i.e., “i” and “ii” of this paragraph). 
     The term “post polymerization crosslinking” is a term that describes a reaction to an already formed bead or gel, where more crosslinking is introduced to the already formed bead or gel to create a bead or gel that has an increased amount of crosslinking. 
     The term “post polymerization modification” is a term that describes a modification to an already formed bead or gel, where a reaction or a treatment introduces an additional functionality. This functionality can be linked either covalently or non-covalently to the already formed bead. 
     The term “quaternized amine assay” (“QAA”) describes a method to estimate the amount of quaternary amines present in a given crosslinked polymer sample. This assay measures chloride binding of a crosslinked polymer at a pH of 11.5. At this pH, primary, secondary and tertiary amines are not substantially protonated and do not substantially contribute to chloride binding. Therefore, any binding observed under these conditions can be attributed to the presence of permanently charged quaternary amines. The test solution used for QAA assay is 100 mM sodium chloride at a pH of 11.5. The concentration of chloride ions is similar to that in the SGF assay which is used to assess total binding capacity of crosslinked polymers. Quaternary amine content as a percentage of total amines present is calculated as follows: 
     
       
         
           
             
               % 
                
               
                   
               
                
               Quaternary 
                
               
                   
               
                
               amines 
             
             = 
             
               
                 
                   Chloride 
                    
                   
                       
                   
                    
                   
                     bound 
                      
                     
                       
                           
                       
                        
                       
                           
                       
                     
                     ( 
                     
                       mmol 
                       / 
                       g 
                     
                     ) 
                   
                    
                   
                       
                   
                    
                   in 
                    
                   
                       
                   
                    
                   QAA 
                 
                 
                   Chloride 
                    
                   
                       
                   
                    
                   bound 
                    
                   
                       
                   
                    
                   
                     ( 
                     
                       mmol 
                       / 
                       g 
                     
                     ) 
                   
                    
                   
                       
                   
                    
                   in 
                    
                   
                       
                   
                    
                   SGF 
                 
               
               × 
               100 
             
           
         
       
     
     To perform the QAA assay, the free-amine polymer being tested is prepared at a concentration of 2.5 mg/ml (e.g. 25 mg dry mas) in 10 mL of QAA buffer. The mixture is incubated at 37° C. for ˜16 hours with agitation on a rotisserie mixer. After incubation and mixing, 600 microliters of supernatant is removed and filtered using a 800 microliter, 0.45 micrometer pore size, 96-well poly propylene filter plate. With the samples arrayed in the filter plate and the collection plate fitted on the bottom, the unit is centrifuged at 1000×g for 1 minute to filter the samples. After filtration into the collection plate, the respective filtrates are diluted appropriately before measuring for chloride content. The IC method (e.g. ICS-2100 Ion Chromatography, Thermo Fisher Scientific) used for the analysis of chloride content in the filtrates consists of a 15 mM KOH mobile phase, an injection volume of 5 microliters, with a run time of three minutes, a washing/rinse volume of 1000 microliters, and flow rate of 1.25 mL/min. To determine the chloride bound to the polymer, the following calculation is completed: 
     
       
         
           
             
               Binding 
                
               
                   
               
                
               capacity 
                
               
                   
               
                
               expressed 
                
               
                   
               
                
               as 
                
               
                   
               
                
               mmol 
                
               
                   
               
                
               
                 chloride 
                 / 
                 g 
               
                
               
                   
               
                
               dry 
                
               
                   
               
                
               polymer 
             
             = 
             
               
                 ( 
                 
                   
                     Cl 
                      
                     
                         
                     
                      
                     start 
                   
                   - 
                   
                     Cl 
                      
                     
                         
                     
                      
                     eq 
                   
                 
                 ) 
               
               
                 2 
                 . 
                 5 
               
             
           
         
       
     
     where Cl start corresponds to the starting concentration of chloride in the QAA buffer, C eq corresponds to the equilibrium value of chloride in the measured filtrates after exposure to the test polymer, and 2.5 is the polymer concentration in mg/ml. 
     The terms “short chain carboxylic acid” or “short chain fatty acid” take their normal meaning in the art. In certain embodiments, the terms “short chain carboxylic acid” or “short chain fatty acid” refer to carboxylic acids having a chain length of 0, 1, 2, 3, 4, 5 or 6 carbon atoms long. A non-exhaustive list of examples of short chain carboxylic acids includes: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, and lactic acid. 
     “Simulated Gastric Fluid” or “SGF” Assay describes a test to determine total chloride binding capacity for a test polymer using a defined buffer that simulates the contents of gastric fluid as follows: Simulated gastric fluid (SGF) consists of 35 mM NaCl, 63 mM HCl, pH 1.2. To perform the assay, the free-amine polymer being tested is prepared at a concentration of 2.5 mg/ml (25 mg dry mass) in 10 mL of SGF buffer. The mixture is incubated at 37° C. overnight for ˜12-16 hours with agitation on a rotisserie mixer. Unless another time period is otherwise stated, SGF binding data or binding capacities recited herein are determined in a time period of this duration. After incubation and mixing, the tubes containing the polymer are centrifuged for 2 minutes at 500-1000×g to pellet the test samples. Approximately 750 microliters of supernatant are removed and filtered using an appropriate filter, for example a 0.45 micrometer pore-size syringe filter or an 800 microliter, 1 micrometer pore-size, 96-well, glass filter plate that has been fitted over a 96-well 2 mL collection plate. With the latter arrangement, multiple samples tested in SGF buffer can be prepared for analysis, including the standard controls of free amine sevelamer, free amine bixalomer and a control tube containing blank buffer that is processed through all of the assay steps. With the samples arrayed in the filter plate and the collection plate fitted on the bottom, the unit is centrifuged at 1000×g for 1 minute to filter the samples. In cases of small sample sets, a syringe filter may be used in lieu of the filter plate, to retrieve ˜2-4 mL of filtrate into a 15 mL container. After filtration, the respective filtrates are diluted 4× with water and the chloride content of the filtrate is measured via ion chromatography (IC). The IC method (e.g. Dionex ICS-2100, Thermo Scientific) consists of an AS11 column and a 15 mM KOH mobile phase, an injection volume of 5 microliters, with a run time of 3 minutes, a washing/rinse volume of 1000 microliters, and flow rate of 1.25 mL/min. To determine the chloride bound to the polymer, the following calculation is completed: 
     
       
         
           
             
               
                 
                   ( 
                   
                     
                       Cl 
                        
                       
                           
                       
                        
                       start 
                     
                     - 
                     
                       Cl 
                        
                       
                           
                       
                        
                       eq 
                     
                   
                   ) 
                 
                 × 
                 4 
               
               
                 2 
                 . 
                 5 
               
             
             . 
           
         
       
     
     Binding capacity expressed as mmol chloride/g polymer: where Cl start corresponds to the starting concentration of chloride in the SGF buffer, Cl eq corresponds to the equilibrium value of chloride in the diluted measured filtrates after exposure to the test polymer, 4 is the dilution factor and 2.5 is the polymer concentration in mg/ml. 
     “Simulated Small Intestine Inorganic Buffer” or “SIB” is a test to determine the chloride and phosphate binding capacity of free amine test polymers in a selective specific interfering buffer assay (SIB). The chloride and phosphate binding capacity of free amine test polymers, along with the chloride and phosphate binding capacity of free amine sevelamer and bixalomer control polymers, was determined using the selective specific interfering buffer assay (SIB) as follows: The buffer used for the SIB assay comprises 36 mM NaCl, 20 mM NaH 2 PO 4 , 50 mM 2-(N-morpholino)ethanesulfonic acid (MES) buffered to pH 5.5. The SIB buffer contains concentrations of chloride, phosphate and pH that are present in the human duodenum and upper gastrointestinal tract (Stevens T, Conwell D L, Zuccaro G, Van Lente F, Khandwala F, Purich E, et al. Electrolyte composition of endoscopically collected duodenal drainage fluid after synthetic porcine secretin stimulation in healthy subjects. Gastrointestinal endoscopy. 2004; 60(3):351-5, Fordtran J, Locklear T. Ionic constituents and osmolality of gastric and small-intestinal fluids after eating. Digest Dis Sci. 1966; 11(7):503-21) and is an effective measure of the selectivity of chloride binding compared to phosphate binding by a polymer. To perform the assay, the free amine polymer being tested is prepared at a concentration of 2.5 mg/ml (25 mg dry mass) in 10 mL of SIB buffer. The mixture is incubated at 37° C. for 1 hour with agitation on a rotisserie mixer. Unless another time period is otherwise stated, SIB binding data or binding capacities recited herein are determined in a time period of this duration. After incubation and mixing, the tubes containing the polymer are centrifuged for 2 minutes at 1000×g to pellet the test samples. 750 microliter of supernatant is removed and filtered using an 800 microliter, 1 micrometer pore-size, 96-well, glass filter plate that has been fitted over a 96-well 2 mL collection plate; with this arrangement multiple samples tested in SIB buffer can be prepared for analysis, including the standard controls of free amine sevelamer, free amine bixalomer and a control tube containing blank buffer that is processed through all of the assay steps. With the samples arrayed in the filter plate and the collection plate fitted on the bottom, the unit is centrifuged at 1000×g for 1 minute to filter the samples. In cases of small sample sets, a syringe filter (0.45 micrometer) may be used in lieu of the filter plate, to retrieve ˜2-4 mL of filtrate into a 15 mL vial. After filtration into the collection plate, the respective filtrates are diluted before measuring for chloride or phosphate content. For the measurement of chloride and phosphate, the filtrates under analysis are diluted 4× with water. The chloride and phosphate content of the filtrate is measured via ion chromatography (IC). The IC method (e.g. Dionex ICS-2100, Thermo Scientific) consists of an AS24A column, a 45 mM KOH mobile phase, an injection volume of 5 microliters, with a run time of about 10 minutes, a washing/rinse volume of 1000 microliter, and flow rate of 0.3 mL/min. To determine the chloride bound to the polymer, the following calculation is completed: 
     
       
         
           
             
               Binding 
                
               
                   
               
                
               capacity 
                
               
                   
               
                
               expressed 
                
               
                   
               
                
               as 
                
               
                   
               
                
               mmol 
                
               
                   
               
                
               
                 chloride 
                 / 
                 g 
               
                
               
                   
               
                
               polymer 
             
             = 
             
               
                 
                   ( 
                   
                     
                       Cl 
                       start 
                     
                     - 
                     
                       Cl 
                       
                         f 
                          
                         inal 
                       
                     
                   
                   ) 
                 
                 × 
                 4 
               
               
                 2 
                 . 
                 5 
               
             
           
         
       
     
     where Cl start  corresponds to the starting concentration of chloride in the SIB buffer, Cl final  corresponds to the final value of chloride in the measured diluted filtrates after exposure to the test polymer, 4 is the dilution factor and 2.5 is the polymer concentration in mg/ml. To determine the phosphate bound to the polymer, the following calculation is completed. 
     
       
         
           
             
               Binding 
                
               
                   
               
                
               capacity 
                
               
                   
               
                
               expressed 
                
               
                   
               
                
               as 
                
               
                   
               
                
               mmol 
                
               
                   
               
                
               
                 phosphate 
                 / 
                 g 
               
                
               
                   
               
                
               polymer 
             
             = 
             
               
                 
                   ( 
                   
                     
                       P 
                       
                         s 
                          
                         t 
                          
                         a 
                          
                         r 
                          
                         t 
                       
                     
                     - 
                     
                       P 
                       
                         f 
                          
                         inal 
                       
                     
                   
                   ) 
                 
                 × 
                 4 
               
               
                 2 
                 . 
                 5 
               
             
           
         
       
     
     where P start  corresponds to the starting concentration of phosphate in the SIB buffer, P final  corresponds to the final value of phosphate in the measured diluted filtrates after exposure to the test polymer, 4 is the dilution factor and 2.5 is the polymer concentration in mg/ml. 
     In certain embodiments, the term “statistically significant” refers to the likelihood that a relationship between two or more variables is caused by something other than random chance. More precisely, the significance level, a, defined for a study is the probability of the study rejecting the null hypothesis, given that it were true, and the p-value, p, of a result is the probability of obtaining a result at least as extreme, given that the null hypothesis were true. The result is statistically significant, by the standards of the study, when p&lt;α. The significance level for a study is chosen before data collection, and typically set to 5% 
     The term “substituted hydrocarbyl,” “substituted alkyl,” “substituted alkenyl,” “substituted aryl,” “substituted heterocyclo,” or “substituted heteroaryl” as used herein denotes hydrocarbyl, alkyl, alkenyl, aryl, heterocyclo, or heteroaryl moieties which are substituted with at least one atom other than carbon and hydrogen, including moieties in which a carbon chain atom is substituted with a hetero atom such as nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or a halogen atom. These substituents include halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, keto, acyl, acyloxy, nitro, amino, amido, nitro, cyano, thiol, ketals, acetals, esters and ethers. 
     “Swelling Ratio” or simply “Swelling” describes the amount of water absorbed by a given amount of polymer divided by the weight of the polymer aliquot. The Swelling Ratio is expressed as: swelling=(g swollen polymer−g dry polymer)/g dry polymer. The method used to determine the Swelling Ratio for any given polymer comprised the following:
         a. 50-100 mg of dry (less than 5 wt % water content) polymer is placed into an 11 mL sealable test tube (with screw cap) of known weight (weight of tube=Weight A).   b. Deionized water (10 mL) is added to the tube containing the polymer. The tube is sealed and tumbled for 16 hours (overnight) at room temperature. After incubation, the tube is centrifuged at 3000×g for 3 minutes and the supernatant is carefully removed by vacuum suction. For polymers that form a very loose sediment, another step of centrifugation is performed.   c. After step (b), the weight of swollen polymer plus tube (Weight B) is recorded.   d. Freeze at −40° C. for 30 minutes. Lyophilize for 48 h. Weigh dried polymer and test tube (recorded as Weight C).   e. Calculate g water absorbed per g of polymer, defined as: [(Weight B−Weight A)−(Weight C−Weight A)]/(Weight C−Weight A).       

     A “target ion” is an ion to which the polymer binds, and usually refers to the major ions bound by the polymer, or the ions whose binding to the polymer is thought to produce the therapeutic effect of the polymer (e.g., proton and chloride binding which leads to net removal of HCl). 
     The term “theoretical capacity” represents the calculated, expected binding of hydrochloric acid in an “SGF” assay, expressed in mmol/g. The theoretical capacity is based on the assumption that 100% of the amines from the monomer(s) and crosslinker(s) are incorporated in the crosslinked polymer based on their respective feed ratios. Theoretical capacity is thus equal to the concentration of amine functionalities in the polymer (mmol/g). The theoretical capacity assumes that each amine is available to bind the respective anions and cations and is not adjusted for the type of amine formed (e.g. it does not subtract capacity of quaternary amines that are not available to bind proton). 
     “Therapeutically effective amount” means the amount of a proton-binding crosslinked polymer that, when administered to a patient for treating a disease, is sufficient to effect such treatment for the disease. The amount constituting a “therapeutically effective amount” will vary depending on the polymer, the severity of the disease and the age, weight, etc., of the mammal to be treated. 
     “Treating” or “treatment” of a disease includes (i) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; or (ii) relieving the disease, i.e., causing regression of the disease or its clinical symptoms. Inhibiting the disease, for example, would include prophylaxis. 
     The term “triallylamine” denotes an amino moiety having three allyl groups. 
     The term “vinyl” denotes a moiety having the structural formula R x H y C═CH—*, where * denotes the point of attachment of the moiety to the remainder of the molecule wherein the point of attachment is a heteroatom or aryl, X and Y are independently 0, 1 or 2, such that X+Y=2, and R is hydrocarbyl or substituted hydrocarbyl. 
     The term “weight percent crosslinker” represents the calculated percentage, by mass, of a polymer sample that is derived from the crosslinker. Weight percent crosslinker is calculated using the feed ratio of the polymerization, and assumes full conversion of the monomer and crosslinker(s). The mass attributed to the crosslinker is equal to the expected increase of molecular weight in the infinite polymer network after reaction (e.g., 1,3-dichloropropane is 113 amu, but only 42 amu are added to a polymer network after crosslinking with DCP because the chlorine atoms, as leaving groups, are not incorporated into the polymer network). 
     When introducing elements of the present invention or the preferred embodiments(s) thereof, the articles “a”, “an”, “the” and “said” are intended to mean that there are one or more of the elements. The terms “comprising”, “including” and “having” are intended to be inclusive and not exclusive (i.e., there may be other elements in addition to the recited elements). 
     Embodiments 
     In accordance with the present disclosure, acid-base disorders may be treated using pharmaceutical compositions comprising a nonabsorbable composition having the capacity to remove clinically significant quantities of protons, the conjugate base of one or more strong acids, and/or one or more strong acids. An individual afflicted with a an acute or chronic acid/base disorder characterized by a baseline serum bicarbonate value of less than 22 mEq/l may thus be treated by oral administration of a pharmaceutical composition comprising the nonabsorbable composition which then transits the individual&#39;s digestive system, binds a target species (protons, one or more conjugate base(s) of a strong acid and/or one or more strong acid(s)) as it transits the digestive system, and removes the bound target species by normal biological function (defecation). 
     In general, the individual afflicted with an acute or chronic acid/base disorder may be at any stage of chronic kidney disease. For example, in one embodiment the afflicted individual has not yet reached end stage renal disease (“ESRD”) sometimes also referred to as end stage chronic kidney disease and is not yet on dialysis (i.e., the individual has a mGFR (or eGFR) of at least 15 mL/min/1.73 m 2 ). In some embodiments, the afflicted individual will be Stage 3B CKD (i.e., the individual has a mGFR (or eGFR) in the range of 30-44 mL/min/1.73 m 2  for at least three months). In some embodiments, the afflicted individual will be Stage 3A CKD (i.e., the individual has a mGFR (or eGFR) in the range of 45-59 mL/min/1.73 m 2  for at least three months). Thus, for example, in some embodiments the afflicted individual has a mGFR or an eGFR of less than 60 mL/min/1.73 m 2  for at least three months. By way of further example, in some embodiments the afflicted individual has a mGFR or an eGFR of less than 45 mL/min/1.73 m 2  for at least three months. By way of further example, in some embodiments the afflicted individual has a mGFR or an eGFR of less than 30 mL/min/1.73 m 2  for at least three months. By way of further example, in some embodiments the afflicted individual has a mGFR or an eGFR of 15-30, 15-45, 15-60, 30-45 or even 30-60 mL/min/1.73 m 2  for at least three months. 
     The baseline serum bicarbonate value may be the serum bicarbonate concentration determined at a single time point or may be the mean or median value of two or more serum bicarbonate concentrations determined at two or more time-points. For example, in one embodiment the baseline serum bicarbonate value may be the value of the serum bicarbonate concentration determined at a single time point and the baseline serum bicarbonate value is used as a basis to determine an acute acidic condition requiring immediate treatment. In another embodiment, the baseline serum bicarbonate treatment value is the mean value of the serum bicarbonate concentration for serum samples drawn at different time points (e.g., different days). By way of further example, in one such embodiment the baseline serum bicarbonate treatment value is the mean value of the serum bicarbonate concentration for serum samples drawn on different days (e.g., at least 2, 3, 4, 5 or more days, that may be consecutive or separated by one or more days or even weeks). By way of further example, in one such embodiment the baseline serum bicarbonate treatment value is the mean value of the serum bicarbonate concentration for serum samples drawn on two consecutive days preceding the initiation of treatment. 
     In one embodiment, the acid-base disorder being treated is characterized by a baseline serum bicarbonate value of less than 21 mEq/l. For example, in one such embodiment the acid-base disorder being treated is characterized by a baseline serum bicarbonate value of less than 20 mEq/l. By way of further example, in one such embodiment the acid-base disorder being treated is characterized by a baseline serum bicarbonate value of less than 19 mEq/l. By way of further example, in one such embodiment the acid-base disorder being treated is characterized by a baseline serum bicarbonate value of less than 18 mEq/l. By way of further example, in one such embodiment the acid-base disorder being treated is characterized by a baseline serum bicarbonate value of less than 17 mEq/l. By way of further example, in one such embodiment the acid-base disorder being treated is characterized by a baseline serum bicarbonate value of less than 16 mEq/l. By way of further example, in one such embodiment the acid-base disorder being treated is characterized by a baseline serum bicarbonate value of less than 15 mEq/l. By way of further example, in one such embodiment the acid-base disorder being treated is characterized by a baseline serum bicarbonate value of less than 14 mEq/l. By way of further example, in one such embodiment the acid-base disorder being treated is characterized by a baseline serum bicarbonate value of less than 13 mEq/l. By way of further example, in one such embodiment the acid-base disorder being treated is characterized by a baseline serum bicarbonate value of less than 12 mEq/l. By way of further example, in one such embodiment the acid-base disorder being treated is characterized by a baseline serum bicarbonate value of less than 11 mEq/l. By way of further example, in one such embodiment the acid-base disorder being treated is characterized by a baseline serum bicarbonate value of less than 10 mEq/l. By way of further example, in one such embodiment the acid-base disorder being treated is characterized by a baseline serum bicarbonate value of less than 9 mEq/l. 
     In general, however, the acid-base disorder being treated is characterized by a baseline serum bicarbonate value of at least 9 mEq/l. For example, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 10 mEq/l. By way of further example, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 11 mEq/l. By way of further example, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 12 mEq/l. By way of further example, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 13 mEq/l. By way of further example, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 14 mEq/l. By way of further example, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 15 mEq/l. By way of further example, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 16 mEq/l. By way of further example, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 17 mEq/l. By way of further example, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 18 mEq/l. By way of further example, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 19 mEq/l. By way of further example, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 20 mEq/l. By way of further example, in one such embodiment, the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 21 mEq/l. 
     In certain embodiments, the acid-base disorder being treated is characterized by a baseline serum bicarbonate value in the range of 9 to 21 mEq/l. For example, in one such embodiment the acid-base disorder is characterized by a baseline serum bicarbonate value in the range of 12 to 20 mEq/l. By way of further example, in one such embodiment the acid-base disorder is characterized by a baseline serum bicarbonate value in the range of 12 to 19 mEq/l. By way of further example, in one such embodiment the acid-base disorder is characterized by a baseline serum bicarbonate value in the range of 12 to 18 mEq/l. By way of further example, in one such embodiment the acid-base disorder is characterized by a baseline serum bicarbonate value in the range of 12 to 17 mEq/l. By way of further example, in one such embodiment the acid-base disorder is characterized by a baseline serum bicarbonate value in the range of 12 to 16 mEq/l. By way of further example, in one such embodiment the acid-base disorder is characterized by a baseline serum bicarbonate value in the range of 9 to 11 mEq/l. By way of further example, in one such embodiment the acid-base disorder is characterized by a baseline serum bicarbonate value in the range of 12-14. By way of further example, in one such embodiment the acid-base disorder is characterized by a baseline serum bicarbonate value in the range of 15-17. By way of further example, in one such embodiment the acid-base disorder is characterized by a baseline serum bicarbonate value in the range of 18-21. 
     In certain embodiments, oral administration of a pharmaceutical composition containing a nonabsorbable composition increases the individual&#39;s serum bicarbonate value from baseline to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 1 mEq/l. For example, in one such embodiment the treatment increases the individual&#39;s serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 1.5 mEq/l. By way of further example in one such embodiment the treatment increases the individual&#39;s serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 2 mEq/l. By way of further example in one such embodiment the treatment the individual&#39;s serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 2.5 mEq/l. By way of further example in one such embodiment the treatment increases the individual&#39;s serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least at least 3 mEq/l. By way of further example in one such embodiment the treatment increases the baseline serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 3.5 mEq/l. By way of further example in one such embodiment the treatment increases the individual&#39;s serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 4 mEq/l. By way of further example in one such embodiment the treatment increases the individual&#39;s serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 5 mEq/l but does not exceed 29 mEq/l. By way of further example in one such embodiment the treatment increases the individual&#39;s serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 5 mEq/l but does not exceed 28 mEq/l. By way of further example in one such embodiment the treatment increases the individual&#39;s serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 5 mEq/l but does not exceed 27 mEq/l. By way of further example in one such embodiment the treatment increases the individual&#39;s serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 5 mEq/l but does not exceed 26 mEq/l. By way of further example in one such embodiment the treatment increases the individual&#39;s serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 6 mEq/l but does not exceed 29 mEq/l. By way of further example in one such embodiment the treatment increases the individual&#39;s serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 6 mEq/l but does not exceed 28 mEq/l. By way of further example in one such embodiment the treatment increases the individual&#39;s serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 6 mEq/l but does not exceed 27 mEq/l. By way of further example in one such embodiment the treatment increases the individual&#39;s serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 6 mEq/l but does not exceed 26 mEq/l. By way of further example in one such embodiment the treatment increases the individual&#39;s serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 7 mEq/l but does not exceed 29 mEq/l. By way of further example in one such embodiment the treatment increases the individual&#39;s serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 7 mEq/l but does not exceed 28 mEq/l. By way of further example in one such embodiment the treatment increases the individual&#39;s serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 7 mEq/l but does not exceed 27 mEq/l. By way of further example in one such embodiment the treatment increases the individual&#39;s serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 7 mEq/l but does not exceed 26 mEq/l. By way of further example in one such embodiment the treatment increases the individual&#39;s serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 8 mEq/l but does not exceed 29 mEq/l. By way of further example in one such embodiment the treatment increases the individual&#39;s serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 8 mEq/l but does not exceed 28 mEq/l. By way of further example in one such embodiment the treatment increases the individual&#39;s serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 8 mEq/l but does not exceed 27 mEq/l. By way of further example in one such embodiment the treatment increases the individual&#39;s serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 8 mEq/l but does not exceed 26 mEq/l. By way of further example in one such embodiment the treatment increases the individual&#39;s serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 9 mEq/l but does not exceed 29 mEq/l. By way of further example in one such embodiment the treatment increases the individual&#39;s serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 9 mEq/l but does not exceed 28 mEq/l. By way of further example in one such embodiment the treatment increases the individual&#39;s serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 9 mEq/l but does not exceed 27 mEq/l. By way of further example in one such embodiment the treatment increases the individual&#39;s serum bicarbonate value to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 9 mEq/l but does not exceed 26 mEq/l. In each of the foregoing exemplary embodiments recited in this paragraph, the treatment enables the increased serum bicarbonate value to be sustained over a prolonged period of at least one week, at least one month, at least two months, at least three months, at least six months, or even at least one year. 
     In certain embodiments, the treatment increases the individual&#39;s serum bicarbonate value from a baseline serum bicarbonate value in the range of 12 to 21 mEq/l to an increased value in the range of 24 mEq/l to 29 mEq/l. For example, in one such embodiment the treatment increases the individual&#39;s serum bicarbonate value from a baseline serum bicarbonate value in the range of 12 to 17 mEq/l to an increased value in the range of 24 mEq/l to 29 mEq/l. By way of further example, in one such embodiment the treatment increases the individual&#39;s serum bicarbonate value from a baseline serum bicarbonate value in the range of 12 to 14 mEq/l to an increased value in the range of 24 mEq/l to 29 mEq/l. By way of further example, in one such embodiment the treatment increases the individual&#39;s serum bicarbonate value from a baseline serum bicarbonate value in the range of 15 to 17 mEq/l to an increased value in the range of 24 mEq/l to 29 mEq/l. By way of further example, in one such embodiment the treatment increases the individual&#39;s serum bicarbonate value from a baseline serum bicarbonate value in the range of 18 to 21 mEq/l to an increased value in the range of 24 mEq/l to 29 mEq/l. In each of the foregoing embodiments recited in this paragraph, the treatment enables the increased serum bicarbonate value to be sustained over a prolonged period of at least one week, at least one month, at least two months, at least three months, at least six months, or even at least one year. 
     In certain embodiments, the treatment achieves a clinically significant increase is achieved within a treatment period of less than one month. For example, in one such embodiment, the treatment achieves a clinically significant increase within a treatment period of 25 days. By way of further example, in one such embodiment the treatment achieves the clinically significant increase is achieved within a treatment period of 3 weeks. By way of further example, in one such embodiment the treatment achieves the clinically significant increase is achieved within a treatment period of 15 days. By way of further example, in one such embodiment the treatment achieves the clinically significant increase is achieved within a treatment period of 2 weeks. By way of further example, in one such embodiment the treatment achieves the clinically significant increase is achieved within a treatment period of 10 days. By way of further example, in one such embodiment the treatment achieves the clinically significant increase is achieved within a treatment period of 1 week. By way of further example, in one such embodiment the treatment achieves the clinically significant increase is achieved within a treatment period of 6 days. By way of further example, in one such embodiment the treatment achieves the clinically significant increase is achieved within a treatment period of 5 days. By way of further example, in one such embodiment the treatment achieves the clinically significant increase is achieved within a treatment period of 4 days. By way of further example, in one such embodiment the treatment achieves the clinically significant increase is achieved within a treatment period of 3 days. By way of further example, in one such embodiment the treatment achieves the clinically significant increase is achieved within a treatment period of 2 days. By way of further example, in one such embodiment the treatment achieves the clinically significant increase is achieved within a treatment period of 1 day. By way of further example, in one such embodiment the treatment achieves the clinically significant increase is achieved within a treatment period of 12 hours. 
     In certain embodiments, the treatment achieves a clinically significant increase is achieved without any change in the individual&#39;s diet or dietary habits relative to the period immediately preceding the initiation of treatment. For example, in one such embodiment the clinically significant increase is achieved independent of the individual&#39;s diet or dietary habits. 
     In certain embodiments, the individual&#39;s serum bicarbonate value returns to the baseline value±2.5 mEq/l within 1 month of the cessation of treatment. For example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±2.5 mEq/l within 3 weeks of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±2.5 mEq/l within 2 weeks of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±2.5 mEq/l within 10 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±2.5 mEq/l within 9 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±2.5 mEq/l within 8 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±2.5 mEq/l within 7 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±2.5 mEq/l within 6 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±2.5 mEq/l within 5 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±2.5 mEq/l within 4 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±2.5 mEq/l within 3 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±2.5 mEq/l within 2 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±2.5 mEq/l within 1 day of the cessation of treatment. 
     In certain embodiments, the individual&#39;s serum bicarbonate value returns to the baseline value±2 mEq/l within 1 month of the cessation of treatment. For example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±2 mEq/l within 3 weeks of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±2 mEq/l within 2 weeks of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±2 mEq/l within 10 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±2 mEq/l within 9 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±2 mEq/l within 8 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±2 mEq/l within 7 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±2 mEq/l within 6 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±2 mEq/l within 5 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±2 mEq/l within 4 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±2 mEq/l within 3 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±2 mEq/l within 2 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±2 mEq/l within 1 day of the cessation of treatment. 
     In certain embodiments, the individual&#39;s serum bicarbonate value returns to the baseline value±1.5 mEq/l within 1 month of the cessation of treatment. For example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±1.5 mEq/l within 3 weeks of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±1.5 mEq/l within 2 weeks of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±1.5 mEq/l within 10 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±1.5 mEq/l within 9 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±1.5 mEq/l within 8 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±1.5 mEq/l within 7 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±1.5 mEq/l within 6 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±1.5 mEq/l within 5 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±1.5 mEq/l within 4 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±1.5 mEq/l within 3 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±1.5 mEq/l within 2 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±1.5 mEq/l within 1 day of the cessation of treatment. 
     In certain embodiments, the individual&#39;s serum bicarbonate value returns to the baseline value±1 mEq/l within 1 month of the cessation of treatment. For example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±1 mEq/l within 3 weeks of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±1 mEq/l within 2 weeks of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±1 mEq/l within 10 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±1 mEq/l within 9 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±1 mEq/l within 8 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±1 mEq/l within 7 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±1 mEq/l within 6 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±1 mEq/l within 5 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±1 mEq/l within 4 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±1 mEq/l within 3 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±1 mEq/l within 2 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value returns to the baseline value±1 mEq/l within 1 day of the cessation of treatment. 
     In certain embodiments, upon the cessation of treatment the individual&#39;s serum bicarbonate value decreases by at least 1 mEq/l within 1 month of the cessation of treatment. For example, in one such embodiment. For example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 1 mEq/l within 3 weeks of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 1 mEq/l within 2 weeks of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 1 mEq/l within 10 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 1 mEq/l within 9 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 1 mEq/l within 8 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 1 mEq/l within 7 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 1 mEq/l within 6 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 1 mEq/l within 5 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 1 mEq/l within 4 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 1 mEq/l within 3 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 1 mEq/l within 2 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 1 mEq/l within 1 day of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 1 mEq/l within 12 hours of the cessation of treatment. 
     In certain embodiments, upon the cessation of treatment the individual&#39;s serum bicarbonate value decreases by at least 1.5 mEq/l within 1 month of the cessation of treatment. For example, in one such embodiment. For example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 1.5 mEq/l within 3 weeks of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 1.5 mEq/l within 2 weeks of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 1.5 mEq/l within 10 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 1.5 mEq/l within 9 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 1.5 mEq/l within 8 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 1.5 mEq/l within 7 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 1.5 mEq/l within 6 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 1.5 mEq/l within 5 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 1.5 mEq/l within 4 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 1.5 mEq/l within 3 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 1.5 mEq/l within 2 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 1.5 mEq/l within 1 day of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 1.5 mEq/l within 12 hours of the cessation of treatment. 
     In certain embodiments, upon the cessation of treatment the individual&#39;s serum bicarbonate value decreases by at least 2 mEq/l within 1 month of the cessation of treatment. For example, in one such embodiment. For example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 2 mEq/l within 3 weeks of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 2 mEq/l within 2 weeks of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 2 mEq/l within 10 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 2 mEq/l within 9 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 2 mEq/l within 8 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 2 mEq/l within 7 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 2 mEq/l within 6 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 2 mEq/l within 5 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 2 mEq/l within 4 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 2 mEq/l within 3 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 2 mEq/l within 2 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 2 mEq/l within 1 day of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 2 mEq/l within 12 hours of the cessation of treatment. 
     In certain embodiments, upon the cessation of treatment the individual&#39;s serum bicarbonate value decreases by at least 2.5 mEq/l within 1 month of the cessation of treatment. For example, in one such embodiment. For example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 2.5 mEq/l within 3 weeks of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 2.5 mEq/l within 2 weeks of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 2.5 mEq/l within 10 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 2.5 mEq/l within 9 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 2.5 mEq/l within 8 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 2.5 mEq/l within 7 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 2.5 mEq/l within 6 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 2.5 mEq/l within 5 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 2.5 mEq/l within 4 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 2.5 mEq/l within 3 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 2.5 mEq/l within 2 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 2.5 mEq/l within 1 day of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 2.5 mEq/l within 12 hours of the cessation of treatment. 
     In certain embodiments, upon the cessation of treatment the individual&#39;s serum bicarbonate value decreases by at least 3 mEq/l within 1 month of the cessation of treatment. For example, in one such embodiment. For example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 3 mEq/l within 3 weeks of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 3 mEq/l within 2 weeks of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 3 mEq/l within 10 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 3 mEq/l within 9 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 3 mEq/l within 8 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 3 mEq/l within 7 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 3 mEq/l within 6 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 3 mEq/l within 5 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 3 mEq/l within 4 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 3 mEq/l within 3 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 3 mEq/l within 2 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 3 mEq/l within 1 day of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 3 mEq/l within 12 hours of the cessation of treatment. 
     In certain embodiments, upon the cessation of treatment the individual&#39;s serum bicarbonate value decreases by at least 3.5 mEq/l within 1 month of the cessation of treatment. For example, in one such embodiment. For example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 3.5 mEq/l within 3 weeks of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 3.5 mEq/l within 2 weeks of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 3.5 mEq/l within 10 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 3.5 mEq/l within 9 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 3.5 mEq/l within 8 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 3.5 mEq/l within 7 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 3.5 mEq/l within 6 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 3.5 mEq/l within 5 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 3.5 mEq/l within 4 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 3.5 mEq/l within 3 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 3.5 mEq/l within 2 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 3.5 mEq/l within 1 day of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 3.5 mEq/l within 12 hours of the cessation of treatment. 
     In certain embodiments, upon the cessation of treatment the individual&#39;s serum bicarbonate value decreases by at least 4 mEq/l within 1 month of the cessation of treatment. For example, in one such embodiment. For example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 4 mEq/l within 3 weeks of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 4 mEq/l within 2 weeks of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 4 mEq/l within 10 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 4 mEq/l within 9 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 4 mEq/l within 8 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 4 mEq/l within 7 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 4 mEq/l within 6 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 4 mEq/l within 5 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 4 mEq/l within 4 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 4 mEq/l within 3 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 4 mEq/l within 2 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 4 mEq/l within 1 day of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 4 mEq/l within 12 hours of the cessation of treatment. 
     In certain embodiments, upon the cessation of treatment the individual&#39;s serum bicarbonate value decreases by at least 4.5 mEq/l within 1 month of the cessation of treatment. For example, in one such embodiment. For example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 4.5 mEq/l within 3 weeks of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 4.5 mEq/l within 2 weeks of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 4.5 mEq/l within 10 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 4.5 mEq/l within 9 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 4.5 mEq/l within 8 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 4.5 mEq/l within 7 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 4.5 mEq/l within 6 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 4.5 mEq/l within 5 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 4.5 mEq/l within 4 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 4.5 mEq/l within 3 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 4.5 mEq/l within 2 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 4.5 mEq/l within 1 day of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 4.5 mEq/l within 12 hours of the cessation of treatment. 
     In certain embodiments, upon the cessation of treatment the individual&#39;s serum bicarbonate value decreases by at least 5 mEq/l within 1 month of the cessation of treatment. For example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 5 mEq/l within 3 weeks of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 5 mEq/l within 2 weeks of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 5 mEq/l within 10 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 5 mEq/l within 9 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 5 mEq/l within 8 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 5 mEq/l within 7 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 5 mEq/l within 6 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 5 mEq/l within 5 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 5 mEq/l within 4 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 5 mEq/l within 3 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 5 mEq/l within 2 days of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 5 mEq/l within 1 day of the cessation of treatment. By way of further example, in one such embodiment the individual&#39;s serum bicarbonate value decreases by at least 5 mEq/l within 12 hours of the cessation of treatment. 
     In one embodiment, the baseline serum bicarbonate value is the value of the serum bicarbonate concentration determined at a single time point. In another embodiment, the baseline serum bicarbonate value is the mean value of at least two serum bicarbonate concentrations determined at different time-points. For example, in one such embodiment the baseline serum bicarbonate value is the mean value of at least two serum bicarbonate concentrations for serum samples drawn on different days. By way of further example, the baseline serum bicarbonate value is the mean or median value of at least two serum bicarbonate concentrations for serum samples drawn on non-consecutive days. By way of further example, in one such method the non-consecutive days are separated by at least two days. By way of further example, in one such method the non-consecutive days are separated by at least one week. By way of further example, in one such method the non-consecutive days are separated by at least two weeks. By way of further example, in one such method the non-consecutive days are separated by at least three weeks. 
     In certain embodiments, the daily dose is no more than 100 g/day of the nonabsorbable composition. For example, in one such embodiment the daily dose is no more than 90 g/day of the nonabsorbable composition. By way of further example, in one such embodiment the daily dose is no more than 75 g/day of the nonabsorbable composition. By way of further example, in one such embodiment the daily dose is no more than 65 g/day of the nonabsorbable composition. By way of further example, in one such embodiment the daily dose is no more than 50 g/day of the nonabsorbable composition. By way of further example, in one such embodiment the daily dose is no more than 40 g/day of the nonabsorbable composition. By way of further example, in one such embodiment the daily dose is no more than 30 g/day of the nonabsorbable composition. By way of further example, in one such embodiment the daily dose is no more than 25 g/day of the nonabsorbable composition. By way of further example, in one such embodiment the daily dose is no more than 20 g/day of the nonabsorbable composition. By way of further example, in one such embodiment the daily dose is no more than 15 g/day of the nonabsorbable composition. By way of further example, in one such embodiment the daily dose is no more than 10 g/day of the nonabsorbable composition. By way of further example, in one such embodiment the daily dose is no more than 5 g/day of the nonabsorbable composition. 
     In certain embodiments, the individual is treated with the daily dose for a period of at least one day. For example, in one such embodiment the individual is treated with the daily dose for a period of at least one week. By way of further example, in one such embodiment the individual is treated with the daily dose for a period of at least one month. By way of further example, in one such embodiment the individual is treated with the daily dose for a period of at least two months. By way of further example, in one such embodiment the individual is treated with the daily dose for a period of at least three months. By way of further example, in one such embodiment the individual is treated with the daily dose for a period of at least several months. By way of further example, in one such embodiment the individual is treated with the daily dose for a period of at least six months. By way of further example, in one such embodiment the individual is treated with the daily dose for a period of at least one year. 
     In certain embodiments of the method of the present disclosure, the daily dose of the nonabsorbable composition has the capacity to remove at least about 5 mEq/day of the target species. For example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 6 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 7 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 8 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 9 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 10 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 11 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 12 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 13 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 14 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 15 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 16 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 17 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 18 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 19 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 20 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 21 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 22 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 23 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 24 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 25 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 26 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 27 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 28 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 29 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 30 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 31 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 32 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 33 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 34 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 35 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 36 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 37 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 38 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 39 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 40 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 41 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 42 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 43 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 44 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 45 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 46 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 47 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 48 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 49 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition has the capacity to remove at least about 50 mEq/day of the target species. 
     In certain embodiments of the method of the present disclosure, the daily dose of the nonabsorbable composition removes at least about 5 mEq/day of the target species. For example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 6 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 7 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 8 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 9 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 10 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 11 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 12 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 13 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 14 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 15 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 16 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 17 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 18 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 19 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 20 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 21 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 22 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 23 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 24 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 25 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 26 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 27 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 28 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 29 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 30 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 31 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 32 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 33 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 34 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 35 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 36 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 37 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 38 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 39 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 40 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 41 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 42 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 43 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 44 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 45 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 46 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 47 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 48 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 49 mEq/day of the target species. By way of further example, in one such embodiment the daily dose of the nonabsorbable composition removes at least about 50 mEq/day of the target species. 
     In certain embodiments of the method of the present disclosure, the daily dose of the nonabsorbable composition removes less than 60 mEq/day of the target species. For example, in one such method the daily dose removes less than 55 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 50 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 45 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 40 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 35 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 34 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 33 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 32 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 31 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 30 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 29 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 28 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 27 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 26 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 25 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 24 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 23 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 22 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 21 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 20 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 19 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 18 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 17 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 16 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 15 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 14 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 13 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 12 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 11 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 10 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 9 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 8 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 7 mEq/day of the target species. By way of further example, in one such embodiment the daily dose removes less than 6 mEq/day of the target species. 
     In certain embodiments of the method of the present disclosure, the daily dose of the nonabsorbable composition has insufficient capacity to remove more than 60 mEq/day of the target species. For example, in one such method the daily dose has insufficient capacity to remove more than 55 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 50 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 45 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 40 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 35 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 34 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 33 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 32 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 31 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 30 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 29 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 28 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 27 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 26 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 25 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 24 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 23 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 22 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 21 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 20 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 19 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 18 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 17 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 16 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 15 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 14 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 13 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 12 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 11 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 10 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 9 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 8 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 7 mEq/day of the target species. By way of further example, in one such embodiment the daily dose has insufficient capacity to remove more than 6 mEq/day of the target species. 
     In certain embodiments of the method of the present disclosure, the method comprises oral administration of a pharmaceutical composition to increase the individual&#39;s serum bicarbonate levels wherein: (i) the pharmaceutical composition binds a target species in the individual&#39;s digestive system when given orally, the target species being selected from the group consisting of protons, strong acids, and conjugate bases of strong acids; and (ii) the pharmaceutical composition increases the serum bicarbonate level by at least 1 mEq/l in a placebo controlled study, said increase being the difference between the cohort average serum bicarbonate level in a first cohort at the end of the study, relative to the cohort average serum bicarbonate level in a second cohort at the end of the study, wherein the first cohort&#39;s subjects receive the pharmaceutical composition and the second cohort&#39;s subjects receive a placebo, wherein the first and second cohorts each comprise at least 25 subjects, each cohort is prescribed the same diet during the study and the study lasts at least two weeks. In one embodiment, the first cohort receives a daily dose of the pharmaceutical composition that does not exceed 100 g/day. In one embodiment, the first cohort receives a daily dose of the pharmaceutical composition that does not exceed 50 g/day. In one embodiment, the first cohort receives a daily dose of the pharmaceutical composition that does not exceed 30 g/day. In one embodiment, the first cohort receives a daily dose of the pharmaceutical composition that does not exceed 25 g/day. In one embodiment, the first cohort receives a daily dose of the pharmaceutical composition that does not exceed 20 g/day. In one embodiment, the first cohort receives a daily dose of the pharmaceutical composition that does not exceed 15 g/day. In one embodiment, the first cohort receives a daily dose of the pharmaceutical composition that does not exceed 10 g/day. In one embodiment, the first cohort receives a daily dose of the pharmaceutical composition that does not exceed 5 g/day. In one embodiment, the target species is protons. In one embodiment, the target species is chloride ions. In one embodiment, the target species is a strong acid. In one embodiment, the target species is HCl. In one embodiment, the pharmaceutical composition is not absorbed when ingested. 
     In one embodiment, the individual or adult human patient has chronic kidney disease (CKD Stage 3-4; eGFR 20-&lt;60 mL/min/1.73 m 2 ) and a baseline serum bicarbonate value at the start of the study between 12 and 20 mEq/L. In one embodiment, the pharmaceutical composition increases the serum bicarbonate level of the individual or adult human patient by at least 2 mEq/l in the placebo controlled study. In one embodiment, the pharmaceutical composition increases the serum bicarbonate level of the individual or adult human patient by at least 3 mEq/l in the placebo controlled study. In one embodiment, the individual or adult human patient is not yet in need for kidney replacement therapy (dialysis or transplant). In one embodiment, the individual or adult human patient has not yet reached end stage renal disease (“ESRD”). 
     In one embodiment, the individual or adult human patient has a mGFR of at least 15 mL/min/1.73 m 2 . In one embodiment, the individual or adult human patient has an eGFR of at least 15 mL/min/1.73 m 2 . In one embodiment, the individual or adult human patient has a mGFR of at least 30 mL/min/1.73 m 2 . In one embodiment, the individual or adult human patient has an eGFR of at least 30 mL/min/1.73 m 2 . In one embodiment, the individual or adult human patient has a mGFR of less than 45 mL/min/1.73 m 2  for at least three months. In one embodiment, the individual or adult human patient has an eGFR of less than 45 mL/min/1.73 m 2  for at least three months. In one embodiment, the individual or adult human patient has a mGFR of less than 60 mL/min/1.73 m 2  for at least three months. In one embodiment, the individual or adult human patient has an eGFR of less than 60 mL/min/1.73 m 2  for at least three months. In one embodiment, the individual or adult human patient has Stage 3A CKD, Stage 3B CKD, or Stage 4 CKD. 
     While the methods described above refer to daily dose, a further aspect of the disclosure include the methods disclosed herein in which the dose is administered less frequently than once per day (while still being administered on a regular basis). In any of the disclosure, the daily dose specified may, instead, be administrated on a less frequent basis. For example, the doses disclosed here may be administered once every two or three days. Or the doses disclosed here may be administered once, twice or three times a week. 
     In addition to (or as a surrogate for) serum bicarbonate, other biomarkers of acid-base imbalance may be used as a measure of acid-base status. For example, blood (serum or plasma) pH, total CO 2 , anion gap, and/or the concentration of other electrolytes (e.g., sodium, potassium, calcium, magnesium, chloride and/or sulfate) may be used as an indicator of acid-base imbalance. Similarly, net acid excretion (“NAE”), urine pH, urine ammonium concentration, and/or the concentration of other electrolytes in the urine (e.g., sodium, potassium, calcium, magnesium, chloride and/or sulfate) may be used as an indicator of acid-base imbalance. 
     
       
         
           
               
               
               
               
             
               
                   
               
               
                   
                 Biomarker 
                 Normal/ 
                 Analytical  
               
               
                 Fluid 
                 of interest 
                 Target Value 
                 Technique 
               
               
                   
               
             
            
               
                 Blood 
                 Total CO 2   
                 23-29 mmol/L 
                 Blood gas  
               
               
                 (serum 
                   
                   
                 analyzer; 
               
               
                 or 
                   
                   
                 enzymatic assay;  
               
               
                 plasma) 
                   
                   
                 ion 
               
               
                   
                   
                   
                 selective electrode 
               
               
                   
                 Anion gap 
                 3-11 mEq/L 
                 Obtained from  
               
               
                   
                   
                   
                 standard 
               
               
                   
                   
                   
                 chemistry  
               
               
                   
                   
                   
                 electrolyte  
               
               
                   
                   
                   
                 panel 
               
               
                   
                 pH 
                 7.36 to 7.44 
                 Blood gas  
               
               
                   
                   
                   
                 analyzer; 
               
               
                   
                   
                   
                 enzymatic assay;  
               
               
                   
                   
                   
                 ion 
               
               
                   
                   
                   
                 selective electrode 
               
               
                   
                 Electrolytes 
                 Na = 135-145  
                 Obtained from  
               
               
                   
                   
                 mEq/L; 
                 standard 
               
               
                   
                   
                 K = 3.5-5 mEq/L; 
                 chemistry  
               
               
                   
                   
                 Total Ca = 8-10.5  
                 electrolyte 
               
               
                   
                   
                 mEq/L, 
                 panel; 
               
               
                   
                   
                 depending on age  
                 ion selective  
               
               
                   
                   
                 and sex; 
                 electrodes 
               
               
                   
                   
                 Mg = 1.5-2.5  
                 can be used for Na,  
               
               
                   
                   
                 mEq/L, 
                 Cl and K 
               
               
                   
                   
                 depending on age; 
                   
               
               
                   
                   
                 Cl = 95-105  
                   
               
               
                   
                   
                 mEq/L; 
                   
               
               
                   
                   
                 phosphate =  
                   
               
               
                   
                   
                 2.5-4.5 mEq/L; 
                   
               
               
                   
                   
                 sulfate = 1 mEq/L 
                   
               
               
                 urine 
                 pH 
                 4.5-8.0 
                 pH meter 
               
               
                   
                 ammonium 
                 3-65 mmol/L 
                 Enzymatic 
               
               
                   
                 citrate 
                 150-1,191 mg/ 
                 Enzymatic 
               
               
                   
                   
                 24-hour urine 
                   
               
               
                   
                   
                 collection; ranges  
                   
               
               
                   
                   
                 for 20 to 60 
                   
               
               
                   
                   
                 years of age 
                   
               
               
                   
                 sodium 
                 20 mEq/L in spot  
                 Ion-selective  
               
               
                   
                   
                 samples,  
                 electrode 
               
               
                   
                   
                 41-227 mEq/L  
                   
               
               
                   
                   
                 per day 
                   
               
               
                   
                   
                 (depending upon  
                   
               
               
                   
                   
                 salt and fluid 
                   
               
               
                   
                   
                 intake) 
                   
               
               
                   
                 potassium 
                 17-77 mmol/ 
                 Ion-selective  
               
               
                   
                   
                 24 hours; spot 
                 electrode 
               
               
                   
                   
                 sample is  
                   
               
               
                   
                   
                 ~45 mmol/L 
                   
               
               
                   
                 calcium 
                 Urinary calcium is  
                 Enzymatic 
               
               
                   
                   
                 &lt;250 mg/ 
                   
               
               
                   
                   
                 24 hours in males,  
                   
               
               
                   
                   
                 &lt;200 mg/ 
                   
               
               
                   
                   
                 24 hours in  
                   
               
               
                   
                   
                 females 
                   
               
               
                   
                 magnesium 
                 Urinary  
                 Enzymatic 
               
               
                   
                   
                 magnesium is  
                   
               
               
                   
                   
                 51-269 mg/ 
                   
               
               
                   
                   
                 24 hours;  
                   
               
               
                   
                   
                 spot values 
                   
               
               
                   
                   
                 are usually  
                   
               
               
                   
                   
                 reported as a ratio 
                   
               
               
                   
                   
                 with creatinine  
                   
               
               
                   
                   
                 and are &gt;0.035 
                   
               
               
                   
                   
                 mg Mg/mg  
                   
               
               
                   
                   
                 creatinine 
                   
               
               
                   
                 chloride 
                 Urinary chloride  
                 Ion-selective  
               
               
                   
                   
                 is 40-224 
                 electrode 
               
               
                   
                   
                 mmol/24 hours 
                   
               
               
                   
                 Urine  
                 UAG =  
                 UAG =  
               
               
                   
                 Anion 
                 0-10 mEq/L; 
                 (Na +  + K + ) − Cl −   
               
               
                   
                 Gap 
                 Metabolic acidosis  
                 in urine. It is a  
               
               
                   
                 (“UAG”) 
                 indicated 
                 measure of 
               
               
                   
                   
                 when UAG &gt; 
                 ammonium  
               
               
                   
                   
                 20 mEq/L 
                 excretion, the 
               
               
                   
                   
                   
                 primary mechanism  
               
               
                   
                   
                   
                 for acid excretion. 
               
               
                   
                 Net Acid 
                 Urinary net acid  
                 24-hour urine  
               
               
                   
                 Excretion 
                 excretion is 
                 collection 
               
               
                   
                   
                 the total amount  
                 required;  
               
               
                   
                   
                 of acid 
                 Direct NAE 
               
               
                   
                   
                 excreted by the  
                 measurement  
               
               
                   
                   
                 kidney per 
                 (mEq/day) = 
               
               
                   
                   
                 day; the NAE  
                 [NH 4   + ] + [TA] −  
               
               
                   
                   
                 value depends 
                 [HCO 3   − ], 
               
               
                   
                   
                 on the age of the  
                 where TA is  
               
               
                   
                   
                 subject, 
                 concentration 
               
               
                   
                   
                 gender, and  
                 of titratable  
               
               
                   
                   
                 protein intake; 
                 acids 
               
               
                   
                   
                 typical NAE  
                 Indirect NAE 
               
               
                   
                   
                 values range from 
                 measurement  
               
               
                   
                   
                 9 mEq/day to  
                 (mEq/day) = 
               
               
                   
                   
                 38 mEq/day 
                 (Cl + P + SO 4  +  
               
               
                   
                   
                   
                 organic 
               
               
                   
                   
                   
                 anions) −  
               
               
                   
                   
                   
                 (Na + K + Ca + 
               
               
                   
                   
                   
                 Mg). 
               
               
                   
               
            
           
         
       
     
     In one embodiment, treatment of an individual as described herein may improve an individuals&#39; serum anion gap. For example, treating an acid base imbalance with a neutral composition having the capacity to bind both protons and anions (unaccompanied by the delivery of sodium or potassium ions) can increase serum bicarbonate without an accompanying increase in sodium or potassium (see Example 3 and  FIGS. 13A, 130 and 13D ). Consequently, the serum anion gap may be improved (decreased) by at least 1 mEq/l or more (e.g., at least 2 mEq/l) within a period as short as 2 weeks (see Example 3). 
     The various aspects and embodiments may have a range of advantages, such as improved or successful treatment of metabolic acidosis. Such improvements may also include reduced side effects, increased patient compliance, reduced drug loads, increased speed of treatment, increased magnitude of treatment, avoiding unwanted changes to other electrolytes and/or reduced drug-drug interactions. A further improvement may include reducing a patient&#39;s anion gap (as defined above) as part of the methods and other aspects disclosed herein. Further useful features of the disclosed aspects can be found in the examples. 
     Certain Specific Compositions for Use in Treatment 
     As previously noted, one aspect disclosed here is a composition for use in a method of treating metabolic acidosis in an adult human patient wherein in said treatment 0.1-12 g of said composition is administered to the patient per day, said composition being a nonabsorbable composition having the capacity to remove protons from the patient, wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 2.5 mEq/g in a Simulated Small Intestine Inorganic (“SIB”) assay. This aspect is based on the data in the examples showing the absorption and removal of HCl to successfully treat patients, allowing the amount of the composition to be set based on its capacity to bind chloride in the SIB assay. As shown in the examples, a composition with this specified level of chloride binding in the “SIB” assay can be used in the specified dose range to successfully treat metabolic acidosis in adult humans. In this aspect, the composition may be administered orally, and so would be an orally administered nonabsorbable composition as defined herein. 
     This aspect is based on the data in the examples showing the absorption and removal of HCl to successfully treat patients using a composition according to this aspect, allowing the amount of the composition to be set based on its capacity to bind chloride in the SIB assay. Surprisingly, the amounts required for successful treatment were relatively low. 
     Another aspect of the present disclosure is a composition for use in a method of treating metabolic acidosis in an adult human patient by increasing that patient&#39;s serum bicarbonate value by at least 1 mEq/L over 15 days of treatment, said composition being a nonabsorbable composition having the capacity to remove protons from the patient. In this aspect, the composition may be administered orally, and so would be an orally administered nonabsorbable composition as defined herein. 
     This aspect is based on the data in the examples showing the absorption and removal of HCl to successfully treat patients using a composition according to this aspect which provides new detail regarding the reductions possible using a composition of the disclosure. This aspect includes surprisingly rapid increases in the patient&#39;s serum bicarbonate level, for example in the first few days, as well as surprisingly large increases in serum bicarbonate level. 
     Another aspect of the present disclosure is a composition for use in a method of treating metabolic acidosis in an adult human patient, said patient having a serum bicarbonate level of less than 20 mEq/L prior to treatment, said composition being a nonabsorbable composition having the capacity to remove protons from the patient. In this aspect, the composition may be administered orally, and so would be an orally administered nonabsorbable composition as defined herein. 
     This aspect is based on the data in the examples showing, for the first time, the successful treatment of patients with a low serum bicarbonate level, for example levels that have not been shown to be so readily treated previously. The patients with lower serum bicarbonate levels responded particularly well to the treatment and this improvement for this subgroup is one advantage of this aspect. 
     Another aspect of the present disclosure is a composition for use in a method of treating metabolic acidosis in an adult human patient by increasing that patient&#39;s serum bicarbonate value by at least 1 mEq/L over 15 days of treatment, wherein in said treatment &gt;12-100 g of said polymer is administered to the patient per day, said composition being a nonabsorbable composition having the capacity to remove protons from the patient, wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 2.5 mEq/g in a Simulated Small Intestine Inorganic Buffer (“SIB”) assay. In this aspect, the composition may be administered orally, and so would be an orally administered nonabsorbable composition as defined herein. 
     Another aspect of the present disclosure is a composition for use in a method of treating metabolic acidosis in an adult human patient wherein in said treatment &gt;12-100 g of said composition is administered to the patient per day, said composition being a nonabsorbable composition having the capacity to remove protons from the patient, wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of less than 2.5 mEq/g in a Simulated Small Intestine Inorganic Buffer (“SIB”) assay. In this aspect, the composition may be administered orally, and so would be an orally administered nonabsorbable composition as defined herein. 
     The chloride ion binding capacity in the SIB assay is affected by both the composition&#39;s selectivity for binding chloride and the total space available for chloride binding. The term “composition” refers to the active pharmaceutical ingredient, including any counter ions, but not to excipients. So, the “amount” of the composition is the amount of active pharmaceutical ingredient without including other parts of any unit dose form. 
     More specifically in these aspects, the amount of composition may be any amount disclosed herein in other sections within the range 0.1 g-12 g. For example, 1-11 g, 2-10 g, 3-9 g, 3-8 g, 3-7 g, 3-6 g, 3.5-5.5 g, 4-5 g, or 4.5-5 g of said polymer is administered to the patient per day, or 0.5 g, 1 g, 1.5 g, 2 g, 2.5 g, 3 g, 3.5 g, 4.0 g, 4.5 g or 5.0 g of the composition is administered to the patient per day. 
     More specifically in these aspects, the chloride ion binding capacity in a Simulated Small Intestine Inorganic Buffer (“SIB”) assay may be greater than 3, 3.5, 4, or 4.5 mEq/g. One upper limit for the chloride ion binding capacity in a SIB assay is 10 mEq/g. Other the upper limits may be 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 or 10 mEq/g, or there may be no upper limit specified. 
     All combinations of the amount of composition and the chloride ion binding capacity mentioned here are also disclosed. For example, in one embodiment, the composition has a chloride ion binding capacity in a SIB assay is of at least 4.5 mEq/g and only 0.1-6 gs of composition is administered in the method of treating metabolic acidosis. 
     The composition in these aspects can additionally have any of the properties or features specified elsewhere herein. For example, the composition may be a nonabsorbable composition as described in the following section. In a similar fashion, the methods of treatment specified in these aspects may include any of the features disclosed in the preceding section regarding certain methods of treatment. 
     Nonabsorbable Compositions 
     As previously noted, the nonabsorbable compositions having the medical uses described herein possess the capacity to remove clinically significant quantities of one or more target species: (i) protons, (ii) the conjugate base(s) of one or more strong acids (e.g., chloride, bisulfate (HSO 4   − ) and/or sulfate (SO 4 -) −  ions) and/or (iii) one or more strong acids (e.g., HCl and/or H 2 SO 4 ). To bind such target species, the nonabsorbable compositions may be selected from the group consisting of cation exchange compositions, anion exchange compositions, amphoteric ion exchange compositions, neutral compositions having the capacity to bind both protons and anions, composites thereof and mixtures thereof. 
     In general, the nonabsorbable composition has a preferred particle size range that is (i) large enough to avoid passive or active absorption through the GI tract and (ii) small enough to not cause grittiness or unpleasant mouth feel when ingested as a powder, sachet and/or chewable tablet/dosage form with a mean particle size of at least 3 microns. For example, in one such embodiment the nonabsorbable composition comprises a population of particles having a mean particle size (volume distribution) in the range of 5 to 1,000 microns. By way of further example, in one such embodiment the nonabsorbable composition comprises a population of particles having a mean particle size (volume distribution) in the range of 5 to 500 microns. By way of further example, in one such embodiment the nonabsorbable composition comprises a population of particles having a mean particle size (volume distribution) in the range of 10 to 400 microns. By way of further example, in one such embodiment the nonabsorbable composition comprises a population of particles having a mean particle size (volume distribution) in the range of 10 to 300 microns. By way of further example, in one such embodiment the nonabsorbable composition comprises a population of particles having a mean particle size (volume distribution) in the range of 20 to 250 microns. By way of further example, in one such embodiment the nonabsorbable composition comprises a population of particles having a mean particle size (volume distribution) in the range of 30 to 250 microns. By way of further example, in one such embodiment the nonabsorbable composition comprises a population of particles having a mean particle size (volume distribution) in the range of 40 to 180 microns. In certain embodiments, less than 7% of the particles in the population (volume distribution) have a diameter less than 10 microns. For example, in such embodiments less than 5% of the particles in the particles in the population (volume distribution) have a diameter less than 10 microns. By way of further example, in such embodiments less than 2.5% of the particles in the particles in the population (volume distribution) have a diameter less than 10 microns. By way of further example, in such embodiments less than 1% of the particles in the particles in the population (volume distribution) have a diameter less than 10 microns. In all embodiments, the particle size may be measured using the protocol set out in the abbreviations and definitions section (above). 
     To minimize GI side effects in patients that are often related to a large volume polymer gel moving through the GI tract, a low Swelling Ratio of the nonabsorbable composition is preferred (0.5 to 10 times its own weight in water). For example, in one such embodiment the nonabsorbable composition has a Swelling Ratio of less than 9. By way of further example, in one such embodiment the nonabsorbable composition has a Swelling Ratio of less than 8. By way of further example, in one such embodiment the nonabsorbable composition has a Swelling Ratio of less than 7. By way of further example, in one such embodiment the nonabsorbable composition has a Swelling Ratio of less than 6. By way of further example, in one such embodiment the nonabsorbable composition has a Swelling Ratio of less than 5. By way of further example, in one such embodiment the nonabsorbable composition has a Swelling Ratio of less than 4. By way of further example, in one such embodiment the nonabsorbable composition has a Swelling Ratio of less than 3. By way of further example, in one such embodiment the nonabsorbable composition has a Swelling Ratio of less than 2. 
     The amount of the target species (proton, conjugate base of a strong acid and/or strong acid) that is bound as the nonabsorbable composition transits the GI tract is largely a function of the binding capacity of the composition for the target species (protons, the conjugate base of a strong acid, and/or a strong acid) and the quantity of the nonabsorbable composition administered per day as a daily dose. In general, the theoretical binding capacity for a target species may be determined using a SGF assay and determining the amount of a species that appeared in or disappeared from the SGF buffer during the SGF assay. For example, the theoretical proton binding capacity of a cation exchange resin may be determined by measuring the increase in the amount of cations (other than protons) in the buffer during a SGF assay. Similarly, the theoretical anion binding capacity of an anion exchange resin (in a form other than the chloride form) may be determined by measuring the increase in the amount of anions (other than chloride ions) in the buffer during a SGF assay. Additionally, the theoretical anion binding capacity of a neutral composition for protons and the conjugate base of a strong acid may be determined by measuring the decrease in chloride concentration in the buffer during a SGF assay. 
     In general, the nonabsorbable composition will have a theoretical binding capacity for the target species of at least about 0.5 mEq/g (as determined in an SGF assay). For example, in some embodiments the nonabsorbable composition will have a theoretical binding capacity for the target species of at least about 1 mEq/g. By way of further example, in some embodiments the nonabsorbable composition will have a theoretical binding capacity for the target species of at least about 2 mEq/g. By way of further example, in some embodiments the nonabsorbable composition will have a theoretical binding capacity for the target species of at least about 3 mEq/g. By way of further example, in some embodiments the nonabsorbable composition will have a theoretical binding capacity for the target species of at least about 4 mEq/g. By way of further example, in some embodiments the nonabsorbable composition will have a theoretical binding capacity for the target species of at least about 5 mEq/g. By way of further example, in some embodiments the nonabsorbable composition will have a theoretical binding capacity for the target species of at least about 7.5 mEq/g. By way of further example, in some embodiments the nonabsorbable composition will have a theoretical binding capacity for the target species of at least about 10 mEq/g. By way of further example, in some embodiments the nonabsorbable composition will have a theoretical binding capacity for the target species of at least about 12.5 mEq/g. By way of further example, in some embodiments the nonabsorbable composition will have a theoretical binding capacity for the target species of at least about 15 mEq/g. By way of further example, in some embodiments the nonabsorbable composition will have a theoretical binding capacity for the target species of at least about 20 mEq/g. In general, the nonabsorbable composition will typically have a theoretical binding capacity for the target species that is not in excess of about 35 mEq/g. For example, in some embodiments, the theoretical binding capacity of the nonabsorbable compositions for the target species that is not be excess of 30 mEq/g. Thus, for example, the theoretical binding capacity of the nonabsorbable compositions for the target species may range from 2 to 25 mEq/g, 3 to 25 mEq/g, 5 to 25 mEq/g, 10 to 25 mEq/g, 5 to 20 mEq/g, 6 to 20 mEq/g, 7.5 to 20 mEq/g, or even 10 to 20 mEq/g. In those embodiments in which the target species comprises protons and at least one conjugate base, the binding capacities recited in this paragraph are the theoretical binding capacities for protons and the theoretical binding capacities for the conjugate base(s), independently and individually, and not the sum thereof. 
     In general, the nonabsorbable composition will have a theoretical binding capacity for protons of at least about 0.5 mEq/g (as determined in an SGF assay). For example, in some embodiments the nonabsorbable composition will have a theoretical binding capacity for protons of at least about 1 mEq/g. By way of further example, in some embodiments the nonabsorbable composition will have a theoretical binding capacity for protons of at least about 2 mEq/g. By way of further example, in some embodiments the nonabsorbable composition will have a theoretical binding capacity for protons of at least about 3 mEq/g. By way of further example, in some embodiments the nonabsorbable composition will have a theoretical binding capacity for protons of at least about 4 mEq/g. By way of further example, in some embodiments the nonabsorbable composition will have a theoretical binding capacity for protons of at least about 5 mEq/g. By way of further example, in some embodiments the nonabsorbable composition will have a theoretical binding capacity for protons of at least about 7.5 mEq/g. By way of further example, in some embodiments the nonabsorbable composition will have a theoretical binding capacity for protons of at least about 10 mEq/g. By way of further example, in some embodiments the nonabsorbable composition will have a theoretical binding capacity for protons of at least about 12.5 mEq/g. By way of further example, in some embodiments the nonabsorbable composition will have a theoretical binding capacity for protons of at least about 15 mEq/g. By way of further example, in some embodiments the nonabsorbable composition will have a theoretical binding capacity for protons of at least about 20 mEq/g. In general, the nonabsorbable composition will typically have a theoretical binding capacity for protons that is not in excess of about 35 mEq/g. For example, in some embodiments, the theoretical binding capacity of the nonabsorbable compositions for protons that is not be excess of 30 mEq/g. Thus, for example, the theoretical binding capacity of the nonabsorbable compositions for protons may range from 2 to 25 mEq/g, 3 to 25 mEq/g, 5 to 25 mEq/g, 10 to 25 mEq/g, 5 to 20 mEq/g, 6 to 20 mEq/g, 7.5 to 20 mEq/g, or even 10 to 20 mEq/g. In those embodiments in which the target species comprises protons and at least one conjugate base, the binding capacities recited in this paragraph are the theoretical binding capacities for protons and the theoretical binding capacities for the conjugate base(s), independently and individually, and not the sum thereof. 
     Phosphate, bicarbonate, bicarbonate equivalents, the conjugate bases of bile and fatty acids are potential interfering anions for chloride or other conjugate bases of strong acids (e.g., HSO 4   −  and SO 4   2− ) in the stomach and small intestine. Therefore, rapid and preferential binding of chloride over phosphate, bicarbonate equivalents, and the conjugate bases of bile and fatty acids in the small intestine is desirable and the SIB assay may be used to determine kinetics and preferential binding. Since the transit time of the colon is slow (2-3 days) relative to the small intestine, and since conditions in the colon will not be encountered by an orally administered nonabsorbable composition until after stomach and small intestine conditions have been encountered, kinetics of chloride binding by a nonabsorbable composition do not need to be as rapid in the colon or under in vitro conditions designed to mimic the late small intestine/colon. It is, however, desirable that chloride binding and selectivity over other interfering anions is high, for example, at 24 and/or 48 hours or longer. 
     In one embodiment, the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 1 mEq/g in a Simulated Small Intestine Inorganic Buffer (“SIB”) assay. For example, in one such embodiment the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 1.5 mEq/g in a SIB assay. By way of further example, in one such embodiment the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 2 mEq/g in a SIB assay. By way of further example, in one such embodiment the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 2.5 mEq/g in a SIB assay. By way of further example, in one such embodiment the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 3 mEq/g in a SIB assay. By way of further example, in one such embodiment the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 3.5 mEq/g in a SIB assay. By way of further example, in one such embodiment the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 4 mEq/g in a SIB assay. By way of further example, in one such embodiment the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 4.5 mEq/g in a SIB assay. By way of further example, in one such embodiment the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 5 mEq/g in a SIB assay. By way of further example, in one such embodiment the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 5.5 mEq/g in a SIB assay. By way of further example, in one such embodiment the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 6 mEq/g in a SIB assay. 
     In one embodiment, the nonabsorbable composition binds a significant amount of chloride relative to phosphate as exhibited, for example, in a SIB assay. For example, in one embodiment the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.1:1, respectively. By way of further example, in one such embodiment the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.2:1, respectively. By way of further example, in one such embodiment the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.25:1, respectively. By way of further example, in one such embodiment the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.3:1, respectively. By way of further example, in one such embodiment the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.35:1, respectively. By way of further example, in one such embodiment the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.4:1, respectively. By way of further example, in one such embodiment the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.45:1, respectively. By way of further example, in one such embodiment the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.5:1, respectively. By way of further example, in one such embodiment the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 2:3, respectively. By way of further example, in one such embodiment the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.75:1, respectively. By way of further example, in one such embodiment the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.9:1, respectively. By way of further example, in one such embodiment the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 1:1, respectively. By way of further example, in one such embodiment the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 1.25:1, respectively. By way of further example, in one such embodiment the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 1.5:1, respectively. By way of further example, in one such embodiment the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 1.75:1, respectively. By way of further example, in one such embodiment the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 2:1, respectively. By way of further example, in one such embodiment the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 2.25:1, respectively. By way of further example, in one such embodiment the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 2.5:1, respectively. By way of further example, in one such embodiment the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 2.75:1, respectively. By way of further example, in one such embodiment the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 3:1, respectively. By way of further example, in one such embodiment the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 4:1, respectively. By way of further example, in one such embodiment the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 5:1, respectively. 
     In one embodiment, the orally administered nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in Simulated Gastric Fluid of at least 1 mEq/g in a SGF assay. For example, in one such embodiment the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 2 mEq/g. By way of further example, in one such embodiment the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 3 mEq/g. By way of further example, in one such embodiment the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 4 mEq/g. By way of further example, in one such embodiment the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 5 mEq/g. By way of further example, in one such embodiment the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 6 mEq/g. By way of further example, in one such embodiment the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 7 mEq/g. By way of further example, in one such embodiment the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 8 mEq/g. By way of further example, in one such embodiment the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 9 mEq/g. By way of further example, in one such embodiment the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 10 mEq/g. By way of further example, in one such embodiment the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 11 mEq/g. By way of further example, in one such embodiment the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 12 mEq/g. By way of further example, in one such embodiment the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 13 mEq/g. By way of further example, in one such embodiment the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity in a SGF assay of at least 14 mEq/g. By way of further example, in one such embodiment the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity after 1 hour in SGF that is at least 50% of the proton-binding capacity and the chloride binding capacity, respectively, of the nonabsorbable composition at 24 hours in SGF. By way of further example, in one such embodiment the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity after 1 hour in SGF that is at least 60% of the proton-binding capacity and the chloride binding capacity, respectively, of the nonabsorbable composition at 24 hours in SGF. By way of further example, in one such embodiment the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity after 1 hour in SGF that is at least 70% of the proton-binding capacity and the chloride binding capacity, respectively, of the nonabsorbable composition at 24 hours in SGF. By way of further example, in one such embodiment the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity after 1 hour in SGF that is at least 80% of the proton-binding capacity and the chloride binding capacity, respectively, of the nonabsorbable composition at 24 hours in SGF. By way of further example, in one such embodiment the nonabsorbable composition is characterized by a proton-binding capacity and a chloride binding capacity after 1 hour in SGF that is at least 90% of the proton-binding capacity and the chloride binding capacity, respectively, of the nonabsorbable composition at 24 hours in SGF. 
     In one embodiment, the nonabsorbable composition is a cation exchange material comprising an insoluble (in the gastric environment) support structure and exchangeable cations. The cation exchange material may be organic (e.g., polymeric), inorganic (e.g., a zeolite) or a composite thereof. The exchangeable cations may be selected, for example, from the group consisting of lithium, sodium, potassium, calcium, magnesium, iron and combinations thereof, and more preferably from the group consisting of sodium, potassium, calcium, magnesium, and combinations thereof. In such embodiments it is generally preferred that the nonabsorbable composition contain a combination of exchangeable cations that establish or maintain electrolyte homeostasis. For example, in one such embodiment the nonabsorbable composition optionally contains exchangeable sodium ions, but when included, the amount of the sodium ions in a daily dose is insufficient to increase the patient&#39;s serum sodium ion concentration to a value outside the range of 135 to 145 mEq/l. By way of further example, in one such embodiment the nonabsorbable composition optionally contains exchangeable potassium ions, but when included, the amount of the potassium ions in a daily dose is insufficient to increase the patient&#39;s serum potassium ion concentration to a value outside the range of 3.7 to 5.2 mEq/L. By way of further example, in one such embodiment the nonabsorbable composition optionally contains exchangeable magnesium ions, but when included, the amount of the magnesium ions in a daily dose is insufficient to increase the patient&#39;s serum magnesium ion concentration to a value outside the range of 1.7 to 2.2 mg/dL. By way of further example, in one such embodiment the nonabsorbable composition optionally contains exchangeable calcium ions, but when included, the amount of the calcium ions in a daily dose is insufficient to increase the patient&#39;s serum calcium ion concentration to a value outside the range of 8.5 to 10.2 mg/dL. By way of further example, in one such embodiment the nonabsorbable composition contains a combination of exchangeable cations selected from the group consisting of sodium, potassium, calcium, magnesium, and combinations thereof, designed to maintain serum Na +  levels within the range of 135 to 145 mEq/l, serum K +  levels within the range of 3.7 to 5.2 mEq/L, serum Mg 2+  levels within the range of 1.7 to 2.2 mg/dL and serum Ca 2+  levels within the range of 8.5 to 10.2 mg/dL. 
     In one embodiment, the nonabsorbable composition is a cation exchange material comprising an insoluble (in the gastric environment) support structure, optionally containing exchangeable sodium ions cations. The cation exchange material may be organic (e.g., polymeric), inorganic (e.g., a molecular sieve) or a composite thereof. In one such embodiment, the nonabsorbable composition contains less than 12% by weight sodium. For example, in one such embodiment the nonabsorbable composition contains less than 9% by weight sodium. By way of further example, in one such embodiment the nonabsorbable composition contains less than 6% by weight sodium. By way of further example, in one such embodiment the nonabsorbable composition contains less than 3% by weight sodium. By way of further example, in one such embodiment the nonabsorbable composition contains less than 1% by weight sodium. By way of further example, in one such embodiment the nonabsorbable composition contains less than 0.1% by weight sodium. By way of further example, in one such embodiment the nonabsorbable composition contains less than 0.01% by weight sodium. By way of further example, in one such embodiment the nonabsorbable composition contains between 0.05 and 3% by weight sodium. 
     In one exemplary embodiment, the nonabsorbable composition is a resin comprising any of a wide range of crosslinked polymeric materials that are able to bind protons in aqueous solutions. Exemplary crosslinked polymeric material comprises a polyanion crosslinked material selected from poly(carboxylic acids), poly(acrylic acids), poly(sulfonic acids), poly(maleic acids), poly(phenols), functionalized polyols and poly(alcohols), poly(hydroxamic acids), poly(imides) and copolymers thereof. In one embodiment, the polyanion is coordinated to exchangeable monovalent cations, divalent cations, or a combination thereof. Exemplary monovalent cations include lithium, sodium, and potassium, or any combination thereof. Exemplary divalent cations include magnesium and calcium or combinations thereof. 
     In one exemplary embodiment, the nonabsorbable composition is a cation exchange resin comprising a polyanion backbone that exchanges cations for protons and has an average pKa of at least 4. For example, in one embodiment, the polyanion backbone has an average pKa of 4-5. By way of further example, in one such embodiment the polyanion backbone has an average pKa of 5-6. By way of further example, in one such embodiment the polyanion backbone has an average pKa of 6-7. By way of further example, in one such embodiment the polyanion backbone has an average pKa of greater than 7. Exemplary cation exchange resins include poly(carboxylic acids), poly(acrylic acids), poly(sulfonic acids), poly(maleic acids), poly(phenols), functionalized polyols and poly(alcohols), poly(hydroxamic acids), poly(imides) and copolymers thereof. In one embodiment, these polyanion backbones are further functionalized with functional groups to affect the pKa. These functional groups can increase pKa when electron donating, or decrease pKa when electron withdrawing. Exemplary electron donating groups include amino, hydroxyl, methyl ether, ether, phenyl, and amido. Exemplary electron withdrawing groups include fluoro, chloro, halo, sulphonyl, nitroxyl, trifluoromethyl, and cyano. Further exemplary cation exchange resins include resins modified with protonable functional groups including carboxylic acids and functionalized alcohols. 
     Polymeric cation exchanger resins may be prepared using a range of chemistries, including for example, (i) substitution polymerization of polyfunctional reagents at least one of which comprises basic anionic or conjugate-acid moieties, (2) radical polymerization of a monomer comprising at least one acid or conjugate-acid containing moiety, and (3) crosslinking of a basic anionic or conjugate-acid containing intermediate with a polyfunctional crosslinker, optionally containing basic anionic or conjugate-acid moieties. The resulting crosslinked polymers may thus, for example, be crosslinked homopolymers or crosslinked copolymers. By way of further example, the resulting crosslinked polymers will typically possess repeat units comprising basic anionic or conjugate-acid, separated by the same or varying lengths of repeating linker (or intervening) units. In some embodiments, the polymers comprise repeat units comprising a basic anionic or conjugate-acid moiety and an intervening linker unit. In other embodiments, multiple basic anionic or conjugate-acid containing repeat units are separated by one or more linker units. Additionally, the polyfunctional crosslinkers may comprise proton binding functional groups, e.g. basic anionic, (“active crosslinkers”) or may lack proton binding functional groups such as acrylates (“passive crosslinkers”). 
     In some embodiments, a basic anion or conjugate-acid monomer is polymerized and the polymer is concurrently crosslinked in a substitution polymerization reaction. The basic anion or conjugate-acid reactant (monomer) in the concurrent polymerization and crosslinking reaction can react more than one time for the substitution polymerization. In one such embodiment, the basic anion or conjugate-acid monomer is a branched basic anion or conjugate-acid possessing at least two reactive moieties to participate in the substitution polymerization reaction. 
     In one embodiment, the nonabsorbable composition comprises a cation exchange ceramic material. Porous inorganic binders exhibit a range of properties. Functionally, they are able to sequester materials on the basis of their size and polarity, as they exhibit a framework charge with porous structure. They are structurally diverse and can be crystalline or non-crystalline crystalline (amorphous). Classes of porous materials that fall under the class of inorganic binders include hydrous oxides (e.g., aluminum oxide) and metal alumino-silicate compounds where the metal can be an alkali or alkali earth metal such sodium, potassium, lithium, magnesium or calcium. Many of these compounds have well-defined crystalline structures. This class of compounds has been used for various biopharmaceutical applications. 
     The pore diameters of inorganic microporous and mesoporous materials are measured in ångströms (Å) or nanometers (nm). According to IUPAC notation, microporous materials have pore diameters of less than 2 nm (20 Å) and macroporous materials have pore diameters of greater than 50 nm (500 Å); the mesoporous category thus lies in the middle with pore diameters between 2 and 50 nm (20-500 Å). The porosity of inorganic porous materials can be tuned or designed, by the appropriate use of poragen or “co-monomer metals” within the lattices of the porous material. By the appropriate choice of elements, the pore size has been seen to range in size from 3 Å to 8 Å. These compositions have a porous system allowing solute together with other dissolved species to enter the porous framework of the material, resulting in absorption of the dissolved species. Tuning the cavities and pore size of the materials, can allow adsorption of molecules of particular dimensions, while rejecting those of larger dimensions. From a binding perspective using size as a selectivity mechanism the chloride ion has the advantage of its small size (the radius of chloride anion is 1.8 Å, and the molecular weight of chloride anion is 35.5) compared to the other species present in the digestive tract. 
     
       
         
           
               
               
             
               
                   
               
               
                 Molecules absorbed  
                 Molecules excluded  
               
               
                 (small, polar organic  
                 (large, non polar and  
               
               
                 or inorganic) 
                 high molecular weight) 
               
               
                   
               
             
            
               
                 Water  
                 Bile acids  
               
               
                 (Solubility in water;  
                 (Solubility in water;  
               
               
                 miscible, Mw 18) 
                 0.24%, Mw 392.5) 
               
               
                 HCl 
                 Phosphoric acid  
               
               
                 (Soluble in water  
                 (Solubility in water;  
               
               
                 (38%), Mw 36.5) 
                 miscible, Mw 98.0) 
               
               
                 Acetic acid  
                 Fatty acids  
               
               
                 (Solubility in water;  
                 (Solubility in water,  
               
               
                 miscible, Mw 60.0) 
                 non miscible,, Mw &gt; 200 
               
               
                   
               
            
           
         
       
     
     Exemplary cation exchange ceramic materials include any of a wide range of microporous or mesoporous ceramic materials. In one embodiment, the nonabsorbable composition comprises a molecular sieve, such as a molecular sieve selected from the group consisting of silica, titanosilicate, metalloaluminate, aluminophosphate and gallogerminate molecular sieves. In one embodiment, the nonabsorbable composition comprises a zeolite, a borosilicate, a gallosilicate, a ferrisilicate or a chromosilicate molecular sieve. 
     Inorganic porous materials exhibit the property of sequestering substances from an external environment. The mechanism to bind proton or chloride or HCl can be either an adsorptive or absorptive mechanism, where the ions are bound via the specific porosity of the matrix, or an ion exchange mechanism. The strong adsorptive force in zeolite molecular sieves are due to the polarity of the surface (hydroxyl metalloid) and cations that are exposed within the crystal lattice. The cations on the surface act as a site of strong localized positive charge that electrostatically attract the partial negative charges of polar molecules (for example, the chloride of HCl). A basic formula for zeolite can be represented by, M 2/n O.Al 2 O 3 .xSiO 2 .yH 2 O where M is a cation of n valence. The fundamental building block of the molecular sieve structure is tetrahedral with 4 oxygen anions surrounding a silicon or alumina cation. Sodium ions or other cations (e.g. potassium, calcium) make up the positive charge deficit of the alumina tetrahedron to extend the crystal lattice. In many molecular sieve types the sodium can be exchanged or the sodium can function as a permanent positive charge within the crystal lattice thus providing the electrostatic interaction. Given these mechanisms, hydrochloric acid can be sequestered from solution via a cation exchange mechanism (sodium for proton), anion exchange mechanism (hydroxide for chloride), or via electrostatic interaction of the hydrochloric acid ionic species. 
     The methods used to bind HCl are well known in the art and involve contacting the molecular sieve with a solution containing the desired HCl concentration in water. Exchange conditions include a temperature of about 25° C. to about 100° C., and a time of about 20 minutes to about 2 hours. These conditions include conditions and exposure times encountered in the gastrointestinal tract. 
     In one embodiment, the nonabsorbable composition is an anion exchange material comprising an insoluble (in the gastric environment) support structure and exchangeable anions. The anion exchange material may be organic (e.g., polymeric), inorganic (e.g., an apatite, hydrotalcite or a hydrated gel of aluminum, iron(III) or zirconium hydroxide) or a composite thereof. 
     In one embodiment, the nonabsorbable composition comprises an anion exchange material. Exemplary anion exchange materials include strongly and weakly basic anion exchange materials. For example, the anion exchange material may include any of a wide range of polymers comprising quaternary amine moieties, phosphonium salts, N-heteroaromatic salts, or combinations thereof. Other exemplary anion exchange materials include poly(ionic liquids), wherein the side chain is selected from the group consisting of salts of tetraalkyl ammonium, imidazolium, pyridinium, pyrrolidonium, guanidinium, piperidinium, and tetraalkyl phosphonium cations and combinations thereof. By way of further example, in one such embodiment the anion exchange material is a halide responsive polymer such that a conformational change occurs when about 1 mEq/g to about 35 mEq/g of chloride is initially bound to the polymer and subsequently retained for the duration of the GI transit time. In certain embodiments, the halide response conformational change occurs when 2 mEq/g to about 25 mEq/g chloride is bound, and in certain more specific embodiments, the halide response conformational change occurs when 3 to 25 mEq/g, 5 to 25 mEq/g, 10 to 25 mEq/g, 5 to 20 mEq/g, 6 to 20 mEq/g, 7.5 to 20 mEq/g, or even 10 to 20 mEq/g chloride is bound. The polymeric backbone of any of the aforementioned polymers can derive from vinyl, allyl, styrenic, acrylamide, meth(acrylamide), or copolymers thereof. By way of further example, the anion exchange functionality may be incorporated into the backbone of the polymer. Examples include poly(tetraalkyl ammonium), poly(imidazolium), poly(pyridinium), poly(pyrrolidonium), poly(piperidinium), and poly(tetraalkyl phosphonium) cations or combinations thereof. The exchangeable anion can consist of hydroxide, bicarbonate, acetate, nitrate or any pharmaceutically and biologically acceptable base or combination thereof. 
     In one embodiment, the nonabsorbable composition is an anion exchange material comprising at least 1 mEq/g of an anion selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anion, or a combination thereof. In this embodiment, the nonabsorbable composition has the capacity to induce an increase in the individual&#39;s serum bicarbonate value, at least in part, by delivering a physiologically significant amount of hydroxide, carbonate, citrate or other bicarbonate equivalent, or a combination thereof. Exemplary bicarbonate equivalent anions include acetate, lactate and the conjugate bases of other short chain carboxylic acids. In one such embodiment, the nonabsorbable composition comprises at least 2 mEq/g of an anion selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anion. By way of further example, in one such embodiment the nonabsorbable composition comprises at least 3 mEq/g of an anion selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anion. By way of further example, in one such embodiment the nonabsorbable composition comprises at least 4 mEq/g of an anion selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anion. By way of further example, in one such embodiment the nonabsorbable composition comprises at least 5 mEq/g of an anion selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anion. 
     In one embodiment, the nonabsorbable composition is an anion exchange material comprising less than 10 mEq/g of an anion selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anion, or a combination thereof. In one such embodiment, the nonabsorbable composition comprises less than 7.5 mEq/g of an anion selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anion. By way of further example, in one such embodiment the nonabsorbable composition comprises less than 5 mEq/g of an anion selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anion. By way of further example, in one such embodiment the nonabsorbable composition comprises less than 2.5 mEq/g of an anion selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anion. By way of further example, in one such embodiment the nonabsorbable composition comprises less than 1 mEq/g of an anion selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anion. By way of further example, in one such embodiment the nonabsorbable composition comprises less than 0.1 mEq/g of an anion selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anion. 
     In one embodiment, the nonabsorbable composition comprises an amphoteric ion exchange resin. Exemplary amphoteric ion-exchange resins include crosslinked polystyrene, polyethylene or the like as a base material and quaternary ammonium group, carboxylic acid group and the like in (i) the same pendant groups (e.g., betaine-containing pendant groups) such as the amphoteric resin sold under the trade designation DIAION AMP03 (Mitsubishi Chemical Corporation) or (ii) different pendant groups (e.g., mixed charged copolymers containing the residues of at least two different monomers, one containing ammonium groups and one containing carboxylic acid groups), to provide a function of ion-exchanging the both of cations and negative ions. Exemplary amphoteric ion-exchange resins containing a mixture of cation and anion exchange sites also include resins in which a linear polymer is trapped inside a crosslinked ion exchange resin, such as the amphoteric resin sold under the trade designation DOWEX™ Retardion 11A8 (Dow Chemical Company). 
     In one embodiment, the nonabsorbable composition comprises a neutral composition having the capacity to bind both protons and anions. Exemplary neutral nonabsorbable compositions that bind both protons and anions include polymers functionalized with propylene oxide, polymers functionalized with Michael acceptors, expanded porphyrins, covalent organic frameworks, and polymers containing amine and/or phosphine functional groups. 
     In those embodiments in which the nonabsorbable composition binds chloride ions, it is generally preferred that the nonabsorbable composition selectively bind chloride ions relative to other counter ions such as bicarbonate equivalent anions, phosphate anions, and the conjugate bases of bile and fatty acids. Stated differently, it is generally preferred in these embodiments that the nonabsorbable composition (i) remove more chloride ions than bicarbonate equivalent anions (ii) remove more chloride ions than phosphate anions, and (iii) remove more chloride ions than the conjugate bases of bile and fatty acids. Advantageously, therefore, treatment with the nonabsorbable composition does not induce or exacerbate hypophosphatemia (i.e., a serum phosphorous concentration of less than about 2.4 mg/dL, does not significantly elevate low density lipoproteins (“LDL”), or otherwise negatively impact serum or colon levels of metabolically relevant anions. 
     In some embodiments, the pharmaceutical composition comprises a crosslinked polymer containing the residue of an amine corresponding to Formula 1: 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2  and R 3  are independently hydrogen, hydrocarbyl, substituted hydrocarbyl provided, however, at least one of R 1 , R 2  and R 3  is other than hydrogen. Stated differently, at least one of R 1 , R 2  and R 3  is hydrocarbyl or substituted hydrocarbyl, and the others of R 1 , R 2  and R 3  are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl. In one embodiment, for example, R 1 , R 2  and R 3  are independently hydrogen, aryl, aliphatic, heteroaryl, or heteroaliphatic provided, however, each of R 1 , R 2  and R 3  are not hydrogen. By way of further example, in one such embodiment R 1 , R 2  and R 3  are independently hydrogen, saturated hydrocarbons, unsaturated aliphatic, unsaturated heteroaliphatic, heteroalkyl, heterocyclic, aryl or heteroaryl, provided, however, each of R 1 , R 2  and R 3  are not hydrogen. By way of further example, in one such embodiment R 1 , R 2  and R 3  are independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ethereal, heteroaryl or heterocyclic provided, however, each of R 1 , R 2  and R 3  are not hydrogen. By way of further example, in one such embodiment R 1 , R 2  and R 3  are independently hydrogen, alkyl, aminoalkyl, alkanol, aryl, haloalkyl, hydroxyalkyl, ethereal, heteroaryl or heterocyclic provided, however, each of R 1 , R 2  and R 3  are not hydrogen. By way of further example, in one such embodiment R 1  and R 2  (in combination with the nitrogen atom to which they are attached) together constitute part of a ring structure, so that the monomer as described by Formula 1 is a nitrogen-containing heterocycle (e.g., piperidine) and R 3  is hydrogen, or heteroaliphatic. By way of further example, in one embodiment R 1 , R 2  and R 3  are independently hydrogen, aliphatic or heteroaliphatic provided, however, at least one of R 1 , R 2  and R 3  is other than hydrogen. By way of further example, in one embodiment R 1 , R 2  and R 3  are independently hydrogen, allyl, or aminoalkyl. 
     In one embodiment, the crosslinked polymer comprises the residue of an amine corresponding to Formula 1 wherein R 1 , R 2 , and R 3  are independently hydrogen, heteroaryl, aryl, aliphatic or heteroaliphatic provided, however, at least one of R 1 , R 2 , and R 3  is aryl or heteroaryl. For example, in this embodiment R 1  and R 2 , in combination with the nitrogen atom to which they are attached, may form a saturated or unsaturated nitrogen-containing heterocyclic ring. By way of further example, R 1  and R 2 , in combination with the nitrogen atom to which they are attached may constitute part of a pyrrolidino, pyrole, pyrazolidine, pyrazole, imidazolidine, imidazole, piperidine, pyridine, piperazine, diazine, or triazine ring structure. By way of further example, R 1  and R 2 , in combination with the nitrogen atom to which they are attached may constitute part of a piperidine ring structure. 
     In one embodiment, the crosslinked polymer comprises the residue of an amine corresponding to Formula 1 wherein R 1 , R 2 , and R 3  are independently hydrogen, aliphatic, or heteroaliphatic provided, however, at least one of R 1 , R 2 , and R 3  is other than hydrogen. For example, in this embodiment R 1 , R 2 , and R 3  may independently be hydrogen, alkyl, alkenyl, allyl, vinyl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ethereal, or heterocyclic provided, however, at least one of R 1 , R 2 , and R 3  is other than hydrogen. By way of further example, in one such embodiment R 1  and R 2 , in combination with the nitrogen atom to which they are attached, may form a saturated or unsaturated nitrogen-containing heterocyclic ring. By way of further example, in one such embodiment R 1  and R 2 , in combination with the nitrogen atom to which they are attached may constitute part of a pyrrolidino, pyrole, pyrazolidine, pyrazole, imidazolidine, imidazole, piperidine, piperazine, or diazine ring structure. By way of further example, in one such embodiment R 1  and R 2 , in combination with the nitrogen atom to which they are attached may constitute part of a piperidine ring structure. By way of further example, in one such embodiment the amine corresponding to Formula 1 is acyclic and at least one of R 1 , R 2 , and R 3  is aliphatic or heteroaliphatic. By way of further example, in one such embodiment R 1 , R 2 , and R 3  are independently hydrogen, alkyl, allyl, vinyl, alicyclic, aminoalkyl, alkanol, or heterocyclic, provided at least one of R 1 , R 2 , and R 3  is other than hydrogen. 
     In one embodiment, the crosslinked polymer comprises the residue of an amine corresponding to Formula 1 and the crosslinked polymer is prepared by substitution polymerization of the amine corresponding to Formula 1 with a polyfunctional crosslinker (optionally also comprising amine moieties) wherein R 1 , R 2 , and R 3  are independently hydrogen, alkyl, aminoalkyl, or alkanol, provided at least one of R 1 , R 2 , and R 3  is other than hydrogen. 
     In some embodiments, the molecular weight per nitrogen of the polymers of the present disclosure may range from about 40 to about 1000 Daltons. In one embodiment, the molecular weight per nitrogen of the polymer is from about 40 to about 500 Daltons. In another embodiment, the molecular weight per nitrogen of the polymer is from about 50 to about 170 Daltons. In another embodiment, the molecular weight per nitrogen of the polymer is from about 60 to about 110 Daltons. 
     In some embodiments, an amine-containing monomer is polymerized and the polymer is concurrently crosslinked in a substitution polymerization reaction in the first reaction step. The amine reactant (monomer) in the concurrent polymerization and crosslinking reaction can react more than one time for the substitution polymerization. In one such embodiment, the amine monomer is a linear amine possessing at least two reactive amine moieties to participate in the substitution polymerization reaction. In another embodiment, the amine monomer is a branched amine possessing at least two reactive amine moieties to participate in the substitution polymerization reaction. Crosslinkers for the concurrent substitution polymerization and crosslinking typically have at least two amine-reactive moieties such as alkyl-chlorides, and alkyl-epoxides. In order to be incorporated into the polymer, primary amines react at least once and potentially may react up to three times with the crosslinker, secondary amines can react up to twice with the crosslinkers, and tertiary amines can only react once with the crosslinker. In general, however, the formation of a significant number of quaternary nitrogens/amines is generally not preferred because quaternary amines cannot bind protons. 
     Exemplary amines that may be used in substitution polymerization reactions described herein include 1,3-Bis[bis(2-aminoethyl)amino]propane, 3-Amino-1-{[2-(bis{2-[bis(3-aminopropyl)amino]ethyl}amino)ethyl](3-aminopropyl)amino}propane, 2-[Bis(2-aminoethyl)amino]ethanamine, Tris(3-aminopropyl)amine, 1,4-Bis[bis(3-aminopropyl)amino]butane, 1,2-Ethanediamine, 2-Amino-1-(2-aminoethylamino)ethane, 1,2-Bis(2-aminoethylamino)ethane, 1,3-Propanediamine, 3,3′-Diaminodipropylamine, 2,2-dimethyl-1,3-propanediamine, 2-methyl-1,3-propanediamine, N,N′-dimethyl-1,3-propanediamine, N-methyl-1,3-diaminopropane, 3,3′-diamino-N-methyldipropylamine, 1,3-diaminopentane, 1,2-diamino-2-methylpropane, 2-methyl-1,5-diaminopentane, 1,2-diaminopropane, 1,10-diaminodecane, 1,8-diaminooctane, 1,9-diaminooctane, 1,7-diaminoheptane, 1,6-diaminohexane, 1,5-diaminopentane, 3-bromopropylamine hydrobromide, N,2-dimethyl-1,3-propanediamine, N-isopropyl-1,3-diaminopropane, N,N′-bis(2-aminoethyl)-1,3-propanediamine, N,N′-bis(3-aminopropyl)ethylenediamine, N,N′-bis(3-aminopropyl)-1,4-butanediamine tetrahydrochloride, 1,3-diamino-2-propanol, N-ethylethylenediamine, 2,2′-diamino-N-methyldiethylamine, N,N′-diethylethylenediamine, N-isopropylethylenediamine, N-methylethylenediamine, N,N′-di-tert-butylethylenediamine, N,N′-diisopropylethylenediamine, N,N′-dimethylethylenediamine, N-butylethylenediamine, 2-(2-aminoethylamino)ethanol, 1,4,7,10,13,16-hexaazacyclooctadecane, 1,4,7,10-tetraazacyclododecane, 1,4,7-triazacyclononane, N,N′-bis(2-hydroxyethyl)ethylenediamine, piperazine, bis(hexamethylene)triamine, N-(3-hydroxypropyl)ethylenediamine, N-(2-Aminoethyl)piperazine, 2-Methylpiperazine, Homopiperazine, 1,4,8,11-Tetraazacyclotetradecane, 1,4,8,12-Tetraazacyclopentadecane, 2-(Aminomethyl)piperidine, 3-(Methylamino)pyrrolidine 
     Exemplary crosslinking agents that may be used in substitution polymerization reactions and post-polymerization crosslinking reactions include, but are not limited to, one or more multifunctional crosslinking agents such as: dihaloalkanes, haloalkyloxiranes, alkyloxirane sulfonates, di(haloalkyl)amines, tri(haloalkyl) amines, diepoxides, triepoxides, tetraepoxides, bis (halomethyl)benzenes, tri(halomethyl)benzenes, tetra(halomethyl)benzenes, epihalohydrins such as epichlorohydrin and epibromohydrin poly(epichlorohydrin), (iodomethyl)oxirane, glycidyl tosylate, glycidyl 3-nitrobenzenesulfonate, 4-tosyloxy-1,2-epoxybutane, bromo-1,2-epoxybutane, 1,2-dibromoethane, 1,3-dichloropropane, 1,2-dichloroethane, 1-bromo-2-chloroethane, 1,3-dibromopropane, bis(2-chloroethyl)amine, tris(2-chloroethyl)amine, and bis(2-chloroethyl)methylamine, 1,3-butadiene diepoxide, 1,5-hexadiene diepoxide, diglycidyl ether, 1,2,7,8-diepoxyoctane, 1,2,9,10-diepoxydecane, ethylene glycol diglycidyl ether, propylene glycol diglycidyl ether, 1,4-butanediol diglycidyl ether, 1,2 ethanedioldiglycidyl ether, glycerol diglycidyl ether, 1,3-diglycidyl glyceryl ether, N,N-diglycidylaniline, neopentyl glycol diglycidyl ether, diethylene glycol diglycidyl ether, 1,4-bis(glycidyloxy)benzene, resorcinol digylcidyl ether, 1,6-hexanediol diglycidyl ether, trimethylolpropane diglycidyl ether, 1,4-cyclohexanedimethanol diglycidyl ether, 1,3-bis-(2,3-epoxypropyloxy)-2-(2,3-dihydroxypropyloxy)propane, 1,2-cyclohexanedicarboxylic acid diglycidyl ester, 2,2′-bis(glycidyloxy) diphenylmethane, bisphenol F diglycidyl ether, 1,4-bis(2′,3′epoxypropyl)perfluoro-n-butane, 2,6-di(oxiran-2-ylmethyl)-1,2,3,5,6,7-hexahydropyrrolo[3,4-f]isoindol-1,3,5,7-tetraone, bisphenol A diglycidyl ether, ethyl 5-hydroxy-6,8-di(oxiran-2-ylmethyl)-4-oxo-4-h-chromene-2-carboxylate, bis[4-(2,3-epoxy-propylthio)phenyl]-sulfide, 1,3-bis(3-glycidoxypropyl) tetramethyldisiloxane, 9,9-bis[4-(glycidyloxy)phenyl]fluorine, triepoxyisocyanurate, glycerol triglycidyl ether, N,N-diglycidyl-4-glycidyloxyaniline, isocyanuric acid (S,S,S)-triglycidyl ester, isocyanuric acid (R,R,R)-triglycidyl ester, triglycidyl isocyanurate, trimethylolpropane triglycidyl ether, glycerol propoxylate triglycidyl ether, triphenylolmethane triglycidyl ether, 3,7,14-tris[[3-(epoxypropoxy)propyl]dimethylsilyloxy]-1,3,5,7,9,11,14-heptacyclopentyltricyclo [7,3,3,15,11]heptasiloxane, 4,4′methylenebis(N,N-diglycidylaniline), bis(halomethyl)benzene, bis(halomethyl)biphenyl and bis(halomethyl)naphthalene, toluene diisocyanate, acrylol chloride, methyl acrylate, ethylene bisacrylamide, pyrometallic dianhydride, succinyl dichloride, dimethylsuccinate, 3-chloro-1-(3-chloropropylamino-2-propanol, 1,2-bis(3-chloropropylamino)ethane, Bis(3-chloropropyl)amine, 1,3-Dichloro-2-propanol, 1,3-Dichloropropane, 1-chloro-2,3-epoxypropane, tris[(2-oxiranyl)methyl]amine. 
     In some embodiments, the carbon to nitrogen ratio of the polymers of the present disclosure may range from about 2:1 to about 6:1, respectively. For example, in one such embodiment, the carbon to nitrogen ratio of the polymers of the present disclosure may range from about 2.5:1 to about 5:1, respectively. By way of further example, in one such embodiment, the carbon to nitrogen ratio of the polymers of the present disclosure may range from about 3:1 to about 4.5:1, respectively. By way of further example, in one such embodiment, the carbon to nitrogen ratio of the polymers of the present disclosure may range from about 3.25:1 to about 4.25:1, respectively. By way of further example, in one such embodiment, the carbon to nitrogen ratio of the polymers of the present disclosure may range from about 3.4:1 to about 4:1, respectively. In another embodiment, the molecular weight per nitrogen of the polymer is from about 60 to about 110 Daltons. 
     In some embodiments, the crosslinked polymer comprises the residue of an amine corresponding to Formula 1a and the crosslinked polymer is prepared by radical polymerization of an amine corresponding to Formula 1a: 
     
       
         
         
             
             
         
       
     
     wherein R 4  and R 5  are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl. In one embodiment, for example, R 4  and R 5  are independently hydrogen, saturated hydrocarbon, unsaturated aliphatic, aryl, heteroaryl, unsaturated heteroaliphatic, heterocyclic, or heteroalkyl. By way of further example, in one such embodiment R 4  and R 5  are independently hydrogen, aliphatic, heteroaliphatic, aryl, or heteroaryl. By way of further example, in one such embodiment R 4  and R 5  are independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ethereal, heteroaryl or heterocyclic. By way of further example, in one such embodiment R 4  and R 5  are independently hydrogen, alkyl, allyl, aminoalkyl, alkanol, aryl, haloalkyl, hydroxyalkyl, ethereal, or heterocyclic. By way of further example, in one such embodiment R 4  and R 5  (in combination with the nitrogen atom to which they are attached) together constitute part of a ring structure, so that the monomer as described by Formula 1a is a nitrogen-containing heterocycle (e.g., piperidine). By way of further example, in one embodiment R 4  and R 5  are independently hydrogen, aliphatic or heteroaliphatic. By way of further example, in one embodiment R 4  and R 5  are independently hydrogen, allyl, or aminoalkyl. 
     In some embodiments, the crosslinked polymer comprises the residue of an amine corresponding to Formula 1b and the crosslinked polymer is prepared by substitution polymerization of the amine corresponding to Formula 1b with a polyfunctional crosslinker (optionally also comprising amine moieties): 
     
       
         
         
             
             
         
       
     
     wherein R 4  and R 5  are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl, R 6  is aliphatic and R 61  and R 62  are independently hydrogen, aliphatic, or heteroaliphatic. In one embodiment, for example, R 4  and R 5  are independently hydrogen, saturated hydrocarbon, unsaturated aliphatic, aryl, heteroaryl, heteroalkyl, or unsaturated heteroaliphatic. By way of further example, in one such embodiment R 4  and R 5  are independently hydrogen, aliphatic, heteroaliphatic, aryl, or heteroaryl. By way of further example, in one such embodiment R 4  and R 5  are independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ethereal, heteroaryl or heterocyclic. By way of further example, in one such embodiment R 4  and R 5  are independently hydrogen, alkyl, alkenyl, aminoalkyl, alkanol, aryl, haloalkyl, hydroxyalkyl, ethereal, heteroaryl or heterocyclic. By way of further example, in one such embodiment R 4  and R 5  (in combination with the nitrogen atom to which they are attached) together constitute part of a ring structure, so that the monomer as described by Formula 1a is a nitrogen-containing heterocycle (e.g., piperidine). By way of further example, in one embodiment R 4  and R 5  are independently hydrogen, aliphatic or heteroaliphatic. By way of further example, in one embodiment R 4  and R 5  are independently hydrogen, allyl, or aminoalkyl. By way of further example, in each of the embodiments recited in this paragraph, R 6  may be methylene, ethylene or propylene, and R 61  and R 62  may independently be hydrogen, allyl or aminoalkyl. 
     In some embodiments, the crosslinked polymer comprises the residue of an amine corresponding to Formula 1c: 
     
       
         
         
             
             
         
       
     
     wherein R 7  is hydrogen, aliphatic or heteroaliphatic and R 8  is aliphatic or heteroaliphatic. For example, in one such embodiment, for example, R 7  is hydrogen and R 8  is aliphatic or heteroaliphatic. By way of further example, in one such embodiment R 7  and R 8  are independently aliphatic or heteroaliphatic. By way of further example, in one such embodiment at least one of R 7  and R 8  comprises an allyl moiety. By way of further example, in one such embodiment at least one of R and R 8  comprises an aminoalkyl moiety. By way of further example, in one such embodiment R 7  and R 8  each comprise an allyl moiety. By way of further example, in one such embodiment R 7  and R 8  each comprise an aminoalkyl moiety. By way of further example, in one such embodiment R comprises an allyl moiety and R 8  comprises an aminoalkyl moiety. 
     In some embodiments, the crosslinked polymer comprises the residue of an amine corresponding to Formula 2: 
     
       
         
         
             
             
         
       
     
     wherein 
     m and n are independently non-negative integers; 
     R 10 , R 20 , R 30 , and R 40  are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl; 
     X 1  is 
     
       
         
         
             
             
         
       
     
     X 2  is hydrocarbyl or substituted hydrocarbyl; 
     each X 11  is independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxyl, amino, boronic acid, or halo; and 
     z is a non-negative number. 
     In one embodiment, the crosslinked polymer comprises the residue of an amine corresponding to Formula 2, the crosslinked polymer is prepared by (i) substitution polymerization of the amine corresponding to Formula 2 with a polyfunctional crosslinker (optionally also comprising amine moieties) or (2) radical polymerization of an amine corresponding to Formula 2, and m and n are independently 0, 1, 2 or 3 and n is 0 or 1. 
     In one embodiment, the crosslinked polymer comprises the residue of an amine corresponding to Formula 2, the crosslinked polymer is prepared by (i) substitution polymerization of the amine corresponding to Formula 2 with a polyfunctional crosslinker (optionally also comprising amine moieties) or (2) radical polymerization of an amine corresponding to Formula 2, and R 10 , R 20 , R 30 , and R 40  are independently hydrogen, aliphatic, aryl, heteroaliphatic, or heteroaryl. By way of further example, in one such embodiment R 10 , R 20 , R 30 , and R 40  are independently hydrogen, aliphatic, or heteroaliphatic. By way of further example, in one such embodiment R 10 , R 20 , R 30 , and R 40  are independently hydrogen, alkyl, allyl, vinyl, or aminoalkyl. By way of further example, in one such embodiment R 10 , R 20 , R 30 , and R 40  are independently hydrogen, alkyl, allyl, vinyl, —(CH 2 ) d NH 2 , —(CH 2 ) d N[(CH 2 ) e NH 2 )] 2  where d and e are independently 2-4. In each of the foregoing exemplary embodiments of this paragraph, m and z may independently be 0, 1, 2 or 3 and n is 0 or 1. 
     In one embodiment, the crosslinked polymer comprises the residue of an amine corresponding to Formula 2, the crosslinked polymer is prepared by (i) substitution polymerization of the amine corresponding to Formula 2 with a polyfunctional crosslinker (optionally also comprising amine moieties) or (2) radical polymerization of an amine corresponding to Formula 2, and X 2  is aliphatic or heteroaliphatic. For example, in one such embodiment X 2  is aliphatic or heteroaliphatic and R 10 , R 20 , R 30 , and R 40  are independently hydrogen, aliphatic, heteroaliphatic. By way of further example, in one such embodiment X 2  is alkyl or aminoalkyl and R 10 , R 20 , R 30 , and R 40  are independently hydrogen, aliphatic, or heteroaliphatic. By way of further example, in one such embodiment X 2  is alkyl or aminoalkyl and R 10 , R 20 , R 30 , and R 40  are independently hydrogen, alkyl, allyl, vinyl, or aminoalkyl. In each of the foregoing exemplary embodiments of this paragraph, m and z may independently be 0, 1, 2 or 3 and n is 0 or 1. 
     In one embodiment, the crosslinked polymer comprises the residue of an amine corresponding to Formula 2, the crosslinked polymer is prepared by (i) substitution polymerization of the amine corresponding to Formula 2 with a polyfunctional crosslinker (optionally also comprising amine moieties) or (2) radical polymerization of an amine corresponding to Formula 2, and m is a positive integer. For example, in one such embodiment m is a positive integer, z is zero and R 20  is hydrogen, aliphatic or heteroaliphatic. By way of further example, in one such embodiment m is a positive integer (e.g., 1 to 3), z is a positive integer (e.g., 1 to 2), X 11  is hydrogen, aliphatic or heteroaliphatic, and R 20  is hydrogen, aliphatic or heteroaliphatic. By way of further example, in one such embodiment m is a positive integer, z is zero, one or two, X 11  is hydrogen alkyl, alkenyl, or aminoalkyl, and R 20  is hydrogen, alkyl, alkenyl, or aminoalkyl. 
     In one embodiment, the crosslinked polymer comprises the residue of an amine corresponding to Formula 2, the crosslinked polymer is prepared by (i) substitution polymerization of the amine corresponding to Formula 2 with a polyfunctional crosslinker (optionally also comprising amine moieties) or (2) radical polymerization of an amine corresponding to Formula 2, and n is a positive integer and R 30  is hydrogen, aliphatic or heteroaliphatic. By way of further example, in one such embodiment n is 0 or 1, and R 30  is hydrogen, alkyl, alkenyl, or aminoalkyl. 
     In one embodiment, the crosslinked polymer comprises the residue of an amine corresponding to Formula 2, the crosslinked polymer is prepared by (i) substitution polymerization of the amine corresponding to Formula 2 with a polyfunctional crosslinker (optionally also comprising amine moieties) or (2) radical polymerization of an amine corresponding to Formula 2, and m and n are independently non-negative integers and X 2  is aliphatic or heteroaliphatic. For example, in one such embodiment m is 0 to 2, n is 0 or 1, X 2  is aliphatic or heteroaliphatic, and R 10 , R 20 , R 30 , and R 40  are independently hydrogen, aliphatic, or heteroaliphatic. By way of further example, in one such embodiment m is 0 to 2, n is 0 or 1, X 2  is alkyl or aminoalkyl, and R 10 , R 20 , R 30 , and R 40  are independently hydrogen, aliphatic, or heteroaliphatic. By way of further example, in one such embodiment m is 0 to 2, n is 0 or 1, X 2  is alkyl or aminoalkyl, and R 10 , R 20 , R 30 , and R 40  are independently hydrogen, alkyl, alkenyl, or aminoalkyl. 
     In some embodiments, the crosslinked polymer comprises the residue of an amine corresponding to Formula 2a and the crosslinked polymer is prepared by substitution polymerization of the amine corresponding to Formula 2a with a polyfunctional crosslinker (optionally also comprising amine moieties): 
     
       
         
         
             
             
         
       
     
     wherein 
     m and n are independently non-negative integers; 
     each R 11  is independently hydrogen, hydrocarbyl, heteroaliphatic, or heteroaryl; 
     R 21  and R 31 , are independently hydrogen or heteroaliphatic; 
     R 41  is hydrogen, substituted hydrocarbyl, or hydrocarbyl; 
     X 1  is 
     
       
         
         
             
             
         
       
     
     X 2  is alkyl or substituted hydrocarbyl; 
     each X 12  is independently hydrogen, hydroxy, amino, aminoalkyl, boronic acid or halo; and 
     z is a non-negative number. 
     In one embodiment, the crosslinked polymer comprises the residue of an amine corresponding to Formula 2a, the crosslinked polymer is prepared by substitution polymerization of the amine corresponding to Formula 1 with a polyfunctional crosslinker (optionally also comprising amine moieties). For example, in one such embodiment, m and z are independently 0, 1, 2 or 3, and n is 0 or 1. 
     In one embodiment, the crosslinked polymer comprises the residue of an amine corresponding to Formula 2a, the crosslinked polymer is prepared by substitution polymerization of the amine corresponding to Formula 2a with a polyfunctional crosslinker (optionally also comprising amine moieties), and each R 11  is independently hydrogen, aliphatic, aminoalkyl, haloalkyl, or heteroaryl, R 21  and R 31  are independently hydrogen or heteroaliphatic and R 41  is hydrogen, aliphatic, aryl, heteroaliphatic, or heteroaryl. For example, in one such embodiment each R 11  is hydrogen, aliphatic, aminoalkyl, or haloalkyl, R 21  and R 31  are independently hydrogen or heteroaliphatic and R 41  is hydrogen, alkylamino, aminoalkyl, aliphatic, or heteroaliphatic. By way of further example, in one such embodiment each R 11  is hydrogen, aliphatic, aminoalkyl, or haloalkyl, R 21  and R 31  are hydrogen or aminoalkyl, and R 41  is hydrogen, aliphatic, or heteroaliphatic. By way of further example, in one such embodiment each R 11  and R 41  is independently hydrogen, alkyl, or aminoalkyl, and R 21  and R 31  are independently hydrogen or heteroaliphatic. By way of further example, in one such embodiment each R 11  and R 41  is independently hydrogen, alkyl, —(CH 2 ) d NH 2 , —(CH 2 ) d N[(CH 2 ) e NH 2 )]2 where d and e are independently 2-4, and R 21  and R 31  are independently hydrogen or heteroaliphatic. In each of the foregoing exemplary embodiments of this paragraph, m and z may independently be 0, 1, 2 or 3, and n is 0 or 1. 
     Exemplary amines for the synthesis of polymers comprising repeat units corresponding to Formula 2a include, but are not limited to, amines appearing in Table A. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE A 
               
               
                   
               
               
                 Abbrevia- 
                   
                   
                   
                 MW 
               
               
                 tion 
                 IUPAC name 
                 Other names 
                   
                 (g/mol) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 C2A3BTA 
                 1,3-Bis[bis(2-amino- ethyl)amino]propane 
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 288.48 
               
               
                   
               
               
                 C2A3G2 
                 3-Amino-1-{[2-(bis{2- [bis(3-aminopropyl)ami- no]ethyl}amino)ethyl](3- aminopropyl)ami- no}propane 
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 488.81 
               
               
                   
               
               
                 C2PW 
                 2-[Bis(2-amino- ethyl)amino]ethanamine 
                 2,2′,2″-Triamino- triethylamine or 2,2′,2″-Nitrilo- triethylamine 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 146.24 
               
               
                   
               
               
                 C3PW 
                 Tris(3-amino- propyl)amine 
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 188.32 
               
               
                   
               
               
                 C4A3BTA 
                 1,4-Bis[bis(3-amino- propyl)amino]butane 
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 316.54 
               
               
                   
               
               
                 EDA1 
                 1,2-Ethanediamine 
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 60.1 
               
               
                   
               
               
                 EDA2 
                 2-Amino-1-(2-amino- ethylamino)ethane 
                 Bis(2-aminoethyl)amine  or 2,2′-Diamino- diethylamine 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 103.17 
               
               
                   
               
               
                 EDA3 
                 1,2-Bis(2-amino- ethylamino)ethane 
                 N,N′-Bis(2-amino- ethyl)ethane- 1,2-diamine 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 146.24 
               
               
                   
               
               
                 PDA1 
                 1,3-Propanediamine 
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 74.3 
               
               
                   
               
               
                 PDA2 
                 3,3′-Diamino- dipropylamine 
                   
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 131.22 
               
               
                   
               
            
           
         
       
     
     Exemplary crosslinkers for the synthesis of polymers comprising the residue of amines corresponding to Formula 2a include but are not limited to crosslinkers appearing in Table B. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE B 
               
               
                   
               
               
                   
                   
                   
                   
                 MW 
               
               
                 Abbreviation 
                 Common name 
                 IUPAC name 
                   
                 (g/mol) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 BCPA 
                 Bis(3- chloropropyl)amine 
                 Bis(3- chloropropyl)amine 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 206.54 
               
               
                   
               
               
                 DC2OH 
                 1,3- dichloroisopropanol 
                 1,3-Dichloro-2- propanol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 128.98 
               
               
                   
               
               
                 DCE 
                 dichloroethane 
                 1,2-dichloroethane 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 98.96 
               
               
                   
               
               
                 DCP 
                 Dichloropropane 
                 1,3-Dichloropropane 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 112.98 
               
               
                   
               
               
                 ECH 
                 Epichlorohydrin 
                 1-chloro-2,3- epoxypropane 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 92.52 
               
               
                   
               
               
                 TGA 
                 Triglycidyl amine 
                 Tris[(2- oxiranyl)methyl]amine 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 185.22 
               
               
                   
               
               
                 BCPOH 
                 Bis(3-chloropropyl) amine-OH 
                 3-Chloro-1-(3- chloropropylamino)-2- propanol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 186.08 
               
               
                   
               
               
                 BCPEDA 
                 Bis(chloropropyl) ethylenediamine 
                 1,2-Bis(3- chloropropylamino)eth- ane 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 213.15 
               
               
                   
               
            
           
         
       
     
     In some embodiments, the crosslinked polymer comprises the residue of an amine corresponding to Formula 2b and the crosslinked polymer is prepared by radical polymerization of an amine corresponding to Formula 2b: 
     
       
         
         
             
             
         
       
     
     wherein 
     m and n are independently non-negative integers; 
     each R 12  is independently hydrogen, substituted hydrocarbyl, or hydrocarbyl; 
     R 22  and R 32  are independently hydrogen substituted hydrocarbyl, or hydrocarbyl; 
     R 42  is hydrogen, hydrocarbyl or substituted hydrocarbyl; 
     X 1  is 
     
       
         
         
             
             
         
       
     
     X 2  is alkyl, aminoalkyl, or alkanol; 
     each X 13  is independently hydrogen, hydroxy, alicyclic, amino, aminoalkyl, halogen, alkyl, heteroaryl, boronic acid or aryl; 
     z is a non-negative number, and 
     the amine corresponding to Formula 2b comprises at least one allyl group. 
     In one embodiment, the crosslinked polymer comprises the residue of an amine corresponding to Formula 2b, the crosslinked polymer is prepared by radical polymerization of an amine corresponding to Formula 2b, and m and z are independently 0, 1, 2 or 3, and n is 0 or 1. 
     In one embodiment, the crosslinked polymer comprises the residue of an amine corresponding to Formula 2b, the crosslinked polymer is prepared by radical polymerization of an amine corresponding to Formula 1, and (i) R 12  or R 42  independently comprise at least one allyl or vinyl moiety, (ii) m is a positive integer and R 22  comprises at least one allyl or vinyl moiety, and/or (iii) n is a positive integer and R 32  comprises at least one allyl moiety. For example, in one such embodiment, m and z are independently 0, 1, 2 or 3 and n is 0 or 1. For example, in one such embodiment R 12  or R 42 , in combination comprise at least two allyl or vinyl moieties. By way of further example, in in one such embodiment, m is a positive integer and R 12 , R 22  and R 42 , in combination comprise at least two allyl or vinyl moieties. By way of further example, in in one such embodiment, n is a positive integer and R 12 , R 32  and R 42 , in combination comprise at least two allyl or vinyl moieties. By way of further example, in in one such embodiment, m is a positive integer, n is a positive integer and R 12 , R 22 , R 32  and R 42 , in combination, comprise at least two allyl or vinyl moieties. 
     In one embodiment, the crosslinked polymer comprises the residue of an amine corresponding to Formula 2b, the crosslinked polymer is prepared by radical polymerization of an amine corresponding to Formula 2b, and each R 12  is independently hydrogen, aminoalkyl, allyl, or vinyl, R 22  and R 32  are independently hydrogen, alkyl, aminoalkyl, haloalkyl, alkenyl, alkanol, heteroaryl, alicyclic heterocyclic, or aryl, and R 42  is hydrogen or substituted hydrocarbyl. For example, in one such embodiment each R 12  is aminoalkyl, allyl or vinyl, R 22  and R 32  are independently hydrogen, alkyl, aminoalkyl, haloalkyl, alkenyl, or alkanol, and R 42  is hydrogen or substituted hydrocarbyl. By way of further example, in one such embodiment each R 12  and R 42  is independently hydrogen, alkyl, allyl, vinyl, —(CH 2 ) d NH 2  or —(CH 2 ) d N[(CH 2 ) e NH 2 ] 2  where d and e are independently 2-4, and R 22  and R 32  are independently hydrogen or heteroaliphatic. 
     Exemplary amines and crosslinkers (or the salts thereof, for example the hydrochloric acid, phosphoric acid, sulfuric acid, or hydrobromic acid salts thereof) for the synthesis of polymers described by Formula 2b include but are not limited to the ones in Table C. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE C 
               
               
                   
               
               
                   
                   
                   
                   
                 MW 
               
               
                 Abbreviation 
                 Common name 
                 IUPAC name 
                   
                 (g/mol) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 DABDA1 
                 Diallylbutyldiamine 
                 1,4- Bis(allylamino)butane 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 241.2 
               
               
                   
               
               
                 DAEDA1 
                 Diallylethyldiamine 
                 1,2- Bis(allylamino)ethane 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 213.15 
               
               
                   
               
               
                 DAEDA2 
                 Diallyldiethylenetria- mine 
                 2-(Allylamino)-1-[2- (allylamino)ethyla- mino]ethane 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 292.67 
               
               
                   
               
               
                 DAPDA 
                 Diallylpropyldiamine 
                 1,3- Bis(allylamino)propane 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 227.17 
               
               
                   
               
               
                 POHDA 
                 Diallylamineisopropanol 
                 1,3-Bis(allylamino)- 2-propanol 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 243.17 
               
               
                   
               
               
                 AAH 
                 Allylamine 
                 2-Propen-1- ylamine 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 93.5 
               
               
                   
               
               
                 AEAAH 
                 Aminoethylallylamine 
                 1-(Allylamino)-2- aminoethane 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 173.08 
               
               
                   
               
               
                 BAEAAH 
                 Bis(2- aminoethyl)allylamine 
                 1-[N-Allyl(2- aminoethyl)amino]- 2-aminoethane 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 252.61 
               
               
                   
               
               
                 TAA 
                 Triallylamine 
                 N,N,N-triallylamine 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 137.22 
               
               
                   
               
            
           
         
       
     
     In some embodiments, the crosslinked polymer is derived from a reaction of the resulting polymers that utilize monomers described in any of Formulae 1, 1a, 1b, 1c, 2, 2a and 2b or a linear polymer comprised of a repeat unit described by Formula 3 with external crosslinkers or pre-existing polymer functionality that can serve as crosslinking sites. Formula 3 can be a repeat unit of a copolymer or terpolymer where X 15  is either a random, alternating, or block copolymer. The repeating unit in Formula 3 can also represent the repeating unit of a polymer that is branched, or hyperbranched, wherein the primary branch point can be from any atom in the main chain of the polymer: 
     
       
         
         
             
             
         
       
     
     wherein 
     R 15 , R 16  and R 17  are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxyl, amino, boronic acid or halo; 
     X 15  is 
     
       
         
         
             
             
         
       
     
     X 5  is hydrocarbyl, substituted hydrocarbyl, oxo (—O—), or amino and 
     z is a non-negative number. 
     In one embodiment, R 15 , R 16  and R 17  are independently hydrogen, aryl, or heteroaryl, X 5  is hydrocarbyl, substituted hydrocarbyl, oxo or amino, and m and z are non-negative integers. In another embodiment, R 15 , R 16  and R 17  are independently aliphatic or heteroaliphatic, X 5  is hydrocarbyl, substituted hydrocarbyl, oxo (—O—) or amino, and m and z are non-negative integers. In another embodiment, R 15 , R 16  and R 17  are independently unsaturated aliphatic or unsaturated heteroaliphatic, X 5  is hydrocarbyl, substituted hydrocarbyl, oxo, or amino, and z is a non-negative integer. In another embodiment, R 15 , R 16  and R 17  are independently alkyl or heteroalkyl, X 5  is hydrocarbyl, substituted hydrocarbyl, oxo, or amino, and z is a non-negative integer. In another embodiment, R 15 , R 16  and R 17  are independently alkylamino, aminoalkyl, hydroxyl, amino, boronic acid, halo, haloalkyl, alkanol, or ethereal, X 5  is hydrocarbyl, substituted hydrocarbyl, oxo, or amino, and z is a non-negative integer. In another embodiment, R 15 , R 16  and R 17  are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxyl, amino, boronic acid or halo, X 5  is oxo, amino, alkylamino, ethereal, alkanol, or haloalkyl, and z is a non-negative integer. 
     Exemplary crosslinking agents that may be used in radical polymerization reactions include, but are not limited to, one or more multifunctional crosslinking agents such as: 1,4-bis(allylamino)butane, 1,2-bis(allylamino)ethane, 2-(allylamino)-1-[2-(allylamino)ethylamino]ethane, 1,3-bis(allylamino)propane, 1,3-bis(allylamino)-2-propanol, triallylamine, diallylamine, divinylbenzene, 1,7-octadiene, 1,6-heptadiene, 1,8-nonadiene, 1,9-decadiene, 1,4-divinyloxybutane, 1,6-hexamethylenebisacrylamide, ethylene bisacrylamide, N,N′-bis(vinylsulfonylacetyl)ethylene diamine, 1,3-bis(vinylsulfonyl) 2-propanol, vinylsulfone, N,N′-methylenebisacrylamide polyvinyl ether, polyallylether, divinylbenzene, 1,4-divinyloxybutane, and combinations thereof. 
     Crosslinked polymers derived from the monomers and polymers in formulas 1 through 3 may be synthesized either in solution or bulk or in dispersed media. Examples of solvents that are suitable for the synthesis of polymers of the present disclosure include, but are not limited to water, low boiling alcohols (methanol, ethanol, propanol, butanol), dimethylformamide, dimethylsulfoxide, heptane, chlorobenzene, toluene. 
     Alternative polymer processes may include, a lone polymerization reaction, stepwise addition of individual starting material monomers via a series of reactions, the stepwise addition of blocks of monomers, combinations or any other method of polymerization such as living polymerization, direct polymerization, indirect polymerization, condensation, radical, emulsion, precipitation approaches, spray dry polymerization or using some bulk crosslinking reaction methods and size reduction processes such as grinding, compressing, extrusion. Processes can be carried out as a batch, semi-continuous and continuous processes. For processes in dispersed media, the continuous phase can be non-polar solvents, such as toluene, benzene, hydrocarbon, halogenated solvents, super critical carbon dioxide. With a direct suspension reaction, water can be used and salt can be used to tune the properties of the suspension. 
     The starting molecules described in formulas 1 through 3 may be copolymerized with one or more other monomers of the invention, oligomers or other polymerizable groups. Such copolymer architectures can include, but are not limited to, block or block-like polymers, graft copolymers, and random copolymers. Incorporation of monomers described by formulas 1 through 3 can range from 1% to 99%. In some embodiments, the incorporation of comonomer is between 20% and 80%. 
     Non-limiting examples of comonomers which may be used alone or in combination include: styrene, allylamine hydrochloride, substituted allylamine hydrochloride, substituted styrene, alkyl acrylate, substituted alkyl acrylate, alkyl methacrylate, substituted alkyl methacrylate, acrylonitrile, methacrylonitrile, acrylamide, methacrylamide, N-alkylacrylamide, N-alkylmethacrylamide, N,N-dialkylacrylamide, N,N-dialkylmethacrylamide, isoprene, butadiene, ethylene, vinyl acetate, N-vinyl amide, maleic acid derivatives, vinyl ether, allyle, methallyl monomers and combinations thereof. Functionalized versions of these monomers may also be used. Additional specific monomers or comonomers that may be used in this invention include, but are not limited to, 2-propen-1-ylamine, 1-(allylamino)-2-aminoethane, 1-[N-allyl(2-aminoethyl)amino]-2-aminoethane, methyl methacrylate, ethyl methacrylate, propyl methacrylate (all isomers), butyl methacrylate (all isomers), 2-ethylhexyl methacrylate, isobornyl methacrylate, methacrylic acid, benzyl methacrylate, phenyl methacrylate, methacrylonitrile, amethylstyrene, methyl acrylate, ethyl acrylate, propyl acrylate (all isomers), butyl acrylate (all isomers), 2-ethylhexyl acrylate, isobornyl acrylate, acrylic acid, benzyl acrylate, phenyl acrylate, acrylonitrile, styrene, glycidyl methacrylate, 2-hydroxyethyl methacrylate, hydroxypropyl methacrylate (all isomers), hydroxybutyl methacrylate (all isomers), N,N-dimethylaminoethyl methacrylate, N,N-diethylaminoethyl methacrylate, triethyleneglycol methacrylate, itaconic anhydride, itaconic acid, glycidyl acrylate, 2-hydroxyethyl acrylate, hydroxypropyl acrylate (all isomers), hydroxybutyl acrylate (all isomers), N,N-dimethylaminoethyl acrylate, N,N-diethylaminoethyl acrylate, triethyleneglycol acrylate, methacrylamide, N-methylacrylamide, N,N-dimethylacrylamide, N-tert-butylmethacrylamide, N—N-butylmethacrylamide, N-methylolmethacrylamide, N-ethylolmethacrylamide, N-tert-butylacryl amide, N-Nbutylacrylamide, N-methylolacrylamide, N-ethylolacrylamide, 4-acryloylmorpholine, vinyl benzoic acid (all isomers), diethylaminostyrene (all isomers), a-methylvinyl benzoic acid (all isomers), diethylamino a-methylstyrene (all isomers), p-vinylbenzene sulfonic acid, p-vinylbenzene sulfonic sodium salt, trimethoxysilylpropyl methacrylate, triethoxysilylpropyl methacrylate, tributoxysilylpropyl methacrylate, dimethoxymethylsilylpropyl methacrylate, diethoxymethylsilylpropyl methacrylate, dibutoxymethylsilylpropyl methacrylate, diisopropoxymethylsilylpropyl methacrylate, dimethoxysilylpropyl methacrylate, diethoxysilylpropyl methacrylate, dibutoxysilylpropyl methacrylate, diisopropoxysilylpropyl methacrylate, trimethoxysilylpropyl acrylate, triethoxysilylpropyl acrylate, tributoxysilylpropyl acrylate, dimethoxymethylsilylpropyl acrylate, diethoxymethylsilylpropyl acrylate, dibutoxymethylsilylpropyl acrylate, diisopropoxymethylsilylpropyl acrylate, dimethoxysilylpropyl acrylate, diethoxysilylpropyl acrylate, dibutoxysilylpropyl acrylate, diisopropoxysilylpropyl acrylate, maleic anhydride, N-phenylmaleimide, N-butylmaleimide, N-vinylformamide, N-vinyl acetamide, allylamine, methallylamine, allylalcohol, methyl-vinylether, ethylvinylether, butylvinyltether, butadiene, isoprene, chloroprene, ethylene, vinyl acetate, and combinations thereof. 
     Additional modification to the preformed crosslinked polymer can be achieved through the addition of modifiers, including but not limited to amine monomers, additional crosslinkers, and polymers. Modification can be accomplished through covalent or non-covalent methods. These modifications can be evenly or unevenly dispersed throughout the preformed polymer material, including modifications biased to the surface of the preformed crosslinked polymer. Furthermore, modifications can be made to change the physical properties of the preformed crosslinked polymer, including but not limited to reactions that occur with remaining reactive groups such as haloalkyl groups and allyl groups in the preformed polymer. Reactions and modifications to the preformed crosslinked polymer can include but are not limited to acid-base reactions, nucleophilic substitution reactions, Michael reactions, non-covalent electrostatic interactions, hydrophobic interactions, physical interactions (crosslinking) and radical reactions. 
     In one embodiment, the post-polymerization crosslinked amine polymer is a crosslinked amine polymer comprising a structure corresponding to Formula 4: 
     
       
         
         
             
             
         
       
     
     wherein each R is independently hydrogen or an ethylene crosslink between two nitrogen atoms of the crosslinked amine polymer 
     
       
         
         
             
             
         
       
     
     and a, b, c, and m are integers. Typically, m is a large integer indicating an extended polymer network. In one such embodiment, a ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1:1 to 5:1. For example, in one such embodiment a ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1.5:1 to 4:1. By way of further example, in one such embodiment a ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1.75:1 to 3:1. For example, in one such embodiment a ratio of the sum of a and b is 57, c is 24 and m is large integer indicating an extended polymer network. In each of the foregoing embodiments a ratio of the sum of a and b to c (i.e., a+b:c) may be in the range of about 2:1 to 2.5:1. For example, in such embodiments the ratio of the sum of a and b to c (i.e., a+b:c) may be in the range of about 2.1:1 to 2.2:1. By way of further example, in such embodiments the ratio of the sum of a and b to c (i.e., a+b:c) may be in the range of about 2.2:1 to 2.3:1. By way of further example, in such embodiments the ratio of the sum of a and b to c (i.e., a+b:c) may be in the range of about 2.3:1 to 2.4:1. By way of further example, in such embodiments the ratio of the sum of a and b to c (i.e., a+b:c) may be in the range of about 2.4:1 to 2.5:1. In each of the foregoing embodiments, each R may independently be hydrogen or an ethylene crosslink between two nitrogen atoms. Typically, however, 35-95% of the R substituents will be hydrogen and 5-65% will be an ethylene crosslink 
     
       
         
         
             
             
         
       
     
     For example, in one such embodiment, 50-95% of the R substituents will be hydrogen and 5-50% will be an ethylene crosslink 
     
       
         
         
             
             
         
       
     
     For example, in one such embodiment, 55-90% of the R substituents are hydrogen and 10-45% are an ethylene crosslink 
     
       
         
         
             
             
         
       
     
     By way of further example, in one such embodiment, 60-90% of the R substituents are hydrogen and 10-40% are an ethylene crosslink. By way of further example, in one such embodiment, 65-90% of the R substituents are hydrogen and 10-35% are an ethylene crosslink. 
     
       
         
         
             
             
         
       
     
     By way of further example, in one such embodiment, 70-90% of the R substituents are hydrogen and 10-30% are an ethylene crosslink. By way of further example, in one such embodiment, 75-85% of the R substituents are hydrogen and 15-25% are an ethylene crosslink. By way of further example, in one such embodiment, 65-75% of the R substituents are hydrogen and 25-35% are an ethylene crosslink. By way of further example, in one such embodiment, 55-65% of the R substituents are hydrogen and 35-45% are an ethylene crosslink. In some embodiments, a, b, c and R are such that the carbon to nitrogen ratio of the polymer of Formula 4 may range from about 2:1 to about 6:1, respectively. For example, in one such embodiment, the carbon to nitrogen ratio of the polymer of Formula 4 may range from about 2.5:1 to about 5:1, respectively. By way of further example, in one such embodiment, the carbon to nitrogen ratio of the polymer of Formula 4 may range from about 3:1 to about 4.5:1, respectively. By way of further example, in one such embodiment, the carbon to nitrogen ratio of the polymer of Formula 4 may range from about 3.25:1 to about 4.25:1, respectively. By way of further example, in one such embodiment, the carbon to nitrogen ratio of the polymer of Formula 4 may range from about 3.4:1 to about 4:1, respectively. By way of further example, in one such embodiment, the carbon to nitrogen ratio of the polymer of Formula 4 may range from about 3.5:1 to about 3.9:1, respectively. By way of further example, in one such embodiment, the carbon to nitrogen ratio of the polymer of Formula 4 may range from about 3.55:1 to about 3.85:1, respectively. In each of the foregoing embodiments recited in this paragraph, the polymer of Formula 4 is derived from monomers and crosslinkers, each of which comprise less than 5 wt % oxygen. 
     In certain embodiments, polymers in which crosslinking and/or entanglement were increased were found to have lower swelling than those with lower crosslinking and/or entanglement, yet also had a binding capacity for target ion (e.g., chloride) that was as great as or greater than the lower crosslinking and/or entanglement polymers while binding of interfering ions such as phosphate were significantly reduced. The selectivity effect may be introduced in two different manners: 1) Overall capacity was sacrificed for chloride specificity. Crosslinkers that don&#39;t include chloride binding sites (e.g., epichlorohydrin) allow for increased crosslinking while overall capacity is decreased proportional to the amount of crosslinker incorporated into the polymer. 2) Overall capacity is preserved for chloride specificity: Crosslinkers that include chloride binding sites (e.g., diallylamines) allow for increased crosslinking while overall capacity is staying the same or is reduced by only a small amount. 
     As previously noted, crosslinked polymers having a high capacity for chloride binding and high selectivity for chloride over other competing anions such as phosphate may be prepared in a two-step process in accordance with one embodiment of the present disclosure. In general, the selectivity of the polymer is a function of its crosslinking density and the capacity of the polymer is a function of the free amine density of the crosslinked polymer. Advantageously, the two-step process disclosed herein provides both, high capacity for chloride binding, and high selectivity for chloride over other competing ions by relying primarily upon carbon-carbon crosslinking in the first step, and nitrogen-nitrogen crosslinking in the second step. 
     In the first step, the crosslinking is preferably capacity-sparing, i.e., free amine sparing, crosslinking from carbon to carbon. In the second step, the crosslinking is amine-consuming and is directed towards tuning for selectivity. Based on the desired high capacity, the C—N ratio is preferably optimized to maximize amine functionalities for HCl binding, while still maintaining a spherical polymer particle of controlled particle size to ensure nonabsorption and acceptable mouth feel that is stable under GI conditions. The preferred extent of carbon-carbon crosslinking achieved after the first step is sufficient to permit the resulting bead to swell between 4× and 6× in water (i.e., a Swelling Ratio of 4 to 6). 
     In one embodiment, crosslinked polymers having a high capacity for chloride binding and high selectivity for chloride over other competing anions such as phosphate may be prepared in a two-step process, and the product of the first polymerization step is preferably in the form of beads whose diameter is controlled in the 5 to 1000 micromer range, preferably 10 to 500 micrometers and most preferred 40-180 micrometers. 
     The product of the first polymerization step is preferably in the form of beads whose Swelling Ratio in water is between 2 and 10, more preferably about 3 to about 8, and most preferably about 4 to about 6. 
     Additionally, if the crosslinked polymer beads resulting from the first polymerization step are protonated, this may reduce the amount of nitrogen-nitrogen crosslinking in the second crosslinking step. Accordingly, in certain embodiments the preformed amine polymer is at least partially deprotonated by treatment with a base, preferably a strong base such as a hydroxide base. For example, in one embodiment the base may be NaOH, KOH, NH 4 OH, NaHCO 3 , Na 2 CO 3 , K 2 CO 3 , LiGH, Li 2 CO 3 , CsOH or other metal hydroxides. If the charges are removed from the preformed crosslinked amine polymer bead by deprotonation, the bead will tend to collapse and the crosslinking agent used in the second step may not be able to access binding sites on the polymer unless the bead is prevented from collapsing. One means of preventing the crosslinked polymer bead from collapsing is the use of a swelling agent such as water to swell the bead, thereby allowing the second-step crosslinker to access binding sites. 
     The preformed polymer may be crosslinked to form the post-polymerization crosslinked polymer using any of a range of crosslinking compounds containing at least two amine-reactive functional groups. In one such embodiment, the crosslinker is a compound containing at least two amine-reactive groups selected from the group consisting of halides, epoxides, phosgene, anhydrides, carbamates, carbonates, isocyanates, thioisocyanates, esters, activated esters, carboxylic acids and derivatives thereof, sulfonates and derivatives thereof, acyl halides, aziridines, α,β-unsaturated carbonyls, ketones, aldehydes, and pentafluoroaryl groups. The crosslinker may be, for example, any of the crosslinkers disclosed herein, including a crosslinker selected from Table B. By way of further example, in one such embodiment the crosslinker is a dihalide such as a dichloroalkane. 
     As noted above, in certain embodiments a swelling agent for the preformed amine polymer may be included in the reaction mixture for the second polymerization step along with the crosslinking agent. In general, the swelling agent and the crosslinking agent may be miscible or immiscible and the swelling agent may be any composition or combination of compositions that have the capacity to swell the preformed amine polymer. Exemplary swelling agents include polar solvents such as water, methanol, ethanol, n-propanol, isopropanol, n-butanol, formic acid, acetic acid, acetonitrile, dimethylformamide, dimethylsulfoxide, nitromethane, propylene carbonate, or a combination thereof. Additionally, the amount of swelling agent included in the reaction mixture will typically be less than absorption capacity of the preformed amine polymer for the swelling agent. For example, it is generally preferred that the weight ratio of swelling agent to preformed polymer in the reaction mixture be less than 4:1. By way of further example, in some embodiments the weight ratio of swelling agent to preformed polymer in the reaction mixture will be less than 3:1. By way of further example, in some embodiments the weight ratio of swelling agent to preformed polymer in the reaction mixture will be less than 2:1. By way of further example, in some embodiments the weight ratio of swelling agent to preformed polymer in the reaction mixture will be less than 1:1. By way of further example, in some embodiments the weight ratio of swelling agent to preformed polymer in the reaction mixture will be less than 0.5:1. By way of further example, in some embodiments the weight ratio of swelling agent to preformed polymer in the reaction mixture will be less than 0.4:1. By way of further example, in some embodiments the weight ratio of swelling agent to preformed polymer in the reaction mixture will be less than 0.3:1. In general, however, the weight ratio of swelling agent to preformed polymer in the reaction mixture will typically be at least 0.05:1, respectively. 
     In general, the crosslinked polymers may be crosslinked homopolymers or crosslinked copolymers comprising free amine moieties. The free amine moieties may be separated, for example, by the same or varying lengths of repeating linker (or intervening) units. In some embodiments, the polymers comprise repeat units containing an amine moiety and an intervening linker unit. In other embodiments, multiple amine-containing repeat units are separated by one or more linker units. Additionally, the polyfunctional crosslinkers may comprise HCl binding functional groups, e.g., amines, (“active crosslinkers”) or may lack HCl binding functional groups such as amines (“passive crosslinkers”). 
     In a preferred embodiment, the first polymerization (crosslinking) step yields preformed amine polymer beads having a target size and chloride binding capacity. For example, in one such embodiment the beads have a chloride binding capacity of at least 10 mmol/g in Simulated Gastric Fluid (“SGF”) and a Swelling Ratio in the range of 1 to 6. The resulting preformed amine polymer is then preferably (at least partially) deprotonated with a base and combined with a non-protonating swelling agent to swell the free amine polymer without protonating the amine functions. Furthermore, the amount of the non-protonating swelling agent is selected to tune the subsequent degree of crosslinking effectively forming a template that is then locked into place via the amine consuming crosslinking step. In the second crosslinking step, the swollen, deprotonated preformed amine polymer is crosslinked with a crosslinker containing amine reactive moieties to form a post-polymerization crosslinked polymer. 
     In general, selectivity for chloride over other competing ions is achieved with highly crosslinked polymers. For example, relatively high chloride binding capacity may be be attained by reacting a preformed amine polymer bead with neat crosslinker in the presence of a swelling agent (water). While this “non-dispersed” reaction provides access to high selectivity for chloride over competing ions in the SIB assay, it also results in macroscopically (and microscopically) aggregated polymer beads. Accordingly, it is advantageous to include a solvent (e.g., heptane) in the second crosslinking step to disperse the preformed crosslinked polymer beads so as to avoid inter-bead reactions and resulting aggregation. The use of too much solvent (dispersant), however, can dilute the reaction solution to the point where the resulting bead is not sufficiently crosslinked to have the desired selectivity for chloride over other competing anions. By using a crosslinking agent that also functions as a solvent (dispersant), however, sufficient solvent (dispersant) may be included in the reaction mixture to avoid inter-bead reactions and aggregation without diluting the mixture to the point where the degree of amine-consuming crosslinking is insufficient. For example, in an effort to utilize the dispersing properties of a solvent (to avoid aggregation during the reaction) while maintaining reactivity, DCE and DCP were used neat, thus performing a dual purpose role, as both solvent (dispersant) and crosslinker. Interestingly, DCE was discovered to have excellent dispersal properties as a solvent, when compared to similar reactions with DCP and/or heptane. Additionally, less aggregation was observed when the beads were first dispersed in DCE and then in a second operation, the water is added to swell the beads. If water is added to the preformed amine polymer before the bead is dispersed in the DCE, aggregation may occur. 
     The use of 1,2-dichloroethane (“DCE”) as the crosslinking solvent also generates HCl molecules during the second step. These HCl molecules protonate some of the free amine sites which block the reaction sites for the crosslinking reaction and thereby limit the number of binding sites available for crosslinking. Consequently, the use of DCE creates a self-limiting effect on the secondary crosslinking. 
     In each of the foregoing embodiments, the reaction mixture may contain a wide range of amounts of crosslinking agents. For example, in one embodiment the crosslinker may be used in large excess relative to the amount of preformed amine polymer in the reaction mixtures. Stated differently, in such embodiments the crosslinking agent is a crosslinking solvent, i.e., it is both a solvent for the reaction mixture and a crosslinking agent for the preformed amine polymer. In such embodiments, other solvents may optionally be included in the reaction mixture but are not required. Alternatively, the preformed amine polymer, swelling agent and crosslinker may be dispersed in a solvent that is miscible with the crosslinker and immiscible with the swelling agent. For example, in some embodiments the swelling agent may be a polar solvent; in some such embodiments, for example, the swelling agent may comprise water, methanol, ethanol, n-propanol, isopropanol, formic acid, acetic acid, acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, nitromethane, or a combination thereof. By way of further example, when the swelling agent comprises a polar solvent, the solvent system for the reaction mixture will typically comprise a non-polar solvent such as pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether, dichloromethane, dichloroethane, dichloropropane, dichlorobutane, or a combination thereof. In certain embodiments, the crosslinker and the solvent may be the same; i.e., the solvent is a crosslinking solvent such as 1,2-dichloroethane, 1,3-dichloropropane, 1,4-dichlorobutane or a combination thereof. 
     It is notable that in a crosslinking solvent (e.g., a DCE-dispersed reaction), there is a large excess of crosslinker regardless of the amount of crosslinking solvent (e.g., DCE) used to disperse the bead (e.g., both 1 g:3 mL::bead:DCE and 1 g:10 mL::bead:DCE are a large excess of crosslinker, most of which is not consumed during the reaction). Despite this, the relative degree of crosslinking, and the performance in SIB assay, are unaffected by changes in the ratio of reactive crosslinker to polymer bead. This is possible because the reaction is limited by the acid-neutralizing capacity of the polymer bead, rather than the amount of crosslinker (e.g., DCE). 
     To more efficiently react with DCE or other crosslinker, the amines of the preformed polymer bead preferably have a free electron pair (neutral, deprotonated). As the free amines of the preformed polymer bead react with the crosslinker (e.g., DCE), HCl is produced and the amines become protonated, thus limiting the reaction. For this reason, the preformed amine polymer beads preferably start as the free amine in the second crosslinking step. If the preformed amine polymer bead is protonated after the first step of carbon-carbon crosslinking, amine-consuming crosslinking in the second step will be limited, thus reducing the desired selectivity for chloride over other competing ions. This has been demonstrated by adding known quantities of HCl to preformed amine polymer beads immediately before second step crosslinking with DCE. When less than 3 mol % HCl (to amine in preformed polymer amine bead) is added prior to second step crosslinking, total chloride capacity (SGF) and chloride selectivity in SIB are similar to beads not treated with HCl in the second step. When greater than 5 mol % HCl (to amine in preformed polymer amine bead) is added prior to second step crosslinking, total chloride capacity (SGF) increases and chloride selectivity in SIB decreases, indicating lower incorporation of crosslinker. 
     The benefits of deprotonated preformed polymer beads in the second step crosslinking highlights the advantages of using two steps to achieve the final product. In the first step, to form the amine polymer bead, all monomers (e.g., allylamine and DAPDA) are protonated to remain in the aqueous phase and to avoid the radical transfer reactions that severely limit the polymerization of non-protonated allylamine (and derivatives). Once the bead is formed through carbon-carbon crosslinks, the bead can then be deprotonated and further crosslinked with an amine reactive crosslinker in a second step. 
     Given the large excess of dual crosslinker/solvent, mono-incorporation of this reagent can occur leading to alkyl chloride functional groups on the crosslinked polymer bead that are hydrophobic in nature and can increase non-specific interactions with undesirable solutes other than HCl that are more hydrophobic in nature. Washing with ammonium hydroxide solution converts the alkyl-chloride to alkyl-amine functions that are hydrophilic and minimize non-specific interactions with undesirable solutes. Other modifications that yield more hydrophilic groups than alkyl chloride such as —OH are suitable to quench mono-incorporated crosslinker/solvent. 
     Any of a range of polymerization chemistries may be employed in the first reaction step, provided that the crosslinking mechanism is primarily carbon-carbon crosslinking. Thus, in one exemplary embodiment, the first reaction step comprises radical polymerization. In such reactions, the amine monomer will typically be a mono-functional vinyl, allyl, or acrylamide (e.g., allylamine) and crosslinkers will have two or more vinyl, allyl or acrylamide functionalities (e.g., diallylamine). Concurrent polymerization and crosslinking occurs through radically initiated polymerization of a mixture of the mono- and multifunctional allylamines. The resulting polymer network is thusly crosslinked through the carbon backbone. Each crosslinking reaction forms a carbon-carbon bond (as opposed to substitution reactions in which a carbon-heteroatom bond is formed during crosslinking). During the concurrent polymerization and crosslinking, the amine functionalities of the monomers do not undergo crosslinking reactions and are preserved in the final polymer (i.e., primary amines remain primary, secondary amines remain secondary, and tertiary amines remain tertiary). 
     In those embodiments in which the first reaction step comprises radical polymerization, a wide range of initiators may be used including cationic and radical initiators. Some examples of suitable initiators that may be used include: the free radical peroxy and azo type compounds, such as azodiisobutyronitrile, azodiisovaleronitrile, dimethylazodiisobutyrate, 2,2′azo bis(isobutyronitrile), 2,2′-azobis(N,N′-dimethyl-eneisobutyramidine)dihydrochloride, 2,2′-azobis(2-amidinopropane)dihydrochloride, 2,2′-azobis(N,N′-dimethyleneisobutyramidine), 1,1′-azo bis(I-cyclohexanecarbo-nitrile), 4,4′-azobis(4-cyanopentanoic acid), 2,2′-azobis(isobutyramide)dihydrate, 2,2′-azobis(2-methylpropane), 2,2′-azobis(2-methylbutyronitrile), VAZO 67, cyanopentanoic acid, the peroxypivalates, dodecylbenzene peroxide, benzoyl peroxide, di-t-butyl hydroperoxide, t-butyl peracetate, acetyl peroxide, dicumyl peroxide, cumylhydroperoxide, dimethyl bis(butylperoxy)hexane. 
     Exemplary amine-containing polymers as described above are more fully disclosed and exemplified in WO2016/094685 A1 and WO2014/197725 A1, the entire contents of which are incorporated herein by reference. 
     In one embodiment, the pharmaceutical composition comprises a mixture of any of the previously-identified nonabsorbable materials. For example, in one embodiment the pharmaceutical composition comprises a mixture of a cation exchange composition with at least one anion exchange composition, amphoteric ion exchange composition, or neutral composition having the capacity to bind both protons and anions. In another embodiment, the pharmaceutical composition comprises a mixture of an anion exchange composition with at least one cation exchange composition, amphoteric ion exchange composition, or neutral composition having the capacity to bind both protons and anions. In yet another embodiment, the pharmaceutical composition comprises a mixture of a neutral composition having the capacity to bind both protons and anions with at least one cation exchange composition, amphoteric ion exchange composition, or anion exchange composition. 
     As schematically depicted in  FIGS. 1A-1C  and in accordance with one embodiment, a nonabsorbabl free-amine polymer of the present disclosure is orally ingested and used to treat metabolic acidosis (including by increasing serum bicarbonate and normalizing blood pH) in a mammal by binding HCl in the gastrointestinal (“GI”) tract and removing HCl through the feces. Free-amine polymer is taken orally ( FIG. 1A ) at compliance enhancing dose targeted to chronically bind sufficient amounts of HCl to enable clinically meaningful increase in serum bicarbonate of 3 mEq/L. In the stomach ( FIG. 1B ), free amine becomes protonated by binding H + . Positive charge on polymer is then available to bind Cl − , by controlling access of binding sites through crosslinking and hydrophilicity/hydrophobicity properties, other larger organic anions (e.g., acetate, propionate, butyrate, etc., depicted as X −  and Y − ) are bound to a lesser degree, if at all. The net effect is therefore binding of HCl. In the lower GI tract/colon ( FIG. 1C ), Cl −  is not fully released and HCl is removed from the body through regular bowel movement and fecal excretion, resulting in net alkalinization in the serum. Cl −  bound in this fashion is not available for exchange via the Cl − /HCO 3   −  antiporter system. 
     In one embodiment, the polymer is designed to simultaneously maximize efficacy (net HCl binding and excretion) and minimize GI side effects (through low swelling particle design and particle size distribution). Optimized HCl binding may be accomplished through a careful balance of capacity (number of amine binding sites), selectivity (preferred binding of chloride versus other anions, in particular organic anions in the colon) and retention (not releasing significant amounts of chloride in the lower GI tract to avoid the activity of the Cl − /HCO 3  exchanger [antiporter] in the colon and intestine; if chloride is not tightly bound to the polymer the Cl—/HCO 3   −  exchanger can mediate uptake of chloride ion from the intestinal lumen and reciprocal exchange for bicarbonate from the serum, thus effectively decreasing serum bicarbonate. 
     Competing anions that displace chloride lead to a decrease in net bicarbonate through the following mechanisms. First, displacement of chloride from the polymer in the GI lumen, particularly the colon lumen, provides for a facile exchange with bicarbonate in the serum. The colon has an anion exchanger (chloride/bicarbonate antiporter) that moves chloride from the luminal side in exchange for secreted bicarbonate. When free chloride is released from the polymer in the GI tract it will exchange for bicarbonate, which will then be lost in the stool and cause a reduction in total extracellular bicarbonate (Davis, 1983; D&#39;Agostino, 1953). The binding of short chain fatty acids (SCFA) in exchange for bound chloride on the polymer, will result in the depletion of extracellular HCO 3   −  stores. Short chain fatty acids are the product of bacterial metabolism of complex carbohydrates that are not catabolized by normal digestive processes (Chemlarova, 2007). Short chain fatty acids that reach the colon are absorbed and distributed to various tissues, with the common metabolic fate being the generation of H 2 O and CO 2 , which is converted to bicarbonate equivalents. Thus, binding of SCFA to the polymer to neutralize the proton charge would be detrimental to overall bicarbonate stores and buffering capacity, necessitating the design of chemical and physical features in the polymer that limit SCFA exchange. Finally, phosphate binding to the polymer should be limited as well, since phosphate represents an additional source of buffering capacity in the situation where ammoniagenesis and/or hydrogen ion secretion is compromised in chronic renal disease. 
     For each binding of proton, an anion is preferably bound as the positive charge seeks to leave the human body as a neutral polymer. “Binding” of an ion, is more than minimal binding, i.e., at least about 0.2 mmol of ion/g of polymer, at least about 1 mmol of ion/g of polymer in some embodiments, at least about 1.5 mmol of ion/g of polymer in some embodiments, at least about 3 mmol of ion/g of polymer in some embodiments, at least about 5 mmol of ion/g of polymer in some embodiments, at least about 10 mmol of ion/g of polymer in some embodiments, at least about 12 mmol of ion/g of polymer in some embodiments, at least about 13 mmol of ion/g of polymer in some embodiments, or even at least about 14 mmol of ion/g of polymer in some embodiments. In one embodiment, the polymers are characterized by their high capacity of proton binding while at the same time providing selectivity for anions; selectivity for chloride is accomplished by reducing the binding of interfering anions that include but are not limited to phosphate, citrate, acetate, bile acids and fatty acids. For example, in some embodiments, polymers of the present disclosure bind phosphate with a binding capacity of less than about 5 mmol/g, less than about 4 mmol/g, less than about 3 mmol/g, less than about 2 mmol/g or even less than about 1 mmol/g. In some embodiments, polymers of the invention bind bile and fatty acids with a binding capacity of less than about less than about 5 mmol/g, less than about 4 mmol/g, less than about 3 mmol/g, less than about 2 mmol/g, less than about 1 mmol/g in some embodiments, less than about 0.5 mmol/g in some embodiments, less than about 0.3 mmol/g in some embodiments, and less than about 0.1 mmol/g in some embodiments. 
     Pharmaceutical Compositions &amp; Administration 
     In general, the dosage levels of the nonabsorbable compositions for therapeutic and/or prophylactic uses may range from about 0.5 g/day to about 100 g/day. To facilitate patient compliance, it is generally preferred that the dose be in the range of about 1 g/day to about 50 g/day. For example, in one such embodiment, the dose will be about 2 g/day to about 25 g/day. By way of further example, in one such embodiment, the dose will be about 3 g/day to about 25 g/day. By way of further example, in one such embodiment, the dose will be about 4 g/day to about 25 g/day. By way of further example, in one such embodiment, the dose will be about 5 g/day to about 25 g/day. By way of further example, in one such embodiment, the dose will be about 2.5 g/day to about 20 g/day. By way of further example, in one such embodiment, the dose will be about 2.5 g/day to about 15 g/day. By way of further example, in one such embodiment, the dose will be about 1 g/day to about 10 g/day. Optionally, the daily dose may be administered as a single dose (i.e., one time a day), or divided into multiple doses (e.g., two, three or more doses) over the course of a day. In general, the nonabsorbable compositions may be administered as a fixed daily dose or titrated based on the serum bicarbonate values of the patient in need of treatment or other indicators of acidosis. The titration may occur at the onset of treatment or throughout, as required, and starting and maintenance dosage levels may differ from patient to patient based on severity of the underlying disease. 
     The effectiveness of the nonabsorbable composition may be established in animal models, or in human volunteers and patients. In addition, in vitro, ex vivo and in vivo approaches are useful to establish HCl binding. In vitro binding solutions can be used to measure the binding capacity for proton, chloride and other ions at different pHs. Ex vivo extracts, such as the gastrointestinal lumen contents from human volunteers or from model animals can be used for similar purposes. The selectivity of binding and/or retaining certain ions preferentially over others can also be demonstrated in such in vitro and ex vivo solutions. In vivo models of metabolic acidosis can be used to test the effectiveness of the nonabsorbable composition in normalizing acid/base balance—for example 5/6 nephrectomized rats fed casein-containing chow (as described in Phisitkul S, Hacker C, Simoni J, Tran R M, Wesson D E. Dietary protein causes a decline in the glomerular filtration rate of the remnant kidney mediated by metabolic acidosis and endothelin receptors. Kidney international. 2008; 73(2):192-9), or adenine-fed rats (Terai K, K Mizukami and M Okada. 2008. Comparison of chronic renal failure rats and modification of the preparation protocol as a hyperphosphatemia model. Nephrol. 13: 139-146). 
     In one embodiment, the nonabsorbable compositions are provided (by oral administration) to an animal, including a human, in a dosing regimen of one, two or even multiple (i.e., at least three) doses per day to treat an acid-base disorder (e.g., metabolic acidosis) and achieve a clinically significant and sustained increase of serum bicarbonate as previously described. For example, in one embodiment a daily dose of the nonabsorbable composition (whether orally administered in a single dose or multiple doses over the course of the day) has sufficient capacity to remove at least 5 mmol of protons, chloride ions or each per day. By way of further example, in one such embodiment a daily dose of the nonabsorbable composition has sufficient capacity to remove at least 10 mmol of protons, chloride ions or each per day. By way of further example, in one such embodiment a daily dose of the nonabsorbable composition has sufficient capacity to remove at least 20 mmol of protons, the conjugate base of a strong acid (e.g., Cl − , HSO 4   −  and SO 4   2− ) and/or a strong acid (e.g., HCl or H 2 SO 4 ) each per day. By way of further example, in one such embodiment a daily dose of the nonabsorbable composition has sufficient capacity to remove at least 30 mmol of protons, the conjugate base of a strong acid, and/or a strong acid each per day. By way of further example, in one such embodiment a daily dose of the nonabsorbable composition has sufficient capacity to remove at least 40 mmol of protons, the conjugate base of a strong acid, and/or a strong acid each per day. By way of further example, in one such embodiment a daily dose of the nonabsorbable composition has sufficient capacity to remove at least 50 mmol of protons, the conjugate base of a strong acid, and/or a strong acid each per day. 
     The dosage unit form of the pharmaceutical comprising the nonabsorbable composition may be any form appropriate for oral administration. Such dosage unit forms include powders, tablets, pills, lozenges, sachets, cachets, elixirs, suspensions, syrups, soft or hard gelatin capsules, and the like. In one embodiment, the pharmaceutical composition comprises only the nonabsorbable composition. Alternatively, the pharmaceutical composition may comprise a carrier, a diluent, or excipient in addition to the nonabsorbable composition. Examples of carriers, excipients, and diluents that may be used in these formulations as well as others, include foods, drinks, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, methyl cellulose, methylhydroxybenzoates, propylhydroxybenzoates, propylhydroxybenzoates, and talc. Pharmaceutical excipients useful in the pharmaceutical compositions further include a binder, such as microcrystalline cellulose, colloidal silica and combinations thereof (Prosolv 90), carbopol, providone and xanthan gum; a flavoring agent, such as sucrose, mannitol, xylitol, maltodextrin, fructose, or sorbitol; a lubricant, such as magnesium stearate, stearic acid, sodium stearyl fumurate and vegetable based fatty acids; and, optionally, a disintegrant, such as croscarmellose sodium, gellan gum, low-substituted hydroxypropyl ether of cellulose, sodium starch glycolate. Other additives may include plasticizers, pigments, talc, and the like. Such additives and other suitable ingredients are well-known in the art; see, e.g., Gennaro A R (ed), Remington&#39;s Pharmaceutical Sciences, 20th Edition. 
     In one embodiment, the nonabsorbable composition may be co-administered with other active pharmaceutical agents depending on the condition being treated. This co-administration may include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. For example, for the treatment of metabolic acidosis, the nonabsorbable composition may be co-administered with common treatments that are required to treat underlying co-morbidities including but not limited to edema, hypertension, diabetes, obesity, heart failure and complications of Chronic Kidney Disease. These medications and the nonabsorbable composition can be formulated together in the same dosage form and administered simultaneously as long as they do not display any clinically significant drug-drug-interactions. Alternatively, these treatments and the nonabsorbable composition may be separately and sequentially administered with the administration of one being followed by the administration of the other. 
     In one embodiment, the daily dose of the chronic metabolic acidosis treatment is compliance enhancing (approximately 15 g or less per day) and achieves a clinically significant and sustained increase of serum bicarbonate of approximately 3 mEq/L at these daily doses. The non-absorbed nature of the polymer and the lack of sodium load and/or introduction of other deleterious ions for such an oral drug enable for the first time a safe, chronic treatment of metabolic acidosis without worsening blood pressure/hypertension and/or without causing increased fluid retention and fluid overload. Another benefit is further slowing of the progression of kidney disease and time to onset of lifelong renal replacement therapy (End Stage Renal Disease “ESRD” including 3 times a week dialysis) or need for kidney transplants. Both are associated with significant mortality, low quality of life and significant burden to healthcare systems around the world. In the United States alone, approximately 20% of the 400,000 ESRD patients die and 100,000 new patients start dialysis every year. 
     A further aspect of the present disclosure is a pharmaceutical product comprising a sealed package and the nonabsorbable composition of the present disclosure withing the sealed package. The sealed package is preferably substantially impermeable to moisture and oxygen to increase the stability of the pharmaceutical composition. For example, the dosage unit form may comprise a sealed container (e.g., a sealed sachet) that prevents or reduces ingress of moisture and oxygen upon packaging the nonabsorbable composition in the container. The container size can be optimized to reduce head space in the container after packaging and any head space may be filled with an inert gas such as nitrogen. Furthermore, container material of construction can be chosen to minimize the moisture and oxygen ingress inside the container after packaging. For example, the nonabsorbable composition may be packaged in a multilayer sachet containing at least one or more layer that serves as a barrier layer to moisture and oxygen ingress. In another example, the nonabsorbable composition may be packaged in a single layer or multilayer plastic, metal or glass container that has at least one or more barrier layers incorporated in the structure that limits oxygen and/or moisture ingress after packaging. For example, in one such embodiment the sachet (or other container or package) may comprise a multi-layer laminate of an inner contact layer, an outer layer; and a barrier layer disposed between the contact layer and outer layer. In one exemplary embodiment, the container includes one or more oxygen-scavenging layers. 
     In further embodiments, enumerated as embodiments 1-849 below, the present disclosure includes: 
     Embodiment 1. A method of treating an individual afflicted with an acid-base disorder characterized by a baseline serum bicarbonate value of less than 22 mEq/l, the method comprising oral administration of a daily dose of a pharmaceutical composition having the capacity to bind at least 5 mEq of a target species as it transits the digestive system to increase the serum bicarbonate value to a value within the range of 24 to 29 mEq/l within a treatment period not greater than 1 month, the target species being selected from the group consisting of protons, strong acids, and conjugate bases of strong acids. 
     Embodiment 2. A method of treating an individual afflicted with an acid-base disorder characterized by a baseline serum bicarbonate value of less than 22 mEq/l, the method comprising oral administration of a pharmaceutical composition, wherein the pharmaceutical composition given orally binds at least 5 mEq per day on average of a target species in the digestive system to maintain the serum bicarbonate value at a value within the range of 24 to 29 mEq/l, the target species being selected from the group consisting of protons, strong acids, and conjugate bases of strong acids. 
     Embodiment 3. The method of embodiment 2 wherein the oral administration is as frequent as at least weekly within the treatment period. 
     Embodiment 4. The method of embodiment 2 pharmaceutical composition wherein the oral administration is as frequent as at least semi-weekly within the treatment period. 
     Embodiment 5. The method of embodiment 2 pharmaceutical composition wherein the oral administration is as frequent as at least daily within the treatment period. 
     Embodiment 6. The method of embodiment 1, 2, 3 or 5 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than 21 mEq/l. 
     Embodiment 7. The method of embodiment 1, 2, 3 or 5 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than 20 mEq/l. 
     Embodiment 8. The method of embodiment 1, 2, 3 or 5 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than 19 mEq/l. 
     Embodiment 9. The method of embodiment 1, 2, 3 or 5 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than 18 mEq/l. 
     Embodiment 10. The method of embodiment 1, 2, 3 or 5 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than 17 mEq/l. 
     Embodiment 11. The method of embodiment 1, 2, 3 or 5 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than 16 mEq/l. 
     Embodiment 12. The method of embodiment 1, 2, 3 or 5 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than 15 mEq/l. 
     Embodiment 13. The method of embodiment 1, 2, 3 or 5 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than 14 mEq/l. 
     Embodiment 14. The method of embodiment 1, 2, 3 or 5 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than 13 mEq/l. 
     Embodiment 15. The method of embodiment 1, 2, 3 or 5 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than 12 mEq/l. 
     Embodiment 16. The method of embodiment 1, 2, 3 or 5 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than 11 mEq/l. 
     Embodiment 17. The method of embodiment 1, 2, 3 or 5 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of less than 10 mEq/l. 
     Embodiment 18. The method of any preceding enumerated embodiment wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 9 mEq/l. 
     Embodiment 19. The method of any of embodiments 1-16 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 10 mEq/l. 
     Embodiment 20. The method of any of embodiments 1-15 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 11 mEq/l. 
     Embodiment 21. The method of any of embodiments 1-14 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 12 mEq/l. 
     Embodiment 22. The method of any of embodiments 1-13 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 13 mEq/l. 
     Embodiment 23. The method of any of embodiments 1-12 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 14 mEq/l. 
     Embodiment 24. The method of any of embodiments 1-11 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 15 mEq/l. 
     Embodiment 25. The method of any of embodiments 1-10 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 16 mEq/l. 
     Embodiment 26. The method of any of embodiments 1-9 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 17 mEq/l. 
     Embodiment 27. The method of any of embodiments 1-8 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 18 mEq/l. 
     Embodiment 28. The method of any of embodiments 1-7 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 19 mEq/l. 
     Embodiment 29. The method of any of embodiments 1-6 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 20 mEq/l. 
     Embodiment 30. The method of embodiment 1, 2, 3 or 5 wherein the acid-base disorder is characterized by a baseline serum bicarbonate value of at least 21 mEq/l. 
     Embodiment 34. The method of any preceding enumerated embodiment wherein the method increases the serum bicarbonate value from the baseline serum bicarbonate value to an increased serum bicarbonate value of at least 25 mEq/l. 
     Embodiment 35. The method of any preceding enumerated embodiment wherein the method increases the serum bicarbonate value from the baseline serum bicarbonate value to an increased serum bicarbonate value of at least 26 mEq/l. 
     Embodiment 36. The method of any preceding enumerated embodiment wherein the method increases the serum bicarbonate value from the baseline serum bicarbonate value to an increased serum bicarbonate value of at least 27 mEq/l. 
     Embodiment 37. The method of any preceding enumerated embodiment wherein the method increases the serum bicarbonate value from the baseline serum bicarbonate value to an increased serum bicarbonate value of at least 28 mEq/l. 
     Embodiment 38. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value to an increased serum bicarbonate value not in excess of 29 mEq/l. 
     Embodiment 39. The method of any of embodiments 1 to 36 wherein the method increases the baseline serum bicarbonate value to an increased serum bicarbonate value not in excess of 28 mEq/l. 
     Embodiment 40. The method of any of embodiments 1 to 35 wherein the method increases the baseline serum bicarbonate value to an increased serum bicarbonate value not in excess of 27 mEq/l. 
     Embodiment 41. The method of any of embodiments 1 to 34 wherein the method increases the baseline serum bicarbonate value to an increased serum bicarbonate value not in excess of 26 mEq/l. 
     Embodiment 42. The method of any of embodiments 1 to 33 wherein the method increases the baseline serum bicarbonate value to an increased serum bicarbonate value not in excess of 25 mEq/l. 
     Embodiment 45. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value at least 1 mEq/l. 
     Embodiment 46. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value at least 1.5 mEq/l. 
     Embodiment 47. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value at least 2 mEq/l. 
     Embodiment 48. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value at least 2.5 mEq/l. 
     Embodiment 49. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value at least 3 mEq/l. 
     Embodiment 50. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value at least 3.5 mEq/l. 
     Embodiment 51. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value at least 4 mEq/l. 
     Embodiment 52. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value at least 4.5 mEq/l. 
     Embodiment 53. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value at least 5 mEq/l. 
     Embodiment 54. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value at least 5.5 mEq/l. 
     Embodiment 55. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value at least 6 mEq/l. 
     Embodiment 56. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value at least 6.5 mEq/l. 
     Embodiment 57. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value at least 7 mEq/l. 
     Embodiment 58. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value at least 7.5 mEq/l. 
     Embodiment 59. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value at least 8 mEq/l. 
     Embodiment 60. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value at least 8.5 mEq/l. 
     Embodiment 61. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value at least 9 mEq/l. 
     Embodiment 62. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value to a value within the range of 24 to 29 mEq/l within a treatment period of less than one month. 
     Embodiment 63. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value to a value within the range of 24 to 29 mEq/l within a treatment period of 25 days. 
     Embodiment 64. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value to a value within the range of 24 to 29 mEq/l within a treatment period of 3 weeks. 
     Embodiment 65. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value to a value within the range of 24 to 29 mEq/l within a treatment period of 15 days. 
     Embodiment 66. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value to a value within the range of 24 to 29 mEq/l within a treatment period of 2 weeks. 
     Embodiment 67. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value to a value within the range of 24 to 29 mEq/l within a treatment period of 10 days. 
     Embodiment 68. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value to a value within the range of 24 to 29 mEq/l within a treatment period of 1 week. 
     Embodiment 69. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value to a value within the range of 24 to 29 mEq/l within 6 days of the initiation of the treatment. 
     Embodiment 70. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value to a value within the range of 24 to 29 mEq/l within a treatment period of 5 days. 
     Embodiment 71. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value to a value within the range of 24 to 29 mEq/l within a treatment period of 4 days. 
     Embodiment 72. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value to a value within the range of 24 to 29 mEq/l within a treatment period of 3 days. 
     Embodiment 73. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value to a value within the range of 24 to 29 mEq/l within a treatment period of 2 days. 
     Embodiment 74. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value to a value within the range of 24 to 29 mEq/l within a treatment period of 1 day. 
     Embodiment 75. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value to a value within the range of 24 to 29 mEq/l within a treatment period of 12 hours. 
     Embodiment 76. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value to a value within the range of 24 to 29 mEq/l without any change in the individual&#39;s diet or dietary habits relative to the period immediately preceding the initiation of treatment. 
     Embodiment 77. The method of any preceding enumerated embodiment wherein the method increases the baseline serum bicarbonate value to a value within the range of 24 to 29 mEq/l independent of the individual&#39;s diet or dietary habits. 
     Embodiment 78. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±2.5 mEq/l within 1 month of the cessation of treatment. 
     Embodiment 79. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±2.5 mEq/l within 3 weeks of the cessation of treatment. 
     Embodiment 80. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±2.5 mEq/l within 2 weeks of the cessation of treatment. 
     Embodiment 81. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±2.5 mEq/l within 10 days of the cessation of treatment. 
     Embodiment 82. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±2.5 mEq/l within 9 days of the cessation of treatment. 
     Embodiment 83. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±2.5 mEq/l within 8 days of the cessation of treatment. 
     Embodiment 84. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±2.5 mEq/l within 7 days of the cessation of treatment. 
     Embodiment 85. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±2.5 mEq/l within 6 days of the cessation of treatment. 
     Embodiment 86. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±2.5 mEq/l within 5 days of the cessation of treatment. 
     Embodiment 87. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±2.5 mEq/l within 4 days of the cessation of treatment. 
     Embodiment 88. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±2.5 mEq/l within 3 days of the cessation of treatment. 
     Embodiment 89. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±2.5 mEq/l within 2 days of the cessation of treatment. 
     Embodiment 90. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±2.5 mEq/l within 1 day of the cessation of treatment. 
     Embodiment 91. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±2 mEq/l within 1 month of the cessation of treatment. 
     Embodiment 92. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±2 mEq/l within 3 weeks of the cessation of treatment. 
     Embodiment 93. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±2 mEq/l within 2 weeks of the cessation of treatment. 
     Embodiment 94. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±2 mEq/l within 10 days of the cessation of treatment. 
     Embodiment 95. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±2 mEq/l within 9 days of the cessation of treatment. 
     Embodiment 96. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±2 mEq/l within 8 days of the cessation of treatment. 
     Embodiment 97. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±2 mEq/l within 7 days of the cessation of treatment. 
     Embodiment 98. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±2 mEq/l within 6 days of the cessation of treatment. 
     Embodiment 99. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±2 mEq/l within 5 days of the cessation of treatment. 
     Embodiment 100. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±2 mEq/l within 4 days of the cessation of treatment. 
     Embodiment 101. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±2 mEq/l within 3 days of the cessation of treatment. 
     Embodiment 102. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±2 mEq/l within 2 days of the cessation of treatment. 
     Embodiment 103. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±2 mEq/l within 1 day of the cessation of treatment. 
     Embodiment 104. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±1.5 mEq/l within 1 month of the cessation of treatment. 
     Embodiment 105. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±1.5 mEq/l within 3 weeks of the cessation of treatment. 
     Embodiment 106. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±1.5 mEq/l within 2 weeks of the cessation of treatment. 
     Embodiment 107. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±1.5 mEq/l within 10 days of the cessation of treatment. 
     Embodiment 108. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±1.5 mEq/l within 9 days of the cessation of treatment. 
     Embodiment 109. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±1.5 mEq/l within 8 days of the cessation of treatment. 
     Embodiment 110. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±1.5 mEq/l within 7 days of the cessation of treatment. 
     Embodiment 111. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±1.5 mEq/l within 6 days of the cessation of treatment. 
     Embodiment 112. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±1.5 mEq/l within 5 days of the cessation of treatment. 
     Embodiment 113. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±1.5 mEq/l within 4 days of the cessation of treatment. 
     Embodiment 114. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±1.5 mEq/l within 3 days of the cessation of treatment. 
     Embodiment 115. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±1.5 mEq/l within 2 days of the cessation of treatment. 
     Embodiment 116. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±1.5 mEq/l within 1 day of the cessation of treatment. 
     Embodiment 117. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±1 mEq/l within 1 month of the cessation of treatment. 
     Embodiment 118. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±1 mEq/l within 3 weeks of the cessation of treatment. 
     Embodiment 119. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±1 mEq/l within 2 weeks of the cessation of treatment. 
     Embodiment 120. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±1 mEq/l within 10 days of the cessation of treatment. 
     Embodiment 121. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±1 mEq/l within 9 days of the cessation of treatment. 
     Embodiment 122. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±1 mEq/l within 8 days of the cessation of treatment. 
     Embodiment 123. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±1 mEq/l within 7 days of the cessation of treatment. 
     Embodiment 124. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±1 mEq/l within 6 days of the cessation of treatment. 
     Embodiment 125. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±1 mEq/l within 5 days of the cessation of treatment. 
     Embodiment 126. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±1 mEq/l within 4 days of the cessation of treatment. 
     Embodiment 127. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±1 mEq/l within 3 days of the cessation of treatment. 
     Embodiment 128. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±1 mEq/l within 2 days of the cessation of treatment. 
     Embodiment 129. The method of any preceding enumerated embodiment wherein the individual&#39;s serum bicarbonate value returns to the baseline value±1 mEq/l within 1 day of the cessation of treatment. 
     Embodiment 130. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 1 mEq/l within 1 month of the cessation of treatment. 
     Embodiment 131. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 1 mEq/l within 3 weeks of the cessation of treatment. 
     Embodiment 132. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 1 mEq/l within 2 weeks of the cessation of treatment. 
     Embodiment 133. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 1 mEq/l within 10 days of the cessation of treatment. 
     Embodiment 134. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 1 mEq/l within 9 days of the cessation of treatment. 
     Embodiment 135. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 1 mEq/l within 8 days of the cessation of treatment. 
     Embodiment 136. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 1 mEq/l within 7 days of the cessation of treatment. 
     Embodiment 137. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 1 mEq/l within 6 days of the cessation of treatment. 
     Embodiment 138. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 1 mEq/l within 5 days of the cessation of treatment. 
     Embodiment 139. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 1 mEq/l within 4 days of the cessation of treatment. 
     Embodiment 140. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 1 mEq/l within 3 days of the cessation of treatment. 
     Embodiment 141. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 1 mEq/l within 2 days of the cessation of treatment. 
     Embodiment 142. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 1 mEq/l within 1 day of the cessation of treatment. 
     Embodiment 143. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 1.5 mEq/l within 1 month of the cessation of treatment. 
     Embodiment 144. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 1.5 mEq/l within 3 weeks of the cessation of treatment. 
     Embodiment 145. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 1.5 mEq/l within 2 weeks of the cessation of treatment. 
     Embodiment 146. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 1.5 mEq/l within 10 days of the cessation of treatment. 
     Embodiment 147. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 1.5 mEq/l within 9 days of the cessation of treatment. 
     Embodiment 148. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 1.5 mEq/l within 8 days of the cessation of treatment. 
     Embodiment 149. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 1.5 mEq/l within 7 days of the cessation of treatment. 
     Embodiment 150. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 1.5 mEq/l within 6 days of the cessation of treatment. 
     Embodiment 151. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 1.5 mEq/l within 5 days of the cessation of treatment. 
     Embodiment 152. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 1.5 mEq/l within 4 days of the cessation of treatment. 
     Embodiment 153. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 1.5 mEq/l within 3 days of the cessation of treatment. 
     Embodiment 154. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 1.5 mEq/l within 2 days of the cessation of treatment. 
     Embodiment 155. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 1.5 mEq/l within 1 day of the cessation of treatment. 
     Embodiment 156. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 2 mEq/l within 1 month of the cessation of treatment. 
     Embodiment 157. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 2 mEq/l within 3 weeks of the cessation of treatment. 
     Embodiment 158. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 2 mEq/l within 2 weeks of the cessation of treatment. 
     Embodiment 159. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 2 mEq/l within 10 days of the cessation of treatment. 
     Embodiment 160. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 2 mEq/l within 9 days of the cessation of treatment. 
     Embodiment 161. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 2 mEq/l within 8 days of the cessation of treatment. 
     Embodiment 162. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 2 mEq/l within 7 days of the cessation of treatment. 
     Embodiment 163. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 2 mEq/l within 6 days of the cessation of treatment. 
     Embodiment 164. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 2 mEq/l within 5 days of the cessation of treatment. 
     Embodiment 165. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 2 mEq/l within 4 days of the cessation of treatment. 
     Embodiment 166. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 2 mEq/l within 3 days of the cessation of treatment. 
     Embodiment 167. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 2 mEq/l within 2 days of the cessation of treatment. 
     Embodiment 168. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 2 mEq/l within 1 day of the cessation of treatment. 
     Embodiment 169. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 2.5 mEq/l within 1 month of the cessation of treatment. 
     Embodiment 170. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 2.5 mEq/l within 3 weeks of the cessation of treatment. 
     Embodiment 171. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 2.5 mEq/l within 2 weeks of the cessation of treatment. 
     Embodiment 172. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 2.5 mEq/l within 10 days of the cessation of treatment. 
     Embodiment 173. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 2.5 mEq/l within 9 days of the cessation of treatment. 
     Embodiment 174. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 2.5 mEq/l within 8 days of the cessation of treatment. 
     Embodiment 175. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 2.5 mEq/l within 7 days of the cessation of treatment. 
     Embodiment 176. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 2.5 mEq/l within 6 days of the cessation of treatment. 
     Embodiment 177. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 2.5 mEq/l within 5 days of the cessation of treatment. 
     Embodiment 178. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 2.5 mEq/l within 4 days of the cessation of treatment. 
     Embodiment 179. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 2.5 mEq/l within 3 days of the cessation of treatment. 
     Embodiment 180. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 2.5 mEq/l within 2 days of the cessation of treatment. 
     Embodiment 181. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 2.5 mEq/l within 1 day of the cessation of treatment. 
     Embodiment 182. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 3 mEq/l within 1 month of the cessation of treatment. 
     Embodiment 183. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 3 mEq/l within 3 weeks of the cessation of treatment. 
     Embodiment 184. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 3 mEq/l within 2 weeks of the cessation of treatment. 
     Embodiment 185. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 3 mEq/l within 10 days of the cessation of treatment. 
     Embodiment 186. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 3 mEq/l within 9 days of the cessation of treatment. 
     Embodiment 187. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 3 mEq/l within 8 days of the cessation of treatment. 
     Embodiment 188. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 3 mEq/l within 7 days of the cessation of treatment. 
     Embodiment 189. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 3 mEq/l within 6 days of the cessation of treatment. 
     Embodiment 190. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 3 mEq/l within 5 days of the cessation of treatment. 
     Embodiment 191. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 3 mEq/l within 4 days of the cessation of treatment. 
     Embodiment 192. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 3 mEq/l within 3 days of the cessation of treatment. 
     Embodiment 193. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 3 mEq/l within 2 days of the cessation of treatment. 
     Embodiment 194. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 3 mEq/l within 1 day of the cessation of treatment. 
     Embodiment 195. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 3.5 mEq/l within 1 month of the cessation of treatment. 
     Embodiment 196. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 3.5 mEq/l within 3 weeks of the cessation of treatment. 
     Embodiment 197. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 3.5 mEq/l within 2 weeks of the cessation of treatment. 
     Embodiment 198. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 3.5 mEq/l within 10 days of the cessation of treatment. 
     Embodiment 199. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 3.5 mEq/l within 9 days of the cessation of treatment. 
     Embodiment 200. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 3.5 mEq/l within 8 days of the cessation of treatment. 
     Embodiment 201. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 3.5 mEq/l within 7 days of the cessation of treatment. 
     Embodiment 202. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 3.5 mEq/l within 6 days of the cessation of treatment. 
     Embodiment 203. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 3.5 mEq/l within 5 days of the cessation of treatment. 
     Embodiment 204. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 3.5 mEq/l within 4 days of the cessation of treatment. 
     Embodiment 205. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 3.5 mEq/l within 3 days of the cessation of treatment. 
     Embodiment 206. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 3.5 mEq/l within 2 days of the cessation of treatment. 
     Embodiment 207. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 3.5 mEq/l within 1 day of the cessation of treatment. 
     Embodiment 208. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 4 mEq/l within 1 month of the cessation of treatment. 
     Embodiment 209. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 4 mEq/l within 3 weeks of the cessation of treatment. 
     Embodiment 210. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 4 mEq/l within 2 weeks of the cessation of treatment. 
     Embodiment 211. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 4 mEq/l within 10 days of the cessation of treatment. 
     Embodiment 212. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 4 mEq/l within 9 days of the cessation of treatment. 
     Embodiment 213. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 4 mEq/l within 8 days of the cessation of treatment. 
     Embodiment 214. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 4 mEq/l within 7 days of the cessation of treatment. 
     Embodiment 215. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 4 mEq/l within 6 days of the cessation of treatment. 
     Embodiment 216. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 4 mEq/l within 5 days of the cessation of treatment. 
     Embodiment 217. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 4 mEq/l within 4 days of the cessation of treatment. 
     Embodiment 218. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 4 mEq/l within 3 days of the cessation of treatment. 
     Embodiment 219. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 4 mEq/l within 2 days of the cessation of treatment. 
     Embodiment 220. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 4 mEq/l within 1 day of the cessation of treatment. 
     Embodiment 221. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 4.5 mEq/l within 1 month of the cessation of treatment. 
     Embodiment 222. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 4.5 mEq/l within 3 weeks of the cessation of treatment. 
     Embodiment 223. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 4.5 mEq/l within 2 weeks of the cessation of treatment. 
     Embodiment 224. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 4.5 mEq/l within 10 days of the cessation of treatment. 
     Embodiment 225. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 4.5 mEq/l within 9 days of the cessation of treatment. 
     Embodiment 226. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 4.5 mEq/l within 8 days of the cessation of treatment. 
     Embodiment 227. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 4.5 mEq/l within 7 days of the cessation of treatment. 
     Embodiment 228. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 4.5 mEq/l within 6 days of the cessation of treatment. 
     Embodiment 229. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 4.5 mEq/l within 5 days of the cessation of treatment. 
     Embodiment 230. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 4.5 mEq/l within 4 days of the cessation of treatment. 
     Embodiment 231. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 4.5 mEq/l within 3 days of the cessation of treatment. 
     Embodiment 232. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 4.5 mEq/l within 2 days of the cessation of treatment. 
     Embodiment 233. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 4.5 mEq/l within 1 day of the cessation of treatment. 
     Embodiment 234. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 5 mEq/l within 1 month of the cessation of treatment. 
     Embodiment 235. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 5 mEq/l within 3 weeks of the cessation of treatment. 
     Embodiment 236. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 5 mEq/l within 2 weeks of the cessation of treatment. 
     Embodiment 237. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 5 mEq/l within 10 days of the cessation of treatment. 
     Embodiment 238. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 5 mEq/l within 9 days of the cessation of treatment. 
     Embodiment 239. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 5 mEq/l within 8 days of the cessation of treatment. 
     Embodiment 240. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 5 mEq/l within 7 days of the cessation of treatment. 
     Embodiment 241. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 5 mEq/l within 6 days of the cessation of treatment. 
     Embodiment 242. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 5 mEq/l within 5 days of the cessation of treatment. 
     Embodiment 243. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 5 mEq/l within 4 days of the cessation of treatment. 
     Embodiment 244. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 5 mEq/l within 3 days of the cessation of treatment. 
     Embodiment 245. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 5 mEq/l within 2 days of the cessation of treatment. 
     Embodiment 246. The method of any preceding enumerated embodiment wherein, upon cessation of the treatment, the individual&#39;s serum bicarbonate value decreases by at least 5 mEq/l within 1 day of the cessation of treatment. 
     Embodiment 247. The method of any preceding enumerated embodiment wherein the baseline serum bicarbonate value is the value of the serum bicarbonate concentration determined at a single time point. 
     Embodiment 248. The method of any of embodiments 1 to 246 wherein the baseline serum bicarbonate value is the mean value of at least two serum bicarbonate concentrations determined at different time-points. 
     Embodiment 249. The method of any of embodiments 1 to 246 wherein the baseline serum bicarbonate value is the mean value of at least two serum bicarbonate concentrations for serum samples drawn on different days. 
     Embodiment 250. The method of embodiment 249 wherein the baseline serum bicarbonate value is the mean value of at least two serum bicarbonate concentrations for serum samples drawn on consecutive days. 
     Embodiment 251. The method of embodiment 249 wherein the baseline serum bicarbonate value is the mean value of at least two serum bicarbonate concentrations for serum samples drawn on two consecutive days and prior to the initiation of the treatment. 
     Embodiment 252. The method of embodiment 249 wherein the baseline serum bicarbonate value is the mean or median value of at least two serum bicarbonate concentrations for serum samples drawn on non-consecutive days. 
     Embodiment 253. The method of embodiment 252 wherein the non-consecutive days are separated by at least two days. 
     Embodiment 254. The method of embodiment 252 wherein the non-consecutive days are separated by at least one week. 
     Embodiment 255. The method of embodiment 252 wherein the non-consecutive days are separated by at least two weeks. 
     Embodiment 256. The method of embodiment 252 wherein the non-consecutive days are separated by at least three weeks. 
     Embodiment 257. The method of any preceding enumerated embodiment wherein the individual is being treated for acute metabolic acidosis. 
     Embodiment 258. The method of any preceding enumerated embodiment wherein the individual is being treated for chronic metabolic acidosis. 
     Embodiment 259. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 7.5 mEq of a target species as it transits the digestive system. 
     Embodiment 260. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 10 mEq of a target species as it transits the digestive system. 
     Embodiment 261. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 15 mEq of a target species as it transits the digestive system. 
     Embodiment 262. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 20 mEq of a target species as it transits the digestive system. 
     Embodiment 263. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 25 mEq of a target species as it transits the digestive system. 
     Embodiment 264. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 30 mEq of a target species as it transits the digestive system. 
     Embodiment 265. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 35 mEq of a target species as it transits the digestive system. 
     Embodiment 266. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 40 mEq of a target species as it transits the digestive system. 
     Embodiment 267. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 45 mEq of a target species as it transits the digestive system. 
     Embodiment 268. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 50 mEq of a target species as it transits the digestive system. 
     Embodiment 269. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 55 mEq of a target species as it transits the digestive system. 
     Embodiment 270. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 60 mEq of a target species as it transits the digestive system. 
     Embodiment 271. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 65 mEq of a target species as it transits the digestive system. 
     Embodiment 272. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 70 mEq of a target species as it transits the digestive system. 
     Embodiment 273. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 75 mEq of a target species as it transits the digestive system. 
     Embodiment 274. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 80 mEq of a target species as it transits the digestive system. 
     Embodiment 275. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 85 mEq of a target species as it transits the digestive system. 
     Embodiment 276. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 90 mEq of a target species as it transits the digestive system. 
     Embodiment 277. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 95 mEq of a target species as it transits the digestive system. 
     Embodiment 278. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 100 mEq of a target species as it transits the digestive system. 
     Embodiment 279. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 105 mEq of a target species as it transits the digestive system. 
     Embodiment 280. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least 110 mEq of a target species as it transits the digestive system. 
     Embodiment 281. The method of any preceding enumerated embodiment wherein the daily dose is no more than 100 g/day. 
     Embodiment 282. The method of any preceding enumerated embodiment wherein the daily dose is no more than 90 g/day. 
     Embodiment 283. The method of any preceding enumerated embodiment wherein the daily dose is less than 75 g/day. 
     Embodiment 284. The method of any preceding enumerated embodiment wherein the daily dose is less than 65 g/day. 
     Embodiment 285. The method of any preceding enumerated embodiment wherein the daily dose is less than 50 g/day. 
     Embodiment 286. The method of any preceding enumerated embodiment wherein the daily dose is less than 40 g/day. 
     Embodiment 287. The method of any preceding enumerated embodiment wherein the daily dose is less than 30 g/day. 
     Embodiment 288. The method of any preceding enumerated embodiment wherein the daily dose is less than 25 g/day. 
     Embodiment 289. The method of any preceding enumerated embodiment wherein the daily dose is less than 20 g/day. 
     Embodiment 290. The method of any preceding enumerated embodiment wherein the daily dose is less than 15 g/day. 
     Embodiment 291. The method of any preceding enumerated embodiment wherein the daily dose is less than 10 g/day. 
     Embodiment 292. The method of any preceding enumerated embodiment wherein the daily dose is less than 5 g/day. 
     Embodiment 293. The method of any preceding enumerated embodiment wherein the individual is treated for at least one day. 
     Embodiment 294. The method of any preceding enumerated embodiment wherein the individual is treated for at least one week. 
     Embodiment 295. The method of any preceding enumerated embodiment wherein the individual is treated for at least one month. 
     Embodiment 296. The method of any preceding enumerated embodiment wherein the individual is treated for at least several months. 
     Embodiment 297. The method of any preceding enumerated embodiment wherein the individual is treated for at least six months. 
     Embodiment 298. The method of any preceding enumerated embodiment wherein the individual is treated for at least one year. 
     Embodiment 299. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a population of particles having a median particle diameter size (volume distribution) of at least 3 microns. 
     Embodiment 300. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a population of particles having a median particle diameter size (volume distribution) in the range of 5 to 1,000 microns. 
     Embodiment 301. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a population of particles having a median particle diameter size (volume distribution) in the range of 5 to 500 microns. 
     Embodiment 302. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a population of particles having a median particle diameter size (volume distribution) in the range of 10 to 400 microns. 
     Embodiment 303. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a population of particles having a median particle diameter size (volume distribution) in the range of 10 to 300 microns. 
     Embodiment 304. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a population of particles having a median particle diameter size (volume distribution) in the range of 20 to 250 microns. 
     Embodiment 305. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a population of particles having a median particle diameter size (volume distribution) in the range of 30 to 250 microns. 
     Embodiment 306. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a population of particles having a median particle diameter size (volume distribution) in the range of 40 to 180 microns. 
     Embodiment 307. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a population of particles in which less than 7% of the particles in the population (volume distribution) have a diameter less than 10 microns. 
     Embodiment 308. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a population of particles in which less than 5% of the particles in the particles in the population (volume distribution) have a diameter less than 10 microns. 
     Embodiment 309. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a population of particles in which less than 2.5% of the particles in the particles in the population (volume distribution) have a diameter less than 10 microns. 
     Embodiment 310. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a population of particles in which less than 1% of the particles in the particles in the population (volume distribution) have a diameter less than 10 microns. 
     Embodiment 311. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a population of particles having a particle size range that is (i) large enough to avoid passive or active absorption through the GI tract and (ii) small enough to not cause grittiness or unpleasant mouth feel when ingested as a powder, suspension, gel, and/or tablet. 
     Embodiment 312. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a population of particles have a Swelling Ratio of less than 9. 
     Embodiment 313. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a population of particles have a Swelling Ratio of less than 8. 
     Embodiment 314. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a population of particles have a Swelling Ratio of less than 7. 
     Embodiment 315. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a population of particles have a Swelling Ratio of less than 6. 
     Embodiment 316. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a population of particles have a Swelling Ratio of less than 5. 
     Embodiment 317. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a population of particles have a Swelling Ratio of less than 4. 
     Embodiment 318. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a population of particles have a Swelling Ratio of less than 3. 
     Embodiment 319. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a population of particles have a Swelling Ratio of less than 2. 
     Embodiment 320. The method of any preceding enumerated embodiment wherein the nonabsorbable composition has a theoretical binding capacity for the target species of at least about 0.5 mEq/g. 
     Embodiment 321. The method of any preceding enumerated embodiment wherein the nonabsorbable composition has a theoretical binding capacity for the target species of at least about 1 mEq/g. 
     Embodiment 322. The method of any preceding enumerated embodiment wherein the nonabsorbable composition has a theoretical binding capacity for the target species of at least about 2 mEq/g. 
     Embodiment 323. The method of any preceding enumerated embodiment wherein the nonabsorbable composition has a theoretical binding capacity for the target species of at least about 3 mEq/g. 
     Embodiment 324. The method of any preceding enumerated embodiment wherein the nonabsorbable composition has a theoretical binding capacity for the target species of at least about 4 mEq/g. 
     Embodiment 325. The method of any preceding enumerated embodiment wherein the nonabsorbable composition has a theoretical binding capacity for the target species of at least about 5 mEq/g. 
     Embodiment 326. The method of any preceding enumerated embodiment wherein the nonabsorbable composition has a theoretical binding capacity for the target species of at least about 7.5 mEq/g. 
     Embodiment 327. The method of any preceding enumerated embodiment wherein the nonabsorbable composition has a theoretical binding capacity for the target species of at least about 10 mEq/g. 
     Embodiment 328. The method of any preceding enumerated embodiment wherein the nonabsorbable composition has a theoretical binding capacity for the target species of at least about 12.5 mEq/g. 
     Embodiment 329. The method of any preceding enumerated embodiment wherein the nonabsorbable composition has a theoretical binding capacity for the target species of at least about 15 mEq/g. 
     Embodiment 330. The method of any preceding enumerated embodiment wherein the nonabsorbable composition has a theoretical binding capacity for the target species of at least about 20 mEq/g. 
     Embodiment 331. The method of any preceding enumerated embodiment wherein the nonabsorbable composition has a theoretical binding capacity for the target species of at least about 25 mEq/g. 
     Embodiment 332. The method of any preceding enumerated embodiment wherein the nonabsorbable composition has a theoretical binding capacity for the target species of at least about 30 mEq/g. 
     Embodiment 333. The method of any preceding enumerated embodiment wherein the nonabsorbable composition has a theoretical binding capacity for the target species of at least about 35 mEq/g. 
     Embodiment 334. The method of any preceding enumerated embodiment wherein the nonabsorbable composition has a theoretical binding capacity for the target species in the range of 2 to 25 mEq/g. 
     Embodiment 335. The method of any preceding enumerated embodiment wherein the nonabsorbable composition has a theoretical binding capacity for the target species in the range of 3 to 25 mEq/g. 
     Embodiment 336. The method of any preceding enumerated embodiment wherein the nonabsorbable composition has a theoretical binding capacity for the target species in the range of 5 to 25 mEq/g. 
     Embodiment 337. The method of any preceding enumerated embodiment wherein the nonabsorbable composition has a theoretical binding capacity for the target species in the range of 10 to 25 mEq/g. 
     Embodiment 338. The method of any preceding enumerated embodiment wherein the nonabsorbable composition has a theoretical binding capacity for the target species in the range of 5 to 20 mEq/g. 
     Embodiment 339. The method of any preceding enumerated embodiment wherein the nonabsorbable composition has a theoretical binding capacity for the target species in the range of 6 to 20 mEq/g. 
     Embodiment 340. The method of any preceding enumerated embodiment wherein the nonabsorbable composition has a theoretical binding capacity for the target species in the range of 7.5 to 20 mEq/g. 
     Embodiment 341. The method of any preceding enumerated embodiment wherein the nonabsorbable composition has a theoretical binding capacity for the target species in the range of 10 to 20 mEq/g. 
     Embodiment 342. The method of any preceding enumerated embodiment wherein the theoretical binding capacity for the target species is the theoretical binding capacity as determined in a SGF assay. 
     Embodiment 343. The method of any preceding enumerated embodiment wherein the target species comprises protons. 
     Embodiment 344. The method of any preceding enumerated embodiment wherein the target species comprises the conjugate base of a strong acid. 
     Embodiment 345. The method of any preceding enumerated embodiment wherein the target species comprises the conjugate base of a strong acid selected from the group consisting of chloride, bisulfate and sulfate ions. 
     Embodiment 346. The method of any preceding enumerated embodiment wherein the target species comprises chloride ions. 
     Embodiment 347. The method of any preceding enumerated embodiment wherein the target species comprises a strong acid. 
     Embodiment 348. The method of any preceding enumerated embodiment wherein the target species comprises hydrochloric acid. 
     Embodiment 349. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 1 mEq/g in a SIB assay. 
     Embodiment 350. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 1.5 mEq/g in a SIB assay. 
     Embodiment 351. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 2 mEq/g in a SIB assay. 
     Embodiment 352. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 2.5 mEq/g in a SIB assay. 
     Embodiment 353. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 3 mEq/g in a SIB assay. 
     Embodiment 354. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 3.5 mEq/g in a SIB assay. 
     Embodiment 355. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 4 mEq/g in a SIB assay. 
     Embodiment 356. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 4.5 mEq/g in a SIB assay. 
     Embodiment 357. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 5 mEq/g in a SIB assay. 
     Embodiment 358. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 5.5 mEq/g in a SIB assay. 
     Embodiment 359. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 6 mEq/g in a SIB assay. 
     Embodiment 360. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.1:1, respectively. 
     Embodiment 361. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.2:1, respectively. 
     Embodiment 362. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.25:1, respectively. 
     Embodiment 363. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.3:1, respectively. 
     Embodiment 364. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.35:1, respectively. 
     Embodiment 365. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.4:1, respectively. 
     Embodiment 366. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.45:1, respectively. 
     Embodiment 367. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.5:1, respectively. 
     Embodiment 368. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 2:3, respectively. 
     Embodiment 369. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.75:1, respectively. 
     Embodiment 370. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 0.9:1, respectively. 
     Embodiment 371. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 1:1, respectively. 
     Embodiment 372. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 1.25:1, respectively. 
     Embodiment 373. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 1.5:1, respectively. 
     Embodiment 374. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 1.75:1, respectively. 
     Embodiment 375. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 2:1, respectively. 
     Embodiment 376. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 2.25:1, respectively. 
     Embodiment 377. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 2.5:1, respectively. 
     Embodiment 378. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 2.75:1, respectively. 
     Embodiment 379. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 3:1, respectively. 
     Embodiment 380. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 4:1, respectively. 
     Embodiment 381. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 5:1, respectively. 
     Embodiment 382. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 6:1, respectively. 
     Embodiment 383. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride toc bound phosphate in a SIB assay is at least 7:1, respectively. 
     Embodiment 384. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 8:1, respectively. 
     Embodiment 385. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 9:1, respectively. 
     Embodiment 386. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 10:1, respectively. 
     Embodiment 387. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 12.5:1, respectively. 
     Embodiment 388. The method of any preceding enumerated embodiment wherein the ratio of the amount of bound chloride to bound phosphate in a SIB assay is at least 15:1, respectively. 
     Embodiment 389. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 5 mEq/day of the target species. 
     Embodiment 390. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 6 mEq/day of the target species. 
     Embodiment 391. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 7 mEq/day of the target species. 
     Embodiment 392. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 8 mEq/day of the target species. 
     Embodiment 393. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 9 mEq/day of the target species. 
     Embodiment 394. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 10 mEq/day of the target species. 
     Embodiment 395. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 11 mEq/day of the target species. 
     Embodiment 396. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 12 mEq/day of the target species. 
     Embodiment 397. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 13 mEq/day of the target species. 
     Embodiment 398. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 14 mEq/day of the target species. 
     Embodiment 399. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 15 mEq/day of the target species. 
     Embodiment 400. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 16 mEq/day of the target species. 
     Embodiment 401. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 17 mEq/day of the target species. 
     Embodiment 402. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 18 mEq/day of the target species. 
     Embodiment 403. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 19 mEq/day of the target species. 
     Embodiment 404. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 20 mEq/day of the target species. 
     Embodiment 405. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 21 mEq/day of the target species. 
     Embodiment 406. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 22 mEq/day of the target species. 
     Embodiment 407. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 23 mEq/day of the target species. 
     Embodiment 408. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 24 mEq/day of the target species. 
     Embodiment 409. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 25 mEq/day of the target species. 
     Embodiment 410. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 26 mEq/day of the target species. 
     Embodiment 411. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 27 mEq/day of the target species. 
     Embodiment 412. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 28 mEq/day of the target species. 
     Embodiment 413. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 29 mEq/day of the target species. 
     Embodiment 414. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 30 mEq/day of the target species. 
     Embodiment 415. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 31 mEq/day of the target species. 
     Embodiment 416. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 32 mEq/day of the target species. 
     Embodiment 417. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 33 mEq/day of the target species. 
     Embodiment 418. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 34 mEq/day of the target species. 
     Embodiment 419. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 35 mEq/day of the target species. 
     Embodiment 420. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 36 mEq/day of the target species. 
     Embodiment 421. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 37 mEq/day of the target species. 
     Embodiment 422. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 38 mEq/day of the target species. 
     Embodiment 423. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 39 mEq/day of the target species. 
     Embodiment 424. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 40 mEq/day of the target species. 
     Embodiment 425. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 41 mEq/day of the target species. 
     Embodiment 426. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 42 mEq/day of the target species. 
     Embodiment 427. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 43 mEq/day of the target species. 
     Embodiment 428. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 44 mEq/day of the target species. 
     Embodiment 429. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 45 mEq/day of the target species. 
     Embodiment 430. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 46 mEq/day of the target species. 
     Embodiment 431. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 47 mEq/day of the target species. 
     Embodiment 432. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 48 mEq/day of the target species. 
     Embodiment 433. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 49 mEq/day of the target species. 
     Embodiment 434. The method of any preceding enumerated embodiment wherein the daily dose has the capacity to remove at least about 50 mEq/day of the target species. 
     Embodiment 435. The method of any preceding enumerated embodiment wherein the daily dose removes less than 60 mEq/day of the target species. 
     Embodiment 436. The method of any preceding enumerated embodiment wherein the daily dose removes less than 55 mEq/day of the target species. 
     Embodiment 437. The method of any of embodiments 1 to 433 wherein the daily dose removes less than 50 mEq/day of the target species. 
     Embodiment 438. The method of any of embodiments 1 to 428 wherein the daily dose removes less than 45 mEq/day of the target species. 
     Embodiment 439. The method of any of embodiments 1 to 423 wherein the daily dose removes less than 40 mEq/day of the target species. 
     Embodiment 440. The method of any of embodiments 1 to 418 wherein the daily dose removes less than 35 mEq/day of the target species. 
     Embodiment 441. The method of any of embodiments 1 to 417 wherein the daily dose removes less than 34 mEq/day of the target species. 
     Embodiment 442. The method of any of embodiments 1 to 416 wherein the daily dose removes less than 33 mEq/day of the target species. 
     Embodiment 443. The method of any of embodiments 1 to 415 wherein the daily dose removes less than 32 mEq/day of the target species. 
     Embodiment 444. The method of any of embodiments 1 to 414 wherein the daily dose removes less than 31 mEq/day of the target species. 
     Embodiment 445. The method of any of embodiments 1 to 413 wherein the daily dose removes less than 30 mEq/day of the target species. 
     Embodiment 446. The method of any of embodiments 1 to 412 wherein the daily dose removes less than 29 mEq/day of the target species. 
     Embodiment 447. The method of any of embodiments 1 to 411 wherein the daily dose removes less than 28 mEq/day of the target species. 
     Embodiment 448. The method of any of embodiments 1 to 410 wherein the daily dose removes less than 27 mEq/day of the target species. 
     Embodiment 449. The method of any of embodiments 1 to 409 wherein the daily dose removes less than 26 mEq/day of the target species. 
     Embodiment 450. The method of any of embodiments 1 to 408 wherein the daily dose removes less than 25 mEq/day of the target species. 
     Embodiment 451. The method of any of embodiments 1 to 407 wherein the daily dose removes less than 24 mEq/day of the target species. 
     Embodiment 452. The method of any of embodiments 1 to 406 wherein the daily dose removes less than 23 mEq/day of the target species. 
     Embodiment 453. The method of any of embodiments 1 to 405 wherein the daily dose removes less than 22 mEq/day of the target species. 
     Embodiment 454. The method of any of embodiments 1 to 404 wherein the daily dose removes less than 21 mEq/day of the target species. 
     Embodiment 455. The method of any of embodiments 1 to 403 wherein the daily dose removes less than 20 mEq/day of the target species. 
     Embodiment 456. The method of any of embodiments 1 to 402 wherein the daily dose removes less than 19 mEq/day of the target species. 
     Embodiment 457. The method of any of embodiments 1 to 401 wherein the daily dose removes less than 18 mEq/day of the target species. 
     Embodiment 458. The method of any of embodiments 1 to 400 wherein the daily dose removes less than 17 mEq/day of the target species. 
     Embodiment 459. The method of any of embodiments 1 to 399 wherein the daily dose removes less than 16 mEq/day of the target species. 
     Embodiment 460. The method of any of embodiments 1 to 398 wherein the daily dose removes less than 15 mEq/day of the target species. 
     Embodiment 461. The method of any of embodiments 1 to 397 wherein the daily dose removes less than 14 mEq/day of the target species. 
     Embodiment 462. The method of any of embodiments 1 to 396 wherein the daily dose removes less than 13 mEq/day of the target species. 
     Embodiment 463. The method of any of embodiments 1 to 395 wherein the daily dose removes less than 12 mEq/day of the target species. 
     Embodiment 464. The method of any of embodiments 1 to 394 wherein the daily dose removes less than 11 mEq/day of the target species. 
     Embodiment 465. The method of any of embodiments 1 to 393 wherein the daily dose removes less than 10 mEq/day of the target species. 
     Embodiment 466. The method of any of embodiments 1 to 392 wherein the daily dose removes less than 9 mEq/day of the target species. 
     Embodiment 467. The method of any of embodiments 1 to 391 wherein the daily dose removes less than 8 mEq/day of the target species. 
     Embodiment 468. The method of any of embodiments 1 to 390 wherein the daily dose removes less than 7 mEq/day of the target species. 
     Embodiment 469. The method of any of embodiments 1 to 389 wherein the daily dose removes less than 6 mEq/day of the target species. 
     Embodiment 470. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange material comprising an insoluble (in the gastric environment) support structure and exchangeable cations. 
     Embodiment 471. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange material comprising an insoluble (in the gastric environment) support structure and exchangeable cations wherein the cation exchange material is organic, inorganic or a composite thereof. 
     Embodiment 472. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange material comprising exchangeable cations selected from the group consisting of lithium, sodium, potassium, calcium, magnesium, iron and combinations thereof. 
     Embodiment 473. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange material comprising exchangeable cations selected from the group consisting of sodium, potassium, calcium, magnesium, and combinations thereof. 
     Embodiment 474. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange material comprising exchangeable cations selected from the group consisting of sodium, potassium, and combinations thereof. 
     Embodiment 475. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange material comprising a combination of exchangeable cations that establish or maintain electrolyte homeostasis. 
     Embodiment 476. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange material optionally containing exchangeable sodium ions provided, however, that the amount of the sodium ions in a daily dose is insufficient to increase the patient&#39;s serum sodium ion concentration to a value outside the range of 135 to 145 mEq/l. 
     Embodiment 477. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange material optionally containing exchangeable potassium ions provided, however, that the amount of the sodium ions in a daily dose is insufficient to increase the patient&#39;s serum potassium ion concentration to a value outside the range of 3.7 to 5.2 mEq/L. 
     Embodiment 478. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange material optionally containing exchangeable magnesium ions provided, however, that the amount of the magnesium ions in a daily dose is insufficient to increase the patient&#39;s serum magnesium ion concentration to a value outside the range of 1.7 to 2.2 mg/dL. 
     Embodiment 479. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange material optionally containing exchangeable calcium ions provided, however, that the amount of the calcium ions in a daily dose is insufficient to increase the patient&#39;s serum calcium ion concentration to a value outside the range of 8.5 to 10.2 mg/dL. 
     Embodiment 480. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange material optionally containing a combination of exchangeable cations selected from the group consisting of sodium, potassium, calcium, magnesium, and combinations thereof, designed to maintain serum Na* levels within the range of 135 to 145 mEq/l, serum K +  levels within the range of 3.7 to 5.2 mEq/L, serum Mg 2+  levels within the range of 1.7 to 2.2 mg/dL and serum Ca 2+  levels within the range of 8.5 to 10.2 mg/dL. 
     Embodiment 481. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange material containing exchangeable sodium ions and the composition contains less than 12% by weight sodium. 
     Embodiment 482. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange material containing exchangeable sodium ions and the composition contains less than 9% by weight sodium. 
     Embodiment 483. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange material containing exchangeable sodium ions and the composition contains less than 6% by weight sodium. 
     Embodiment 484. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange material containing exchangeable sodium ions and the composition contains less than 3% by weight sodium. 
     Embodiment 485. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange material containing exchangeable sodium ions and the composition contains less than 1% by weight sodium. 
     Embodiment 486. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange material containing exchangeable sodium ions and the composition contains less than 0.1% by weight sodium. 
     Embodiment 487. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange material containing exchangeable sodium ions and the composition contains less than 0.01% by weight sodium. 
     Embodiment 488. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange material containing exchangeable sodium ions and the composition contains between 0.05 and 3% by weight sodium. 
     Embodiment 489. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a polymeric material having the capacity to bind protons in aqueous solutions. 
     Embodiment 490. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a polymeric material having the capacity to bind protons in aqueous solutions and the nonabsorbable composition is selected from the group consisting of crosslinked polymeric materials containing a polyanion backbone. 
     Embodiment 491. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a polymeric material having the capacity to bind protons in aqueous solutions and the nonabsorbable composition is selected from the group consisting of crosslinked polymeric materials containing a polyanion backbone wherein the polyanion backbone is selected from the group consisting of poly(carboxylic acids), poly(acrylic acids), poly(sulfonic acids), poly(maleic acids), poly(phenols), functionalized polyols and poly(alcohols), poly(hydroxamic acids), poly(imides) and copolymers thereof. 
     Embodiment 492. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a polymeric material having the capacity to bind protons in aqueous solutions, the nonabsorbable composition is selected from the group consisting of crosslinked polymeric materials containing a polyanion backbone, and the polyanion backbone is coordinated to exchangeable monovalent cations, divalent cations, or a combination thereof. 
     Embodiment 493. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange resin comprising a polyanion backbone that exchanges cations for protons and has an average pKa of at least 4. 
     Embodiment 494. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange resin comprising a polyanion backbone that exchanges cations for protons and has an average pKa of 4-5. 
     Embodiment 495. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange resin comprising a polyanion backbone that exchanges cations for protons and has an average pKa of 5-6. 
     Embodiment 496. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange resin comprising a polyanion backbone that exchanges cations for protons and has an average pKa of 6-7. 
     Embodiment 497. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange resin comprising a polyanion backbone that exchanges cations for protons and has an average pKa of at least 7. 
     Embodiment 498. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange resin selected from the group consisting of poly(carboxylic acids), poly(acrylic acids), poly(sulfonic acids), poly(maleic acids), poly(phenols), functionalized polyols and poly(alcohols), poly(hydroxamic acids), poly(imides) and copolymers thereof. 
     Embodiment 499. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange resin selected from the group consisting of poly(carboxylic acids), poly(acrylic acids), poly(sulfonic acids), poly(maleic acids), poly(phenols), functionalized polyols and poly(alcohols), poly(hydroxamic acids), poly(imides) and copolymers thereof wherein the polyanion backbone is further functionalized with functional groups to affect the pKa. 
     Embodiment 500. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange resin selected from the group consisting of poly(carboxylic acids), poly(acrylic acids), poly(sulfonic acids), poly(maleic acids), poly(phenols), functionalized polyols and poly(alcohols), poly(hydroxamic acids), poly(imides) and copolymers thereof wherein the polyanion backbone is further functionalized with functional groups to affect the pKa, the functional groups being electron withdrawing or electron donating functional groups. 
     Embodiment 501. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a cation exchange resin selected from the group consisting of poly(carboxylic acids), poly(acrylic acids), poly(sulfonic acids), poly(maleic acids), poly(phenols), functionalized polyols and poly(alcohols), poly(hydroxamic acids), poly(imides) and copolymers thereof wherein the polyanion backbone is further functionalized with functional groups to affect the pKa, the functional groups being electron withdrawing or electron donating functional groups selected from the group consisting of flouro, chloro, amino, hydroxyl, alkoxy, phenyl, sulphyl, nitroxyl, and cyano. 
     Embodiment 502. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a ceramic material. 
     Embodiment 503. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a ceramic material and the ceramic material is microporous or mesoporous. 
     Embodiment 504. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a ceramic material and the ceramic material is microporous. 
     Embodiment 505. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a ceramic material and the ceramic material is mesoporous. 
     Embodiment 506. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a ceramic material and the ceramic material is a cation exchange ceramic composition. 
     Embodiment 507. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a ceramic material and the ceramic material comprises a molecular sieve. 
     Embodiment 508. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a ceramic material and the ceramic material comprises a molecular sieve selected from the group consisting of silicas, metalloaluminates, aluminophosphates and gallogerminates. 
     Embodiment 509. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a ceramic material and the ceramic material comprises a silica molecular sieve. 
     Embodiment 510. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a ceramic material and the ceramic material comprises a titanoslicate molecular sieve. 
     Embodiment 511. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a ceramic material and the ceramic material comprises a metallosilicate molecular sieve. 
     Embodiment 512. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a ceramic material and the ceramic material comprises a zeolite, a borosilicate, a gallosilicate, a ferrisilicate or a chromosilicate molecular sieve. 
     Embodiment 513. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a ceramic material and the ceramic material comprises a molecular sieve. 
     Embodiment 514. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is an anion exchange material comprising an insoluble (in the gastric environment) support structure and exchangeable anions. 
     Embodiment 515. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is an anion exchange material comprising an insoluble (in the gastric environment) support structure and exchangeable anions and the anion exchange material is organic, inorganic, or a composite thereof. 
     Embodiment 516. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a strongly basic anion exchange material. 
     Embodiment 517. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a weakly basic anion exchange material. 
     Embodiment 518. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is an anion exchange material comprising quaternary amine moieties, phosphonium salts, N-heteroaromatic salts, or combinations thereof. 
     Embodiment 519. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is an anion exchange material comprising a poly(ionic liquid), wherein the side chain is selected from the group consisting of salts of tetraalkyl ammonium, imidazolium, pyridinium, pyrrolidonium, guanidinium, piperidinium, and tetraalkyl phosphonium cations and combinations thereof. 
     Embodiment 520. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is an anion exchange material having the capacity to induce an increase in the individual&#39;s serum bicarbonate value, at least in part, by delivering a physiologically significant amount of hydroxide, carbonate, citrate or other bicarbonate equivalent, or a combination thereof. 
     Embodiment 521. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is an anion exchange material comprising at least 1 mEq/g of an anion selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anion, or a combination thereof. 
     Embodiment 522. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is an anion exchange material comprising at least 2 mEq/g of an anion selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anion. 
     Embodiment 523. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is an anion exchange material comprising at least 5 mEq/g of an anion selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anion. 
     Embodiment 524. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is an anion exchange material comprising at least 10 mEq/g of an anion selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anion. 
     Embodiment 525. The method of any of embodiments 1 to 523 wherein the nonabsorbable composition is an anion exchange material comprising less than 10 mEq/g of an anion selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anion, or a combination thereof. 
     Embodiment 526. The method of any of embodiments 1 to 522 wherein the nonabsorbable composition is an anion exchange material comprising less than 5 mEq/g of an anion selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anion. 
     Embodiment 527. The method of any of embodiments 1 to 522 wherein the nonabsorbable composition is an anion exchange material comprising less than 2.5 mEq/g of an anion selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anion. 
     Embodiment 528. The method of any of embodiments 1 to 520 wherein the nonabsorbable composition is an anion exchange material comprising less than 1 mEq/g of an anion selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anion. 
     Embodiment 529. The method of any of embodiments 1 to 519 wherein the nonabsorbable composition is an anion exchange material comprising less than 0.1 mEq/g of an anion selected from the group consisting of hydroxide, carbonate, citrate or other bicarbonate equivalent anion. 
     Embodiment 530. The method of any of embodiments 521 to 529 wherein the bicarbonate equivalent anion is selected from the group consisting of acetate, lactate and the conjugate bases of other short chain carboxylic acids. 
     Embodiment 531. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is an amphoteric ion exchange resin. 
     Embodiment 532. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a neutral composition having the capacity to bind both protons and anions. 
     Embodiment 533. The method of any preceding enumerated embodiment wherein the nonabsorbable composition is a neutral composition having the capacity to bind both protons and anions selected from the group consisting of polymers functionalized with propylene oxide, polymers functionalized with Michael acceptors, expanded porphyrins, covalent organic frameworks, and polymers containing amine and/or phosphine functional groups. 
     Embodiment 534. The method of any preceding enumerated embodiment wherein the nonabsorbable composition (i) removes more chloride ions than bicarbonate equivalent anions (ii) removes more chloride ions than phosphate anions, and (iii) removes more chloride ions than the conjugate bases of bile and fatty acids. 
     Embodiment 535. The method of any preceding enumerated embodiment wherein the treatment with the nonabsorbable composition does not have a clinically significant impact upon the serum or colon levels of a metabolically relevant species. 
     Embodiment 536. The method of any preceding enumerated embodiment wherein the treatment with the nonabsorbable composition does not have a clinically significant impact upon the serum or colon levels of a metabolically relevant cationic species. 
     Embodiment 537. The method of any preceding enumerated embodiment wherein the treatment with the nonabsorbable composition does not have a clinically significant impact upon the serum or colon levels of a metabolically relevant anionic species. 
     Embodiment 538. The method of any preceding enumerated embodiment wherein the treatment with the nonabsorbable composition does not have a clinically significant impact upon the serum potassium levels of a statistically significant number of individuals. 
     Embodiment 539. The method of any preceding enumerated embodiment wherein the treatment with the nonabsorbable composition does not have a clinically significant impact upon the serum phosphate levels of a statistically significant number of individuals. 
     Embodiment 540. The method of any preceding enumerated embodiment wherein the treatment with the nonabsorbable composition does not have a clinically significant impact upon the serum low density lipoprotein (LDL) levels of a statistically significant number of individuals. 
     Embodiment 541. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a proton-binding, crosslinked amine polymer comprising the residue of an amine corresponding to Formula 1: 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2  and R 3  are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl provided, however, at least one of R 1 , R 2  and R 3  is other than hydrogen. 
     Embodiment 542. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a proton-binding, crosslinked amine polymer comprising the residue of an amine corresponding to Formula 1: 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2  and R 3  are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl provided, however, at least one of R 1 , R 2  and R 3  is other than hydrogen, and the crosslinked amine polymer has (i) an equilibrium proton binding capacity of at least 5 mmol/g and a chloride ion binding capacity of at least 5 mmol/g in an aqueous simulated gastric fluid buffer (“SGF”) containing 35 mM NaCl and 63 mM HCl at pH 1.2 and 37° C., and (ii) an equilibrium swelling ratio in deionized water of about 2 or less. 
     Embodiment 543. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising the residue of an amine corresponding to Formula 1: 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2  and R 3  are independently hydrogen, hydrocarbyl, substituted hydrocarbyl provided, however, at least one of R 1 , R 2  and R 3  is other than hydrogen, the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of about 5 or less, and the crosslinked amine polymer binds a molar ratio of chloride ions to interfering ions of at least 0.35:1, respectively, in an interfering ion buffer at 37° C. wherein the interfering ions are phosphate ions and the interfering ion buffer is a buffered solution at pH 5.5 of 36 mM chloride and 20 mM phosphate. 
     Embodiment 544. The method of any preceding enumerated embodiment wherein the nonabsorbable composition has an equilibrium chloride binding capacity of at least 7.5 mmol/g in an aqueous simulated gastric fluid buffer (“SGF”) containing 35 mM NaCl and 63 mM HCl at pH 1.2 and 37° C. 
     Embodiment 545. The method of any preceding enumerated embodiment wherein the nonabsorbable composition has an equilibrium chloride binding capacity of at least 10 mmol/g in an aqueous simulated gastric fluid buffer (“SGF”) containing 35 mM NaCl and 63 mM HCl at pH 1.2 and 37° C. 
     Embodiment 546. The method of any of embodiments 541 to 545 wherein R 1 , R 2  and R 3  are independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ethereal, heteroaryl or heterocyclic provided, however, each of R 1 , R 2  and R 3  is not hydrogen. 
     Embodiment 547. The method of any of embodiments 541 to 545 wherein R 1 , R 2  and R 3  are independently hydrogen, aliphatic or heteroaliphatic provided, however, at least one of R 1 , R 2  and R 3  is other than hydrogen. 
     Embodiment 548. The method of any of embodiments 541 to 547 wherein the crosslinked amine polymer is prepared by substitution polymerization of the amine with a polyfunctional crosslinker, optionally also comprising amine moieties. 
     Embodiment 549. The method of any of embodiments 541 to 548 wherein the crosslinked amine polymer comprises the residue of an amine corresponding to Formula 1a and the crosslinked amine polymer is prepared by radical polymerization of an amine corresponding to Formula 1a: 
     
       
         
         
             
             
         
       
     
     wherein R 4  and R 5  are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl. 
     Embodiment 550. The method of embodiment 549 wherein R 4  and R 5  are independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ethereal, heteroaryl or heterocyclic. 
     Embodiment 551. The method of embodiment 549 wherein R 4  and R 5  are independently hydrogen, aliphatic or heteroaliphatic. 
     Embodiment 552. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is a nonabsorbable composition comprising a crosslinked amine polymer containing the residue of an amine corresponding to Formula 1b and the crosslinked amine polymer is prepared by substitution polymerization of the amine corresponding to Formula 1b with a polyfunctional crosslinker: 
     
       
         
         
             
             
         
       
     
     wherein R 4  and R 5  are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl, R 6  is aliphatic and R 61  and R 62  are independently hydrogen, aliphatic, or heteroaliphatic. 
     Embodiment 553. The method of embodiment 552 wherein R 4  and R 5  are independently hydrogen, saturated hydrocarbon, unsaturated aliphatic, aryl, heteroaryl, heteroalkyl, or unsaturated heteroaliphatic. 
     Embodiment 554. The method of embodiment 552 wherein R 4  and R 5  are independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ethereal, heteroaryl or heterocyclic. 
     Embodiment 555. The method of embodiment 552 wherein R 4  and R 5  are independently hydrogen, allyl, or aminoalkyl. 
     Embodiment 556. The method of any preceding enumerated embodiment wherein the pharmaceutical composition is in a dosage unit form. 
     Embodiment 557. The method of embodiment 556 wherein the dosage unit form is a capsule, tablet or sachet dosage form. 
     Embodiment 558. The method of any preceding enumerated embodiment wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier, excipient, or diluent. 
     Embodiment 559. The method of any preceding enumerated embodiment wherein the daily dose is administered once-a-day (QD). 
     Embodiment 560. The method of any preceding enumerated embodiment wherein the daily dose is administered twice-a-day (BID). 
     Embodiment 561. The method of any preceding enumerated embodiment wherein the daily dose is administered three times a day. 
     Embodiment 562. The method of any preceding enumerated embodiments wherein the daily dose is obtained from a pharmaceutical product comprising a sealed container and the nonabsorbable composition within the sealed container. 
     Embodiment 563. The method of embodiment 562 wherein the sealed container comprises a moisture barrier. 
     Embodiment 564. The method of embodiment 562 or 563 wherein the sealed container comprises an oxygen barrier. 
     Embodiment 565. The method of any of embodiments 562 to 564 wherein the sealed container is a sealed sachet. 
     Embodiment 566. The method of any of embodiments 562 to 564 wherein the sealed container comprises a multi-layer laminate of an inner contact layer, an outer layer; and a barrier layer disposed between the contact layer and outer layer. 
     Embodiment 567. The method of any of embodiments 562 to 564 wherein the sealed container comprises a multi-layer laminate of an inner contact layer, an outer layer; and an oxygen-barrier layer disposed between the contact layer and outer layer. 
     Embodiment 568. The method of any of embodiments 562 to 564 wherein the sealed container comprises a multi-layer laminate of an inner contact layer, an outer layer; and a moisture-barrier layer disposed between the contact layer and outer layer. 
     Embodiment 569. The method of any of embodiments 562 to 564 wherein the sealed container comprises a multi-layer laminate of an inner contact layer, an outer layer; and an oxygen-barrier layer and a moisture-barrier layer disposed between the contact layer and outer layer. 
     Embodiment 570. The method of any of embodiments 562 to 564 wherein the sealed container comprises a multi-layer laminate of an inner contact layer, an outer layer; and an oxygen-scavenging layer disposed between the contact layer and the outer layer. 
     Embodiment 571. A composition for use in a method of treating metabolic acidosis in an adult human patient wherein in said treatment 0.1-12 g of said composition is administered to the patient per day, said composition being a nonabsorbable composition having the capacity to remove protons from the patient, wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 2.5 mEq/g in a Simulated Small Intestine Inorganic Buffer (“SIB”) assay. 
     Embodiment 572. A composition for use in a method of treating metabolic acidosis in an adult human patient, said patient having a serum bicarbonate level of less than 20 mEq/L prior to treatment, said composition being a nonabsorbable composition having the capacity to remove protons from the patient. 
     Embodiment 573. The composition for use according to embodiment 572, wherein the patient&#39;s serum bicarbonate level is less than 19 mEq/L prior to treatment. 
     Embodiment 574. The composition for use according to embodiment 572, wherein the patient&#39;s serum bicarbonate level is less than 18 mEq/L prior to treatment. 
     Embodiment 575. The composition for use according to embodiment 572, wherein the patient&#39;s serum bicarbonate level is less than 17 mEq/L prior to treatment. 
     Embodiment 576. The composition for use according to embodiment 572, wherein the patient&#39;s serum bicarbonate level is less than 16 mEq/L prior to treatment. 
     Embodiment 577. The composition for use according to embodiment 572, wherein the patient&#39;s serum bicarbonate level is less than 15 mEq/L prior to treatment. 
     Embodiment 578. The composition for use according to embodiment 572, wherein the patient&#39;s serum bicarbonate level is less than 14 mEq/L prior to treatment. 
     Embodiment 579. The composition for use according to embodiment 572, wherein the patient&#39;s serum bicarbonate level is less than 13 mEq/L prior to treatment. 
     Embodiment 580. The composition for use according to embodiment 572, wherein the patient&#39;s serum bicarbonate level is less than 12 mEq/L prior to treatment. 
     Embodiment 581. The composition for use according to embodiment 572, wherein the patient&#39;s serum bicarbonate level is less than 11 mEq/L prior to treatment. 
     Embodiment 582. The composition for use according to embodiment 572, wherein the patient&#39;s serum bicarbonate level is less than 10 mEq/L prior to treatment. 
     Embodiment 583. The composition for use according to embodiment 572 to 582 wherein said patient&#39;s serum bicarbonate value is increased by at least 1 mEq/L over 15 days of treatment. 
     Embodiment 584. The composition of embodiment 572 to 583 wherein in said treatment 0.1-12 g of said polymer is administered to the patient per day. 
     Embodiment 585. The composition of any one of embodiments 572 to 584 wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 2.5 mEq/g in a Simulated Small Intestine Inorganic Buffer (“SIB”) assay. 
     Embodiment 586. A composition for use in a method of treating metabolic acidosis in an adult human patient by increasing that patient&#39;s serum bicarbonate value by at least 1 mEq/L over 15 days of treatment, said composition being a nonabsorbable composition having the capacity to remove protons from the patient. 
     Embodiment 587. The composition of embodiment 571 to 586 wherein in said treatment 0.1-12 g of said polymer is administered to the patient per day. 
     Embodiment 588. The composition of any one of embodiments 572 to 587 wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 2.5 mEq/g in a Simulated Small Intestine Inorganic Buffer (“SIB”) assay. 
     Embodiment 589. The composition according to anyone of embodiments 586 to 588 wherein the patient&#39;s serum bicarobate level value is increased by at least 1 mEq/L over 15 days of treatment. 
     Embodiment 590. The composition for use according to any one of embodiments 586 to 589, wherein the increase in serum bicarbonate level is at least 1.5 mEq/L. 
     Embodiment 591. The composition for use according to any one of embodiments 586 to 590, wherein the increase in serum bicarbonate level is at least 2 mEq/L. 
     Embodiment 592. The composition for use according to any one of embodiments 586 to 591, wherein the increase in serum bicarbonate level is at least 2.5 mEq/L. 
     Embodiment 593. The composition for use according to any one of embodiments 586 to 592, wherein the increase in serum bicarbonate level is at least 3 mEq/L. 
     Embodiment 594. The composition for use according to any one of embodiments 586 to 593, wherein the increase in serum bicarbonate level is at least 3.5 mEq/L. 
     Embodiment 595. The composition for use according to any one of embodiments 586 to 594, wherein the increase in serum bicarbonate level is at least 4 mEq/L. 
     Embodiment 596. The composition for use according to any one of embodiments 586 to 595, wherein the increase in serum bicarbonate level is at least 4.5 mEq/L. 
     Embodiment 597. The composition for use according to any one of embodiments 586 to 596, wherein the increase in serum bicarbonate level is at least 5 mEq/L. 
     Embodiment 598. The composition for use according to embodiment any one of embodiments 586 to 597, wherein the increase is observed during 14 days of treatment. 
     Embodiment 599. The composition for use according to embodiment any one of embodiments 586 to 598, wherein the increase is observed during 13 days of treatment. 
     Embodiment 600. The composition for use according to embodiment any one of embodiments 586 to 599, wherein the increase is observed during 12 days of treatment. 
     Embodiment 601. The composition for use according to embodiment any one of embodiments 586 to 600, wherein the increase is observed during 11 days of treatment. 
     Embodiment 602. The composition for use according to embodiment any one of embodiments 586 to 601, wherein the increase is observed during 10 days of treatment. 
     Embodiment 603. The composition for use according to embodiment any one of embodiments 586 to 602, wherein the increase is observed during 9 days of treatment. 
     Embodiment 604. The composition for use according to embodiment any one of embodiments 586 to 603, wherein the increase is observed during 8 days of treatment. 
     Embodiment 605. The composition for use according to embodiment any one of embodiments 586 to 604, wherein the increase is observed during 7 days of treatment. 
     Embodiment 606. The composition for use according to embodiment any one of embodiments 586 to 605, wherein the increase is observed during 6 days of treatment. 
     Embodiment 607. The composition for use according to embodiment any one of embodiments 586 to 606, wherein the increase is observed during 5 days of treatment. 
     Embodiment 608. The composition for use according to embodiment any one of embodiments 586 to 607, wherein the increase is observed during 4 days of treatment. 
     Embodiment 609. The composition for use according to embodiment any one of embodiments 586 to 608, wherein the increase is observed during 3 days of treatment. 
     Embodiment 610. The composition for use according to embodiment any one of embodiments 586 to 609, wherein the increase is observed during 2 days of treatment. 
     Embodiment 611. The composition for use according to embodiment any one of embodiments 586 to 610, wherein the increase is observed during 1 day of treatment. 
     Embodiment 612. The composition for use according to any one of embodiments 571 to 611 wherein the specified number of days of treatment are the first days of treatment with the composition. 
     Embodiment 613. The composition for use according to embodiment 572-601, wherein in said treatment 0.1-12 g of said polymer is administered to the patient per day. 
     Embodiment 614. The composition for use according to embodiment 613, wherein in said treatment 1-11 g of said polymer is administered to the patient per day. 
     Embodiment 615. The composition for use according to embodiment 613, wherein in said treatment 2-10 g of said polymer is administered to the patient per day. 
     Embodiment 616. The composition for use according to embodiment 613, wherein in said treatment 3-9 g of said polymer is administered to the patient per day. 
     Embodiment 617. The composition for use according to embodiment 613, wherein in said treatment 3-8 g of said polymer is administered to the patient per day. 
     Embodiment 618. The composition for use according to embodiment 613, wherein in said treatment 3-7 g of said polymer is administered to the patient per day. 
     Embodiment 619. The composition for use according to embodiment 613, wherein in said treatment 3-6 g of said polymer is administered to the patient per day. 
     Embodiment 620. The composition for use according to embodiment 613, wherein in said treatment 3.5-5.5 g of said polymer is administered to the patient per day. 
     Embodiment 621. The composition for use according to embodiment 613, wherein in said treatment 4-5 g of said polymer is administered to the patient per day. 
     Embodiment 622. The composition for use according to embodiment 613, wherein in said treatment 1-3 g of said polymer is administered to the patient per day. 
     Embodiment 623. The composition for use according to embodiment 571 or 572, wherein about 0.5 g of the composition is administered to the patient per day. 
     Embodiment 624. The composition for use according to embodiment 571 or 572, wherein about 1 g of the composition is administered to the patient per day. 
     Embodiment 625. The composition for use according to embodiment 571 or 572, wherein about 1.5 g of the composition is administered to the patient per day. 
     Embodiment 626. The composition for use according to embodiment 571 or 572, wherein about 2 g of the composition is administered to the patient per day. 
     Embodiment 627. The composition for use according to embodiment 571 or 572, wherein about 2.5 g of the composition is administered to the patient per day. 
     Embodiment 628. The composition for use according to embodiment 571 or 572, wherein about 3 g of the composition is administered to the patient per day. 
     Embodiment 629. The composition for use according to embodiment 571 or 572, wherein about 3.5 g of the composition is administered to the patient per day. 
     Embodiment 630. The composition for use according to embodiment 571 or 572, wherein about 4.0 g of the composition is administered to the patient per day. 
     Embodiment 631. The composition for use according to embodiment 571 or 572, wherein about 4.5 g of the composition is administered to the patient per day. 
     Embodiment 632. The composition for use according to embodiment 571 or 572, wherein about 5.0 g of the composition is administered to the patient per day. 
     Embodiment 633. The composition for use according to any one of embodiments 571 to 632, wherein the chloride ion binding capacity in a Simulated Small Intestine Inorganic Buffer (“SIB”) assay is at least 3 mEq/g. 
     Embodiment 634. The composition for use according to any one of embodiments 571 to 633, wherein the chloride ion binding capacity in a Simulated Small Intestine Inorganic Buffer (“SIB”) assay is at least 3.5 mEq/g. 
     Embodiment 635. The composition for use according to any one of embodiments 571 to 634, wherein the chloride ion binding capacity in a Simulated Small Intestine Inorganic Buffer (“SIB”) assay is at least 4 mEq/g. 
     Embodiment 636. The composition for use according to any one of embodiments 571 to 635, wherein the chloride ion binding capacity in a Simulated Small Intestine Inorganic Buffer (“SIB”) assay is at least 4.5 mEq/g. 
     Embodiment 637. The composition for use according to any one of embodiments 571 to 636, wherein the chloride ion binding capacity in a Simulated Small Intestine Inorganic Buffer (“SIB”) assay is at least 5 mEq/g. 
     Embodiment 638. The composition for use according anyone of embodiments 571 to 637, wherein the chloride ion binding capacity in a SIB assay is less than 10 mEq/g. 
     Embodiment 639. The composition for use according anyone of embodiments 571 to 638, wherein the chloride ion binding capacity in a SIB assay is less than 9 mEq/g. 
     Embodiment 640. The composition for use according anyone of embodiments 571 to 639, wherein the chloride ion binding capacity in a SIB assay is less than 8 mEq/g. 
     Embodiment 641. The composition for use according anyone of embodiments 571 to 640, wherein the chloride ion binding capacity in a SIB assay is less than 7 mEq/g. 
     Embodiment 642. The composition for use according anyone of embodiments 571 to 641, wherein the chloride ion binding capacity in a SIB assay is less than 6 mEq/g. 
     Embodiment 643. The composition for use according anyone of embodiments 571 to 642, wherein the chloride ion binding capacity in a SIB assay is less than 5 mEq/g. 
     Embodiment 644. A composition for use in a method of treating metabolic acidosis in an adult human patient wherein in said treatment &gt;12-100 g of said composition is administered to the patient per day, said composition being a nonabsorbable composition having the capacity to remove protons from the patient, wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of less than 2.5 mEq/g in a Simulated Small Intestine Inorganic Buffer (“SIB”) assay. 
     Embodiment 645. The composition according to embodiments 644 wherein the patient&#39;s serum bicarbonate value is increased by at least 1 mEq/L over 15 days of treatment. 
     Embodiment 646. A composition for use in a method of treating metabolic acidosis in an adult human patient by increasing that patient&#39;s serum bicarbonate value by at least 1 mEq/L over 15 days of treatment, wherein in said treatment &gt;12-100 g of said polymer is administered to the patient per day, said composition being a nonabsorbable composition having the capacity to remove protons from the patient, wherein the nonabsorbable composition is characterized by a chloride ion binding capacity of at least 2.5 mEq/g in a Simulated Small Intestine Inorganic Buffer (“SIB”) assay. 
     Embodiment 647. The composition for use according to embodiment 645 or 646, wherein the increase in serum bicarbonate level is at least 1 mEq/L. 
     Embodiment 648. The composition for use according to embodiment 645 or 646, wherein the increase in serum bicarbonate level is at least 1.5 mEq/L. 
     Embodiment 649. The composition for use according to embodiment 645 or 646, wherein the increase in serum bicarbonate level is at least 2 mEq/L. 
     Embodiment 650. The composition for use according to embodiment 645 or 646, wherein the increase in serum bicarbonate level is at least 2.5 mEq/L. 
     Embodiment 651. The composition for use according to embodiment 645 or 646, wherein the increase in serum bicarbonate level is at least 3 mEq/L. 
     Embodiment 652. The composition for use according to embodiment 645 or 646, wherein the increase in serum bicarbonate level is at least 3.5 mEq/L. 
     Embodiment 653. The composition for use according to embodiment 645 or 646, wherein the increase in serum bicarbonate level is at least 4 mEq/L. 
     Embodiment 654. The composition for use according to embodiment 645 or 646, wherein the increase in serum bicarbonate level is at least 4.5 mEq/L. 
     Embodiment 655. The composition for use according to embodiment 645 or 646, wherein the increase in serum bicarbonate level is at least 5 mEq/L. 
     Embodiment 656. The composition for use according to embodiment 645 or 646, wherein the increase is observed during 14 days of treatment. 
     Embodiment 657. The composition for use according to embodiment 645 or 646, wherein the increase is observed during 13 days of treatment. 
     Embodiment 658. The composition for use according to embodiment 645 or 646, wherein the increase is observed during 12 days of treatment. 
     Embodiment 659. The composition for use according to embodiment 645 or 646, wherein the increase is observed during 11 days of treatment. 
     Embodiment 660. The composition for use according to embodiment 645 or 646, wherein the increase is observed during 10 days of treatment. 
     Embodiment 661. The composition for use according to embodiment 645 or 646, wherein the increase is observed during 9 days of treatment. 
     Embodiment 662. The composition for use according to embodiment 645 or 646, wherein the increase is observed during 8 days of treatment. 
     Embodiment 663. The composition for use according to embodiment 645 or 646, wherein the increase is observed during 7 days of treatment. 
     Embodiment 664. The composition for use according to embodiment 645 or 646, wherein the increase is observed during 6 days of treatment. 
     Embodiment 665. The composition for use according to embodiment 645 or 646, wherein the increase is observed during 5 days of treatment. 
     Embodiment 666. The composition for use according to embodiment 645 or 646, wherein the increase is observed during 4 days of treatment. 
     Embodiment 667. The composition for use according to embodiment 645 or 646, wherein the increase is observed during 3 days of treatment. 
     Embodiment 668. The composition for use according to embodiment 645 or 646, wherein the increase is observed during 2 days of treatment. 
     Embodiment 669. The composition for use according to embodiment 645 or 646, wherein the increase is observed during 1 day of treatment. 
     Embodiment 670. The composition for use according to any one of embodiments 644 to 654 wherein the specified number of days of treatment are the first days of treatment with the composition. 
     Embodiment 671. A composition for use according to embodiment 644 to 670 wherein 12-100 g is administered to the patient per day. 
     Embodiment 672. A composition for use according to embodiment 644 to 671 wherein 20-90 g is administered to the patient per day. 
     Embodiment 673. A composition for use according to embodiment 644 to 672 wherein 20-80 g is administered to the patient per day. 
     Embodiment 674. A composition for use according to embodiment 644 to 673 wherein 20-70 g is administered to the patient per day. 
     Embodiment 675. A composition for use according to embodiment 644 to 674 wherein 20-60 g is administered to the patient per day. 
     Embodiment 676. A composition for use according to embodiment 644 to 675 wherein 20-50 g is administered to the patient per day. 
     Embodiment 677. A composition for use according to embodiment 644 to 676 wherein 20-40 g is administered to the patient per day. 
     Embodiment 678. A composition for use according to embodiment 644 to 677 wherein 20-35 g is administered to the patient per day. 
     Embodiment 679. A composition for use according to embodiment 644 to 678 wherein 20-30 g is administered to the patient per day. 
     Embodiment 680. A composition for use according to embodiment 644 to 679 wherein 20-25 g is administered to the patient per day. 
     Embodiment 681. The composition for use according to anyone of embodiments 644 to 680, wherein the chloride ion binding capacity in a Simulated Small Intestine Inorganic Buffer (“SIB”) assay is less than 2 mEq/g. 
     Embodiment 682. The composition for use according to anyone of embodiments 644 to 681, wherein the chloride ion binding capacity in a Simulated Small Intestine Inorganic Buffer (“SIB”) assay is less than 1.5 mEq/g. 
     Embodiment 683. The composition for use according to anyone of embodiments 644 to 682, wherein the chloride ion binding capacity in a Simulated Small Intestine Inorganic Buffer (“SIB”) assay is less than 1 mEq/g. 
     Embodiment 684. The composition for use according to anyone of embodiments 644 to 683, wherein the chloride ion binding capacity in a Simulated Small Intestine Inorganic Buffer (“SIB”) assay is less than 0.75 mEq/g. 
     Embodiment 685. The composition for use according to anyone of embodiments 644 to 684, wherein the chloride ion binding capacity in a Simulated Small Intestine Inorganic Buffer (“SIB”) assay is greater than 0.5 mEq/g. 
     Embodiment 686. The composition for use according to anyone of embodiments 644 to 685, wherein the chloride ion binding capacity in a Simulated Small Intestine Inorganic Buffer (“SIB”) assay is greater than 1 mEq/g. 
     Embodiment 687. The composition for use according to anyone of embodiments 644 to 686, wherein the chloride ion binding capacity in a Simulated Small Intestine Inorganic Buffer (“SIB”) assay is greater than 1.5 mEq/g. 
     Embodiment 688. The composition for use according to anyone of embodiments 644 to 687, wherein the chloride ion binding capacity in a Simulated Small Intestine Inorganic Buffer (“SIB”) assay is greater than 2 mEq/g. 
     Embodiment 689. The composition for use according to any preceeding embodiment wherein the composition is administered once per day in order to provide the total specified daily dose. 
     Embodiment 690. The composition for use according to any preceeding embodiment wherein the composition is administered twice per day in order to provide the total specified daily dose. 
     Embodiment 691. The composition for use according to any preceeding embodiment wherein the composition is administered three times per day in order to provide the total specified daily dose. 
     Embodiment 692. The composition for use according to any preceding enumerated embodiment wherein said composition is administered orally. 
     Embodiment 693. The composition for use according to any one of embodiments 571 to 692 wherein the composition is a pharmaceutical composition comprising a proton-binding, crosslinked amine polymer comprising the residue of an amine corresponding to Formula 1: 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2  and R 3  are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl provided, however, at least one of R 1 , R 2  and R 3  is other than hydrogen, and the crosslinked amine polymer has (i) an equilibrium proton binding capacity of at least 5 mmol/g and a chloride ion binding capacity of at least 5 mmol/g in an aqueous simulated gastric fluid buffer (“SGF”) containing 35 mM NaCl and 63 mM HCl at pH 1.2 and 37° C., and (ii) an equilibrium swelling ratio in deionized water of about 2 or less. 
     Embodiment 694. The composition for use according to any one of embodiments 571 to 692 wherein the composition is a pharmaceutical composition comprising a proton-binding, crosslinked amine polymer comprising the residue of an amine corresponding to Formula 1: 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2  and R 3  are independently hydrogen, hydrocarbyl, substituted hydrocarbyl provided, however, at least one of R 1 , R 2  and R 3  is other than hydrogen, the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of about 5 or less, and the crosslinked amine polymer binds a molar ratio of chloride ions to interfering ions of at least 0.35:1, respectively, in an interfering ion buffer at 37° C. wherein the interfering ions are phosphate ions and the interfering ion buffer is a buffered solution at pH 5.5 of 36 mM chloride and 20 mM phosphate. 
     Embodiment 695. The composition for use according to anyone of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 682 wherein the crosslinked amine polymer has an equilibrium chloride binding capacity of at least 7.5 mmol/g in an aqueous simulated gastric fluid buffer (“SGF”) containing 35 mM NaCl and 63 mM HCl at pH 1.2 and 37° C. 
     Embodiment 696. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 682 wherein the crosslinked amine polymer has an equilibrium chloride binding capacity of at least 10 mmol/g in an aqueous simulated gastric fluid buffer (“SGF”) containing 35 mM NaCl and 63 mM HCl at pH 1.2 and 37° C. 
     Embodiment 697. The composition for use according to anyone of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 683 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of about 4 or less. 
     Embodiment 698. The composition for use according to anyone of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 683 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of about 3 or less. 
     Embodiment 699. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 683 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of about 2 or less. 
     Embodiment 700. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any preceding enumerated embodiment wherein R 1 , R 2  and R 3  are independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ethereal, heteroaryl or heterocyclic provided, however, each of R 1 , R 2  and R 3  is not hydrogen. 
     Embodiment 701. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any preceding enumerated embodiment wherein R 1 , R 2  and R 3  are independently hydrogen, aliphatic or heteroaliphatic provided, however, at least one of R 1 , R 2  and R 3  is other than hydrogen. 
     Embodiment 702. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any preceding enumerated embodiment wherein the crosslinked amine polymer is prepared by substitution polymerization of the amine with a polyfunctional crosslinker, optionally also comprising amine moieties. 
     Embodiment 703. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any of embodiments 693 to 701 wherein the crosslinked amine polymer comprises the residue of an amine corresponding to Formula 1a and the crosslinked amine polymer is prepared by radical polymerization of an amine corresponding to Formula 1a: 
     
       
         
         
             
             
         
       
     
     wherein R 4  and R 5  are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl. 
     Embodiment 704. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 703 wherein R 4  and R 5  are independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ethereal, heteroaryl or heterocyclic. 
     Embodiment 705. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 703 wherein R 4  and R 5  are independently hydrogen, aliphatic or heteroaliphatic. 
     Embodiment 706. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any of embodiments 693 to 701 wherein the crosslinked amine polymer comprises the residue of an amine corresponding to Formula 1b and the crosslinked amine polymer is prepared by substitution polymerization of the amine corresponding to Formula 1b with a polyfunctional crosslinker: 
     
       
         
         
             
             
         
       
     
     wherein R 4  and R 5  are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl, R 6  is aliphatic and R 61  and R 62  are independently hydrogen, aliphatic, or heteroaliphatic. 
     Embodiment 707. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 706 wherein R 4  and R 5  are independently hydrogen, saturated hydrocarbon, unsaturated aliphatic, aryl, heteroaryl, heteroalkyl, or unsaturated heteroaliphatic. 
     Embodiment 708. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 706 wherein R 4  and R 5  are independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ethereal, heteroaryl or heterocyclic. 
     Embodiment 709. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 706 wherein R 4  and R 5  are independently hydrogen, allyl, or aminoalkyl. 
     Embodiment 710. The composition for use according to anyone of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any preceding enumerated embodiment wherein the crosslinked amine polymer comprises the residue of an amine corresponding to Formula 1c: 
     
       
         
         
             
             
         
       
     
     wherein R 7  is hydrogen, aliphatic or heteroaliphatic and R 8  is aliphatic or heteroaliphatic. 
     Embodiment 711. The composition for use according to anyone of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any of embodiments 693 to 701 wherein the crosslinked amine polymer comprises the residue of an amine corresponding to Formula 2: 
     
       
         
         
             
             
         
       
     
     wherein 
     m and n are independently non-negative integers; 
     R 10 , R 20 , R 30 , and R 40  are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl; 
     X 1  is 
     
       
         
         
             
             
         
       
     
     X 2  is hydrocarbyl or substituted hydrocarbyl; 
     each X 11  is independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxy, or amino; and 
     z is a non-negative number. 
     Embodiment 712. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 711 wherein R 10 , R 20 , R 30 , and R 40  are independently hydrogen, aliphatic, aryl, heteroaliphatic, or heteroaryl, m and z are independently 0-3 and n is 0 or 1. 
     Embodiment 713. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 711 or 712 wherein X 2  is aliphatic or heteroaliphatic. 
     Embodiment 714. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 711, 712 or 713 wherein m is 1-3 and X 11  is hydrogen, aliphatic or heteroaliphatic. 
     Embodiment 715. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any of embodiments 693 to 701 wherein the crosslinked amine polymer comprises the residue of an amine corresponding to Formula 2a: 
     
       
         
         
             
             
         
       
     
     wherein 
     m and n are independently non-negative integers; 
     each R 11  is independently hydrogen, hydrocarbyl, heteroaliphatic, or heteroaryl; 
     R 21  and R 31 , are independently hydrogen or heteroaliphatic; 
     R 41  is hydrogen, substituted hydrocarbyl, or hydrocarbyl; 
     X 1  is 
     
       
         
         
             
             
         
       
     
     X 2  is alkyl or substituted hydrocarbyl; 
     each X 12  is independently hydrogen, hydroxy, amino, aminoalkyl, boronic acid or halo; and 
     z is a non-negative number. 
     Embodiment 716. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 715 wherein m and z are independently 0-3 and n is 0 or 1. 
     Embodiment 717. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 715 or 716 wherein R 11  is independently hydrogen, aliphatic, aminoalkyl, haloalkyl, or heteroaryl, R 21  and R 31  are independently hydrogen or heteroaliphatic and R 41  is hydrogen, aliphatic, aryl, heteroaliphatic, or heteroaryl. 
     Embodiment 718. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 715 or 716 wherein each R 11  is hydrogen, aliphatic, aminoalkyl, or haloalkyl, R 21  and R 31  are hydrogen or aminoalkyl, and R 41  is hydrogen, aliphatic, or heteroaliphatic. 
     Embodiment 719. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any of embodiments 693 to 701 wherein the crosslinked amine polymer comprises the residue of an amine corresponding to Formula 2b: 
     
       
         
         
             
             
         
       
     
     wherein 
     m and n are independently non-negative integers; 
     each R 12  is independently hydrogen, substituted hydrocarbyl, or hydrocarbyl; 
     R 22  and R 32  are independently hydrogen substituted hydrocarbyl, or hydrocarbyl; 
     R 42  is hydrogen, hydrocarbyl or substituted hydrocarbyl; 
     X 1  is 
     
       
         
         
             
             
         
       
     
     X 2  is alkyl, aminoalkyl, or alkanol; 
     each X 13  is independently hydrogen, hydroxy, alicyclic, amino, aminoalkyl, halogen, alkyl, heteroaryl, boronic acid or aryl; 
     z is a non-negative number; and 
     the amine corresponding to Formula 2b comprises at least one allyl group. 
     Embodiment 720. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 719 wherein m and z are independently 0-3 and n is 0 or 1. 
     Embodiment 721. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 719 or 720 wherein R 12  or R 42  independently comprise at least one allyl or vinyl moiety. 
     Embodiment 722. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 719 or 720 wherein (i) m is a positive integer and R 12 , R 22  and R 42 , in combination comprise at least two allyl or vinyl moieties or (ii) n is a positive integer and R 12 , R 32  and R 42 , in combination, comprise at least two allyl or vinyl moieties. 
     Embodiment 723. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 719 or 720 wherein the crosslinked amine polymer comprises the residue of an amine appearing in Table A. 
     Embodiment 724. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 719, 720 or 723 wherein the crosslinked amine polymer is crosslinked with a crosslinking agent appearing in Table B. 
     Embodiment 725. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any preceding enumerated embodiment wherein the crosslinked amine polymer comprises a repeat unit corresponding to Formula 3: 
     
       
         
         
             
             
         
       
     
     wherein 
     R 15 , R 16  and R 17  are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, hydroxyl, amino, boronic acid or halo; 
     X 15  is 
     
       
         
         
             
             
         
       
     
     X 5  is hydrocarbyl, substituted hydrocarbyl, oxo (—O—), or amino; and 
     z is a non-negative number. 
     Embodiment 726. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 725 wherein R 15 , R 16  and R 17  are independently aliphatic or heteroaliphatic. 
     Embodiment 727. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 725 or 726 wherein X 5  is oxo, amino, alkylamino, ethereal, alkanol, or haloalkyl. 
     Embodiment 728. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any of embodiments 693 to 701 wherein the crosslinked amine polymer is prepared by (i) substitution polymerization of polyfunctional reagents at least one of which comprises amine moieties, (2) radical polymerization of a monomer comprising at least one amine moiety or nitrogen containing moiety, or (3) crosslinking of an amine-containing intermediate with a crosslinking agent, optionally containing amine moieties. 
     Embodiment 729. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 728 wherein the crosslinked amine polymer is a crosslinked homopolymer or a crosslinked copolymer. 
     Embodiment 730. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 728 wherein the crosslinked amine polymer comprises free amine moieties, separated by the same or varying lengths of repeating linker units. 
     Embodiment 731. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 728 wherein the crosslinked amine polymer is prepared by polymerizing an amine-containing monomer with a crosslinking agent in a substitution polymerization reaction. 
     Embodiment 732. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 731 wherein the amine-containing monomer is a linear amine possessing at least two reactive amine moieties to participate in the substitution polymerization reaction. 
     Embodiment 733. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 731 or 732 wherein the amine-containing monomer is 1,3-Bis[bis(2-aminoethyl)amino]propane, 3-Amino-1-{[2-(bis{2-[bis(3-aminopropyl)amino]ethyl}amino)ethyl](3-aminopropyl)amino}propane, 2-[Bis(2-aminoethyl)amino]ethanamine, Tris(3-aminopropyl)amine, 1,4-Bis[bis(3-aminopropyl)amino]butane, 1,2-Ethanediamine, 2-Amino-1-(2-aminoethylamino)ethane, 1,2-Bis(2-aminoethylamino)ethane, 1,3-Propanediamine, 3,3′-Diaminodipropylamine, 2,2-dimethyl-1,3-propanediamine, 2-methyl-1,3-propanediamine, N,N′-dimethyl-1,3-propanediamine, N-methyl-1,3-diaminopropane, 3,3′-diamino-N-methyldipropylamine, 1,3-diaminopentane, 1,2-diamino-2-methylpropane, 2-methyl-1,5-diaminopentane, 1,2-diaminopropane, 1,10-diaminodecane, 1,8-diaminooctane, 1,9-diaminooctane, 1,7-diaminoheptane, 1,6-diaminohexane, 1,5-diaminopentane, 3-bromopropylamine hydrobromide, N,2-dimethyl-1,3-propanediamine, N-isopropyl-1,3-diaminopropane, N,N′-bis(2-aminoethyl)-1,3-propanediamine, N,N′-bis(3-aminopropyl)ethylenediamine, N,N′-bis(3-aminopropyl)-1,4-butanediamine tetrahydrochloride, 1,3-diamino-2-propanol, N-ethylethylenediamine, 2,2′-diamino-N-methyldiethylamine, N,N′-diethylethylenediamine, N-isopropylethylenediamine, N-methylethylenediamine, N,N′-di-tert-butylethylenediamine, N,N′-diisopropylethylenediamine, N,N′-dimethylethylenediamine, N-butylethylenediamine, 2-(2-aminoethylamino)ethanol, 1,4,7,10,13,16-hexaazacyclooctadecane, 1,4,7,10-tetraazacyclododecane, 1,4,7-triazacyclononane, N,N′-bis(2-hydroxyethyl)ethylenediamine, piperazine, bis(hexamethylene)triamine, N-(3-hydroxypropyl)ethylenediamine, N-(2-Aminoethyl)piperazine, 2-Methylpiperazine, Homopiperazine, 1,4,8,11-Tetraazacyclotetradecane, 1,4,8,12-Tetraazacyclopentadecane, 2-(Aminomethyl)piperidine, or 3-(Methylamino)pyrrolidino. 
     Embodiment 734. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any of embodiments 728, 730, 732, and 733 wherein the crosslinking agent is selected from the group consisting of dihaloalkanes, haloalkyloxiranes, alkyloxirane sulfonates, di(haloalkyl)amines, tri(haloalkyl) amines, diepoxides, triepoxides, tetraepoxides, bis (halomethyl)benzenes, tri(halomethyl)benzenes, tetra(halomethyl)benzenes, epihalohydrins such as epichlorohydrin and epibromohydrin poly(epichlorohydrin), (iodomethyl)oxirane, glycidyl tosylate, glycidyl 3-nitrobenzenesulfonate, 4-tosyloxy-1,2-epoxybutane, bromo-1,2-epoxybutane, 1,2-dibromoethane, 1,3-dichloropropane, 1,2-dichloroethane, 1-bromo-2-chloroethane, 1,3-dibromopropane, bis(2-chloroethyl)amine, tris(2-chloroethyl)amine, and bis(2-chloroethyl)methylamine, 1,3-butadiene diepoxide, 1,5-hexadiene diepoxide, diglycidyl ether, 1,2,7,8-diepoxyoctane, 1,2,9,10-diepoxydecane, ethylene glycol diglycidyl ether, propylene glycol diglycidyl ether, 1,4-butanediol diglycidyl ether, 1,2 ethanedioldiglycidyl ether, glycerol diglycidyl ether, 1,3-diglycidyl glyceryl ether, N,N-diglycidylaniline, neopentyl glycol diglycidyl ether, diethylene glycol diglycidyl ether, 1,4-bis(glycidyloxy)benzene, resorcinol digylcidyl ether, 1,6-hexanediol diglycidyl ether, trimethylolpropane diglycidyl ether, 1,4-cyclohexanedimethanol diglycidyl ether, 1,3-bis-(2,3-epoxypropyloxy)-2-(2,3-dihydroxypropyloxy)propane, 1,2-cyclohexanedicarboxylic acid diglycidyl ester, 2,2′-bis(glycidyloxy) diphenylmethane, bisphenol F diglycidyl ether, 1,4-bis(2′,3′epoxypropyl)perfluoro-n-butane, 2,6-di(oxiran-2-ylmethyl)-1,2,3,5,6,7-hexahydropyrrolo[3,4-f]isoindol-1,3,5,7-tetraone, bisphenol A diglycidyl ether, ethyl 5-hydroxy-6,8-di(oxiran-2-ylmethyl)-4-oxo-4-h-chromene-2-carboxylate, bis[4-(2,3-epoxy-propylthio)phenyl]-sulfide, 1,3-bis(3-glycidoxypropyl) tetramethyldisiloxane, 9,9-bis[4-(glycidyloxy)phenyl]fluorine, triepoxyisocyanurate, glycerol triglycidyl ether, N,N-diglycidyl-4-glycidyloxyaniline, isocyanuric acid (S,S,S)-triglycidyl ester, isocyanuric acid (R,R,R)-triglycidyl ester, triglycidyl isocyanurate, trimethylolpropane triglycidyl ether, glycerol propoxylate triglycidyl ether, triphenylolmethane triglycidyl ether, 3,7,14-tris[[3-(epoxypropoxy)propyl]dimethylsilyloxy]-1,3,5,7,9,11,14-heptacyclopentyltricyclo [7,3,3,15, 11]heptasiloxane, 4,4′methylenebis(N, N-diglycidylaniline), bis(halomethyl)benzene, bis(halomethyl)biphenyl and bis(halomethyl)naphthalene, toluene diisocyanate, acrylol chloride, methyl acrylate, ethylene bisacrylamide, pyrometallic dianhydride, succinyl dichloride, dimethylsuccinate, 3-chloro-1-(3-chloropropylamino-2-propanol, 1,2-bis(3-chloropropylamino)ethane, Bis(3-chloropropyl)amine, 1,3-Dichloro-2-propanol, 1,3-Dichloropropane, 1-chloro-2,3-epoxypropane, tris[(2-oxiranyl)methyl]amine, and combinations thereof. 
     Embodiment 735. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 728 wherein the preparation of the crosslinked amine polymer comprises radical polymerization of an amine monomer comprising at least one amine moiety or nitrogen containing moiety. 
     Embodiment 736. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any preceding enumerated embodiment wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of about 1.5 or less. 
     Embodiment 737. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any preceding enumerated embodiment wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of about 1 or less. 
     Embodiment 738. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any preceding enumerated embodiment wherein the crosslinked amine polymer has a chloride ion to phosphate ion binding molar ratio of at least 0.5:1, respectively, in an aqueous simulated small intestine inorganic buffer (“SIB”) containing 36 mM NaCl, 20 mM NaH 2 PO 4 , and 50 mM 2-(N-morpholino)ethanesulfonic acid (MES) buffered to pH 5.5 and at 37° C. 
     Embodiment 739. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any preceding enumerated embodiment wherein the crosslinked amine polymer has a chloride ion to phosphate ion binding molar ratio of at least 1:1, respectively, in an aqueous simulated small intestine inorganic buffer (“SIB”) containing 36 mM NaCl, 20 mM NaH 2 PO 4 , and 50 mM 2-(N-morpholino)ethanesulfonic acid (MES) buffered to pH 5.5 and at 37° C. 
     Embodiment 740. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any preceding enumerated embodiment wherein the crosslinked amine polymer has a chloride ion to phosphate ion binding molar ratio of at least 2:1, respectively, in an aqueous simulated small intestine inorganic buffer (“SIB”) containing 36 mM NaCl, 20 mM NaH 2 PO 4 , and 50 mM 2-(N-morpholino)ethanesulfonic acid (MES) buffered to pH 5.5 and at 37° C. 
     Embodiment 741. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any preceding enumerated embodiment wherein the crosslinked amine polymer has a proton binding capacity of at least 10 mmol/g and a chloride ion binding capacity of at least 10 mmol/g in an aqueous simulated gastric fluid buffer (“SGF”) containing 35 mM NaCl and 63 mM HCl at pH 1.2 and 37° C. 
     Embodiment 742. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any preceding enumerated embodiment wherein the crosslinked amine polymer has an equilibrium proton binding capacity of at least 12 mmol/g and a chloride ion binding capacity of at least 12 mmol/g in an aqueous simulated gastric fluid buffer (“SGF”) containing 35 mM NaCl and 63 mM HCl at pH 1.2 and 37° C. 
     Embodiment 743. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any preceding enumerated embodiment wherein the crosslinked amine polymer has an equilibrium proton binding capacity of at least 14 mmol/g and a chloride ion binding capacity of at least 14 mmol/g in an aqueous simulated gastric fluid buffer (“SGF”) containing 35 mM NaCl and 63 mM HCl at pH 1.2 and 37° C. 
     Embodiment 744. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any preceding enumerated embodiment wherein the percentage of quaternized amines is less than 40%. 
     Embodiment 745. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any preceding enumerated embodiment wherein the percentage of quaternized amines is less than 30%. 
     Embodiment 746. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any preceding enumerated embodiment wherein the percentage of quaternized amines is less than 20%. 
     Embodiment 747. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any preceding enumerated embodiment wherein the percentage of quaternized amines is less than 10%. 
     Embodiment 748. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any preceding enumerated embodiment wherein the percentage of quaternized amines is less than 5%. 
     Embodiment 749. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any preceding enumerated embodiment wherein the crosslinked amine polymer is a gel or a bead having a mean particle size of 40 to 180 micrometers. 
     Embodiment 750. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any preceding enumerated embodiment wherein the crosslinked amine polymer is a gel or a bead having a mean particle size of 60 to 160 micrometers. 
     Embodiment 751. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any preceding enumerated embodiment wherein the crosslinked amine polymer is a gel or a bead having a mean particle size of 80 to 140 micrometers. 
     Embodiment 752. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any one of embodiments 749 to 751 wherein less than about 0.5 volume percent of the particles have a diameter of less than about 10 micrometers. 
     Embodiment 753. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any one of embodiments 749 to 751 wherein less than about 5 volume percent of the particles have a diameter of less than about 20 micrometers. 
     Embodiment 754. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any one of embodiments 749 to 751 wherein less than about 0.5 volume percent of the particles have a diameter of less than about 20 micrometers. 
     Embodiment 755. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any one of embodiments 749 to 751 wherein less than about 5 volume percent of the particles have a diameter of less than about 30 micrometers. 
     Embodiment 756. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any preceding enumerated embodiment in a dosage unit form. 
     Embodiment 757. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of embodiment 756 wherein the dosage unit form is a capsule, tablet or sachet dosage form. 
     Embodiment 758. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any preceding enumerated embodiment wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier, excipient, or diluent. 
     Embodiment 759. The composition for use according to any one of embodiments 571 to 692 wherein the composition is a method of treating and acid/base disorder in an animal including a human by removing HCl through oral administration of a pharmaceutical composition of any of the preceding enumerated embodiments. 
     Embodiment 760. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the method of treatment of embodiment 759 wherein the acid/base disorder is metabolic acidosis. 
     Embodiment 761. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the method of treatment of embodiment 759 wherein the pH is controlled or normalized. 
     Embodiment 762. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the method of treatment of embodiment 759 wherein the serum bicarbonate is controlled or normalized. 
     Embodiment 763. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the method of treatment of embodiment 759 wherein less than 1 g of sodium or potassium is administered per day. 
     Embodiment 764. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the method of treatment of embodiment 759 wherein less than 0.5 g of sodium or potassium is administered per day. 
     Embodiment 765. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the method of treatment of embodiment 759 wherein less than 0.1 g of sodium or potassium is administered per day. 
     Embodiment 766. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the method of treatment of embodiment 759 wherein no sodium or potassium is administered. 
     Embodiment 767. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the pharmaceutical composition of any of embodiments 682-755 wherein a dose of the pharmaceutical composition is titrated based on the serum bicarbonate values of a patient in need of treatment or other indicators of acidosis. 
     Embodiment 768. The composition for use according to any one of embodiments 571 to 692 wherein the composition is a polymer comprising a structure corresponding to Formula 4: 
     
       
         
         
             
             
         
       
     
     wherein each R is independently hydrogen or an ethylene crosslink between two nitrogen atoms of the crosslinked amine polymer 
     
       
         
         
             
             
         
       
     
     and a, b, c, and m are integers. 
     Embodiment 769. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the polymer of embodiment 768 wherein m is a large integer indicating an extended polymer network. 
     Embodiment 770. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the polymer of embodiment 768 or 769 wherein a ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1:1 to 5:1. 
     Embodiment 771. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the polymer of embodiment 768 or 769 wherein a ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1.5:1 to 4:1. 
     Embodiment 772. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the polymer of embodiment 768 or 769 wherein a ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 1.75:1 to 3:1. 
     Embodiment 773. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the polymer of embodiment 768 or 769 wherein a ratio of the sum of a and b to c (i.e., a+b:c) is in the range of about 2:1 to 2.5:1. 
     Embodiment 774. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the polymer of embodiment 768 or 769 wherein the sum of a and b is 57 and c is 24. 
     Embodiment 775. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the polymer of any of embodiments 768 or 774 wherein 50-95% of the R substituents are hydrogen and 5-50% are an ethylene crosslink between two nitrogens of the crosslinked amine polymer. 
     Embodiment 776. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the polymer of any of embodiments 768 or 774 wherein 55-90% of the R substituents are hydrogen and 10-45% are an ethylene crosslink between two nitrogens of the crosslinked amine polymer. 
     Embodiment 777. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the polymer of any of embodiments 768 or 774 wherein 60-90% of the R substituents are hydrogen and 10-40% are an ethylene crosslink between two nitrogens of the crosslinked amine polymer. 
     Embodiment 778. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the polymer of any of embodiments 768 to 774 wherein 65-90% of the R substituents are hydrogen and 10-35% are an ethylene crosslink between two nitrogens of the crosslinked amine polymer. 
     Embodiment 779. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the polymer of any of embodiments 768 to 774 wherein 70-90% of the R substituents are hydrogen and 10-30% are an ethylene crosslink between two nitrogens of the crosslinked amine polymer. 
     Embodiment 780. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the polymer of any of embodiments 768 to 774 wherein 75-85% of the R substituents are hydrogen and 15-25% are an ethylene crosslink between two nitrogens of the crosslinked amine polymer. 
     Embodiment 781. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the polymer of any of embodiments 768 to 774 wherein 80-85% of the R substituents are hydrogen and 15-20% are an ethylene crosslink between two nitrogens of the crosslinked amine polymer. 
     Embodiment 782. The composition for use according to any one of embodiments 571 to 692 wherein the composition is the polymer of any of embodiments 768 to 774 wherein about 81% of the R substituents are hydrogen and about 19% are an ethylene crosslink. 
     Embodiment 783. The composition for use according to any one of embodiments 571 to 592 wherein the method of treatment further includes the feature or features set out in any one of embodiments 1 to 570, or part thereof. 
     Embodiment 784. A composition for use in a method of treating metabolic acidosis in an adult human patient wherein said treatment is administered to the patient less frequently than once per day, said composition being a nonabsorbable composition having the capacity to remove protons from the patient. 
     Embodiment 785. The composition of embodiment 784, wherein the composition is administered on a regular schedule. 
     Embodiment 786. The composition of embodiment 784, wherein the regular schedule is once every two days. 
     Embodiment 787. The composition of embodiment 785, wherein the regular schedule is once every three days. 
     Embodiment 788. The composition of embodiment 785, wherein the regular schedule is twice a week. 
     Embodiment 789. The composition of embodiment 785, wherein the regular schedule is three times a week. 
     Embodiment 790. The composition of embodiment 785, wherein the regular schedule is four times a week. 
     Embodiment 791. The composition of any one of embodiments 784 to 790 wherein the composition is as defined in any preceding enumerated embodiment. 
     Embodiment 792. The composition of any one of embodiments 784 to 791 wherein the method of treatment is as defined in any preceding enumerated embodiment. 
     Embodiment 793. A method of increasing serum bicarbonate levels in an individual afflicted with an acid-base disorder, the method comprising oral administration of a pharmaceutical composition to increase the individual&#39;s serum bicarbonate levels wherein: 
     (i) the pharmaceutical composition binds a target species in the individual&#39;s digestive system when given orally, the target species being selected from the group consisting of protons, strong acids, and conjugate bases of strong acids and 
     (ii) the pharmaceutical composition increases the serum bicarbonate level by at least 1 mEq/l in a placebo controlled study, said increase being the difference between the cohort average serum bicarbonate level in a first cohort at the end of the study, relative to the cohort average serum bicarbonate level in a second cohort at the end of the study, wherein the first cohort&#39;s subjects receive the pharmaceutical composition and the second cohort&#39;s subjects receive a placebo, wherein the first and second cohorts each comprise at least 25 subjects, each cohort is prescribed the same diet during the study and the study lasts at least two weeks. 
     Embodiment 794. The method of embodiment 793 wherein the first cohort receives a daily dose of the pharmaceutical composition that does not exceed 100 g/day. 
     Embodiment 795. The method of embodiment 793 wherein the first cohort receives a daily dose of the pharmaceutical composition that does not exceed 50 g/day. 
     Embodiment 796. The method of embodiment 793 wherein the first cohort receives a daily dose of the pharmaceutical composition that does not exceed 30 g/day. 
     Embodiment 797. The method of embodiment 793 wherein the first cohort receives a daily dose of the pharmaceutical composition that does not exceed 25 g/day. 
     Embodiment 798. The method of embodiment 793 wherein the first cohort receives a daily dose of the pharmaceutical composition that does not exceed 20 g/day. 
     Embodiment 799. The method of embodiment 793 wherein the first cohort receives a daily dose of the pharmaceutical composition that does not exceed 15 g/day. 
     Embodiment 800. The method of embodiment 793 wherein the first cohort receives a daily dose of the pharmaceutical composition that does not exceed 10 g/day. 
     Embodiment 801. The method of embodiment 793 wherein the first cohort receives a daily dose of the pharmaceutical composition that does not exceed 5 g/day. 
     Embodiment 802. The method of any of embodiments 793 to 801 wherein the target species is protons. 
     Embodiment 803. The method of any of embodiments 793 to 801 wherein the target species is chloride ions. 
     Embodiment 804. The method of any of embodiments 793 to 801 wherein the target species is a strong acid. 
     Embodiment 805. The method of any of embodiments 793 to 801 wherein the target species is HCl. 
     Embodiment 806. The method of any of embodiments 793 to 805 wherein the pharmaceutical composition is not absorbed when ingested. 
     Embodiment 807. The method of any of embodiments 793 to 806 wherein the composition is a pharmaceutical composition comprising a proton-binding, crosslinked amine polymer comprising the residue of an amine corresponding to Formula 1: 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2  and R 3  are independently hydrogen, hydrocarbyl, or substituted hydrocarbyl provided, however, at least one of R 1 , R 2  and R 3  is other than hydrogen, and the crosslinked amine polymer has (i) an equilibrium proton binding capacity of at least 5 mmol/g and a chloride ion binding capacity of at least 5 mmol/g in an aqueous simulated gastric fluid buffer (“SGF”) containing 35 mM NaCl and 63 mM HCl at pH 1.2 and 37° C., and (ii) an equilibrium swelling ratio in deionized water of about 2 or less. 
     Embodiment 808. The method of any of embodiments 793 to 806 wherein the composition is a pharmaceutical composition comprising a proton-binding, crosslinked amine polymer comprising the residue of an amine corresponding to Formula 1: 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2  and R 3  are independently hydrogen, hydrocarbyl, substituted hydrocarbyl provided, however, at least one of R 1 , R 2  and R 3  is other than hydrogen, the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of about 5 or less, and the crosslinked amine polymer binds a molar ratio of chloride ions to interfering ions of at least 0.35:1, respectively, in an interfering ion buffer at 37° C. wherein the interfering ions are phosphate ions and the interfering ion buffer is a buffered solution at pH 5.5 of 36 mM chloride and 20 mM phosphate. 
     Embodiment 809. The method of embodiments 807 or 808 wherein the crosslinked amine polymer has an equilibrium chloride binding capacity of at least 7.5 mmol/g in an aqueous simulated gastric fluid buffer (“SGF”) containing 35 mM NaCl and 63 mM HCl at pH 1.2 and 37° C. 
     Embodiment 810. The method of embodiments 807 or 808 wherein the crosslinked amine polymer has an equilibrium chloride binding capacity of at least 10 mmol/g in an aqueous simulated gastric fluid buffer (“SGF”) containing 35 mM NaCl and 63 mM HCl at pH 1.2 and 37° C. 
     Embodiment 811. The method of embodiments 807 or 808 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of about 4 or less. 
     Embodiment 812. The method of embodiments 807 or 808 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of about 3 or less. 
     Embodiment 813. The method of embodiments 807 or 808 wherein the crosslinked amine polymer has an equilibrium swelling ratio in deionized water of about 2 or less. 
     Embodiment 814. The method of any of embodiments 807 to 813 wherein R 1 , R 2  and R 3  are independently hydrogen, alkyl, alkenyl, allyl, vinyl, aryl, aminoalkyl, alkanol, haloalkyl, hydroxyalkyl, ethereal, heteroaryl or heterocyclic provided, however, each of R 1 , R 2  and R 3  is not hydrogen. 
     Embodiment 815. The method of any of embodiments 807 to 813 wherein R 1 , R 2  and R 3  are independently hydrogen, aliphatic or heteroaliphatic provided, however, at least one of R 1 , R 2  and R 3  is other than hydrogen. 
     Embodiment 816. The method of any of embodiments 807 to 813 wherein the crosslinked amine polymer is prepared by substitution polymerization of the amine with a polyfunctional crosslinker, optionally also comprising amine moieties. 
     Embodiment 817. The method of any of embodiments 807 to 816 wherein the potential renal acid load (PRAL value) of the diet is, on average, 0.82 mEq/d). 
     Embodiment 818. The method of any of embodiments 807 to 817 wherein eligible subjects for the study have chronic kidney disease (CKD Stage 3-4; eGFR 20-&lt;60 mL/min/1.73 m 2 ) and a baseline serum bicarbonate value at the start of the study between 12 and 20 mEq/L. 
     Embodiment 819. The method of any of embodiments 807 to 818 wherein the pharmaceutical composition increases the serum bicarbonate level by at least 2 mEq/l in the placebo controlled study. 
     Embodiment 820. The method of any of embodiments 807 to 818 wherein the pharmaceutical composition increases the serum bicarbonate level by at least 3 mEq/l in the placebo controlled study. 
     Embodiment 821. The method or composition of any preceding enumerated embodiment wherein the individual or adult human patient has chronic kidney disease. 
     Embodiment 822. The method or composition of any preceding enumerated embodiment wherein the individual or adult human patient is not yet in need for kidney replacement therapy (dialysis or transplant). 
     Embodiment 823. The method or composition of any preceding enumerated embodiment wherein the individual or adult human patient has not yet reached end stage renal disease (“ESRD”). 
     Embodiment 824. The method or composition of any preceding enumerated embodiment wherein the individual or adult human patient has a mGFR of at least 15 mL/min/1.73 m 2 . 
     Embodiment 825. The method or composition of any preceding enumerated embodiment wherein the individual or adult human patient has an eGFR of at least 15 mL/min/1.73 m 2 . 
     Embodiment 826. The method or composition of any preceding enumerated embodiment wherein the individual or adult human patient has a mGFR of at least 30 mL/min/1.73 m 2 . 
     Embodiment 827. The method or composition of any preceding enumerated embodiment wherein the individual or adult human patient has an eGFR of at least 30 mL/min/1.73 m 2 . 
     Embodiment 828. The method or composition of any preceding enumerated embodiment wherein the individual or adult human patient has a mGFR of less than 45 mL/min/1.73 m 2  for at least three months. 
     Embodiment 829. The method or composition of any preceding enumerated embodiment wherein the individual or adult human patient has an eGFR of less than 45 mL/min/1.73 m 2  for at least three months. 
     Embodiment 830. The method or composition of any preceding enumerated embodiment wherein the individual or adult human patient has a mGFR of less than 60 mL/min/1.73 m 2  for at least three months. 
     Embodiment 831. The method or composition of any preceding enumerated embodiment wherein the individual or adult human patient has an eGFR of less than 60 mL/min/1.73 m 2  for at least three months. 
     Embodiment 832. The method or composition of any preceding enumerated embodiment wherein the individual or adult human patient has Stage 3A CKD, Stage 3B CKD, or Stage 4 CKD. 
     Embodiment 833. A method of treating an individual afflicted with an acid-base disorder characterized by a baseline serum bicarbonate value of less than 22 mEq/l, the method comprising oral administration of a daily dose of a pharmaceutical composition containing a nonabsorbable composition; 
     wherein said oral administration increases the individual&#39;s serum bicarbonate value from baseline to an increased serum bicarbonate value that exceeds the baseline serum bicarbonate value by at least 1 mEq/l; and 
     wherein the treatment enables the increased serum bicarbonate value to be sustained over a prolonged period of at least one week, at least one month, at least two months, at least three months, at least six months, or at least one year. 
     Embodiment 834. The method or pharmaceutical composition of embodiment 833, wherein the method or pharmaceutical composition is one of any preceding enumerated embodiments. 
     Embodiment 835. The method of any preceding enumerated embodiment wherein the treatment decreases the individual&#39;s anion gap by at least 1 mEq/L. 
     Embodiment 836. The method of any preceding enumerated embodiment wherein the treatment decreases the individual&#39;s anion gap by at least 2 mEq/L. 
     Embodiment 837. The method of any preceding enumerated embodiment wherein the treatment decreases the individual&#39;s anion gap by at least 3 mEq/L. 
     Embodiment 838. The method of any preceding enumerated embodiment wherein the treatment decreases the individual&#39;s anion gap by at least 4 mEq/L. 
     Embodiment 839. The method of any preceding enumerated embodiment wherein the treatment decreases the individual&#39;s anion gap by at least 5 mEq/L. 
     Embodiment 840. The method of any preceding enumerated embodiment wherein the treatment decreases the individual&#39;s anion gap by 1-2 mEq/L. 
     Embodiment 841. The method of any preceding enumerated embodiment wherein the treatment decreases the individual&#39;s anion gap by 1-3 mEq/L. 
     Embodiment 842. The method of any preceding enumerated embodiment wherein the treatment decreases the individual&#39;s anion gap by 1-4 mEq/L. 
     Embodiment 843. The method of any preceding enumerated embodiment wherein the treatment decreases the individual&#39;s anion gap by 1-5 mEq/L. 
     Embodiment 844. The method of any preceding enumerated embodiment wherein the treatment decreases the individual&#39;s anion gap by 2-3 mEq/L. 
     Embodiment 845. The method of any preceding enumerated embodiment wherein the treatment decreases the individual&#39;s anion gap by 2-4 mEq/L. 
     Embodiment 846. The method of any preceding enumerated embodiment wherein the treatment decreases the individual&#39;s anion gap by 2-5 mEq/L. 
     Embodiment 846. The method of any preceding enumerated embodiment wherein the treatment decreases the individual&#39;s anion gap by 3-4 mEq/L. 
     Embodiment 847. The method of any preceding enumerated embodiment wherein the treatment decreases the individual&#39;s anion gap by 3-5 mEq/L. 
     Embodiment 848. The method of any preceding enumerated embodiment wherein the treatment decreases the individual&#39;s anion gap by 4-5 mEq/L. 
     Embodiment 849. The method of any preceding enumerated embodiment wherein the treatment decreases the individual&#39;s anion gap by less than 1 mEq/L (e.g. 0.5 mEq/L, or 0.75 mEq/L). 
     Having described the invention in detail, it will be apparent that modifications and variations are possible without departing the scope of the invention defined in the appended claims. Furthermore, it should be appreciated that all examples in the present disclosure are provided as non-limiting examples. 
     EXAMPLES 
     Exemplary Synthetic Approaches for the Preparation of Nonabsorbed Polymers for the Treatment of Acid-Base Imbalance (Reproduced from WO2016/094685 A1) 
     Exemplary Synthesis A 
     Step 1: Two aqueous stock solutions of monomer (50% w/w) were prepared by independently dissolving 43.83 g allylamine hydrochloride and 45.60 g diallylpropyldiamine (“DAPDA”) in water. A 3-neck, 2 L round bottom flask with four side baffles equipped with an overhead stirrer (stirring at 180 rpm), Dean-Stark apparatus and condenser, and nitrogen inlet, was charged with 12 g surfactant (Stepan Sulfonic 100) dissolved in 1,200 g of a heptane/chlorobenzene solution (26/74 v/v), followed by the aqueous stock solutions, and an additional portion of water (59.14 g). In a separate vessel, a 15 wt % solution of initiator 2,2′-azobis(2-methylpropionamidine)-dihydrochloride (“V-50”) (9.08 g) in water was prepared. The two mixtures were independently sparged with nitrogen while the reaction vessel was brought to 67° C. in an oil bath (approximately 30 min). Under inert atmosphere, the initiator solution was added to the reaction mixture, and subsequently heated at 67° C. for 16 hours. A second aliquot of initiator solution (equal to the first) and the reaction mixture, were sparged with nitrogen for 30 minutes and combined before increasing the temperature to 115° C. for a final dehydration step (Dean-Stark). The reaction was held at 115° C. until water stopped collecting in the Dean-Stark trap (6 h, 235 mL removed, &gt;90% of total water, T internal  &gt;99° C.). The reaction was allowed to cool to room temperature, and the stirring stopped to allow the beads to settle. The organic phase was removed from the bead cake by decanting. The beads were purified by washing (MeOH two times, H 2 O once, 1N HCl two times, H 2 O once, 1N NaOH three times, and then H 2 O until the pH of solution after washing was 7) and dried by lyophilization. 
     Step 2: Dry preformed amine polymer beads (15.00 g) prepared in accordance with Step 1 were added to a 250 mL round bottom flask equipped with a stir paddle and nitrogen gas inlet. To the beads was added 1,2-dichloroethane (DCE) (90 mL, resulting in a 1:6 bead to DCE (g/mL) ratio). The beads were dispersed in the DCE using mechanical agitation (˜150 rpm stirring). Water (3.75 mL, resulting in a 0.25:1 water to bead mass ratio) was added directly to the dispersion, and stirring was continued for 30 minutes. After 30 minutes, the flask was immersed into an oil bath held at 70° C. The reaction was held in the oil bath and agitated using mechanical stirring under a nitrogen atmosphere for 16 hours. Methanol (100 mL) was added to the reaction and, solvent was removed by decanting. The beads were then filtered, and then purified by washing (MeOH two times, H 2 O once, 1N HCl two times, H 2 O once, 1N NaOH three times, and then H 2 O until the pH of solution after washing was 7). The purified beads were then dried by lyophilization for 48 hours. Swelling ratio, particle size, chloride binding capacity in SGF and chloride binding capacity (SIB-CI) and phosphate binding capacity (SIB-P) in SIB are presented in Table S-1 for the resulting polymers. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE S-1 
               
             
            
               
                   
               
               
                   
                   
                   
                   
                 Binding  
               
               
                   
                   
                   
                   
                 (mmol/g 
               
               
                   
                   
                   
                 Particle Size 
                 dry weight) 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 Water: 
                 Swell- 
                 (microns) 
                   
                 SIB- 
                 SIB- 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 Unique ID  
                 Bead 
                 ing 
                 D10 
                 D50 
                 D90 
                 SGF 
                 CI 
                 P 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 Averaged  
                 — 
                 5.0 
                 79 
                 129 
                 209 
                 13.9  
                 2.0  
                 6.0 
               
               
                 from 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 019069-A1  
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 FA 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 pooled batch* 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 030008-A1  
                 0.00 
                 1.9 
                 NM 
                 NM 
                 NM 
                 11.8 
                 2.4 
                 4.0 
               
               
                 FA 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 019070-A1  
                 0.05 
                 1.5 
                 64 
                 99 
                 155 
                 11.1 
                 2.4 
                 3.5 
               
               
                 FA 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 019070-A2  
                 0.15 
                 1.1 
                 64 
                 97 
                 147 
                 11.0 
                 3.3 
                 2.5 
               
               
                 AF 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 019070-A3  
                 0.25 
                 1.2 
                 63 
                 102 
                 168 
                 10.4 
                 4.4 
                 1.4 
               
               
                 FA 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 019070-A4  
                 0.35 
                 0.7 
                 59 
                 91 
                 140 
                 10.7 
                 4.5 
                 1.3 
               
               
                 FA 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 019070-A5  
                 0.45 
                 1.6 
                 63 
                 105 
                 184 
                 11.1 
                 3.7 
                 2.5 
               
               
                 FA 
               
               
                   
               
               
                 *Averaged data from 4 batches of preformed polyamine bead 
               
            
           
         
       
     
     Exemplary Syntheses B-E 
     Step 1 Exemplary Synthesis B: To a 500 mL round bottom flask, polyallylamine (14 g, 15 kDa), and water (28 mL) were added. The solution was purged with nitrogen and stirred overhead at 220 rpm for 1 hour to completely dissolve the polymer. Next, 30 wt % aqueous NaOH (7 mL) was added and stirred for 5 minutes. A premade solution of DCE (175 mL), n-heptane (105 mL), and Span 80 (2.8 g) was added to the aqueous solution. The solution was heated to 70° C. and stirred for 16 hours. The Dean-Stark step was initiated by adding cyclohexane (100 mL) and heating the reaction to 95° C. to remove the water (&gt;90%) from the beads. Swelling ratio, chloride binding capacity in SGF and chloride binding capacity (SIB-CI) and phosphate binding capacity (SIB-P) in SIB are presented in Table S-2 (entries 018013-A1 FA and 015026-A1 FA) for the resulting polymer with SGF, SIB—CI and SIB-P values expressed in mmol/g dry bead. 
     Step 1 Exemplary Synthesis C: To a 100 mL round bottom flask, DCP (31 mL), n-heptane (19 mL), and Span 80 (0.5 g) were added. A separate aqueous stock solution of polyallylamine (2.3 g, 900 kDa), Aq NaOH (1 mL, 30 wt %), and water (4 mL) was prepared. The aqueous stock solution was added to the organic solution in the round bottom flask. The solution was purged with nitrogen for 15 minutes, heated to 70° C., and stirred for 16 hours. Methanol (30 mL) was added to the reaction mixture and the organic solvent removed by decanting. The resulting beads were purified and isolated by washing the beads using, MeOH, HCl, aqueous sodium hydroxide, and water. The beads were dried using lyophilization techniques. Swelling ratio, chloride binding capacity in SGF and chloride binding capacity (SIB-CI) and phosphate binding capacity (SIB-P) in SIB are presented in Table S-2 (018001-A2b FA) for the resulting polymer with SGF, SIB—CI and SIB-P values expressed in mmol/g dry bead. 
     Step 1 Exemplary Synthesis D: Polyallylamine 15 kDa (3.0 g) and water (9.05 g) were dissolved in a conical flask. Sodium hydroxide (0.71 g) was added to the solution and the mixture was stirred for 30 minutes. To a 100 mL round bottom flask, equipped side arm and overhead stirrer was added 0.38 g of sorbitan sesquioleate and 37.9 g of toluene. The overhead stirrer was switched on to provide agitation to the reaction solution. Dichloropropanol (0.41 g) was added directly to the polyallylamine solution while stirring. The resulting aqueous polyallylamine solution was added to the toluene solution in the 100 mL flask. The reaction was heated to 50° C. for 16 hours. After this time, the reaction was heated to 80° C. for 1 hour and then cooled to room temperature. The resulting beads were purified and isolated by washing the beads using, MeOH, HCl, aqueous sodium hydroxide, and water. The beads were dried using lyophilization techniques. Swelling ratio, chloride binding capacity in SGF and chloride binding capacity (SIB-CI) and phosphate binding capacity (SIB-P) in SIB are presented in Table S-2 (entries 002054-A3 FA and 011021-A6 FA) for the resulting polymer with SGF, SIB—CI and SIB-P values expressed in mmol/g dry bead. 
     Step 1 Exemplary Synthesis E: Polyallylamine 15 kDa (3.1 g) and water (9.35 g) were dissolved in a conical flask. Sodium hydroxide (0.73 g) was added to the solution and the mixture was stirred for 30 minutes. To a 100 mL round bottom flask, equipped side arm and overhead stirrer was added 0.31 g of sorbitan trioleate and 39.25 g of toluene. The overhead stirrer was switched on to provide agitation to the reaction solution. The aqueous polyallylamine solution was added to the toluene solution in the 100 mL flask. Epichlorohydrin (0.30 g) was added directly to the reaction mixture using a syringe. The reaction was heated to 50° C. for 16 hours. After this time the reaction was heated to 80° C. for 1 hour and then cooled to room temperature. The resulting beads were purified and isolated by washing the beads using, MeOH, HCl, aqueous sodium hydroxide, and water. The beads were dried using lyophilization techniques. Swelling ratio, chloride binding capacity in SGF and chloride binding capacity (SIB-CI) and phosphate binding capacity (SIB-P) in SIB are presented in Table S-2 (entries 002050-A1 FA and 002050-A2 FA) for the resulting polymer with SGF, SIB—CI and SIB-P values expressed in mmol/g dry bead. 
     
       
         
           
               
               
               
               
             
               
                 TABLE S-2 
               
             
            
               
                   
               
               
                   
                   
                   
                 Binding  
               
               
                   
                   
                   
                 (mmol/g dry weight) 
               
            
           
           
               
               
               
               
               
               
            
               
                 Unique ID 
                 Crosslinker 
                 Swelling 
                 SGF 
                 SIB-Cl 
                 SIB-P 
               
               
                   
               
               
                 018013-A1 FA 
                 DCE 
                 6.1 
                 16.9 
                 2.2 
                 7.3 
               
               
                 015026-A1 FA 
                 DCE 
                 5.9 
                 16.6 
                 2.0 
                 7.2 
               
               
                 018001-A2b FA 
                 DCP 
                 4.6 
                 15.9 
                 1.9 
                 7.1 
               
               
                 002054-A3 FA 
                 DC2OH 
                 6.5 
                 14.3 
                 1.6 
                 7.1 
               
               
                 011021-A6 FA 
                 DC2OH 
                 3.0 
                 14.3 
                 1.5 
                 6.1 
               
               
                 002050-A1 FA 
                 ECH 
                 8.3 
                 14.4 
                 1.7 
                 7.0 
               
               
                 002050-A2 FA 
                 ECH 
                 8.8 
                 14.2 
                 1.6 
                 7.1 
               
               
                   
               
            
           
         
       
     
     Step 1 polymers selected from Exemplary Synthesis B and D were subjected to Step 2 crosslinking according to the following general procedure. Dry preformed amine polymer beads were added to a reactor vessel equipped with a stir paddle and nitrogen gas inlet. To the beads was added 1,2-dichloroethane (DCE). The beads were dispersed in the DCE using mechanical agitation. Water was added directly to the dispersion, and stirring was continued. The flask was immersed into an oil bath held at a chosen temperature. The reaction was held in the oil bath and agitated using mechanical stirring under a nitrogen atmosphere for a chosen amount of time. Methanol was added to the reaction and, solvent was removed by decanting. The beads were then filtered, and then purified by washing. Swelling ratio, chloride binding capacity in SGF and chloride binding capacity (SIB-CI) and phosphate binding capacity (SIB-P) in SIB are presented in Table S-3. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE S-3 
               
             
            
               
                   
               
               
                   
                   
                   
                   
                 Binding 
               
               
                   
                 Preformed 
                   
                   
                 (mmol/g dry weight) 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 amine 
                 Step 1 
                   
                   
                 SIB- 
                 SIB- 
               
               
                 Unique ID 
                 polymer 
                 xlinker 
                 Swelling 
                 SGF 
                 CI 
                 P 
               
               
                   
               
               
                 018022-A2 FA 
                 018013-A1 FA 
                 DCE 
                 1.7 
                 14.9 
                 4.0 
                 4.6 
               
               
                 015032-A1 FA 
                 015026-A1 FA 
                 DCE 
                 1.4 
                 13.2 
                 6.1 
                 1.5 
               
               
                 015032-B2 FA 
                 015026-A1 FA 
                 DCE 
                 1.2 
                 13.0 
                 6.1 
                 1.5 
               
               
                 002064-B4 FA 
                 002054-A3 FA 
                 DC2OH 
                 3.1 
                 12.1 
                 1.7 
                 5.6 
               
               
                 002064-B5 FA 
                 002054-A3 FA 
                 DC2OH 
                 2.7 
                 12.3 
                 1.7 
                 5.5 
               
               
                   
               
            
           
         
       
     
     Exemplary Synthesis F 
     Step 2 Exemplary Synthesis F: Dry preformed amine polymer beads (3.00 g) (prepared as described in Step 1 of Exemplary Synthesis A) were added to a 100 mL round bottom flask equipped with a stir paddle and nitrogen gas inlet. To the beads was added DCP (4.30 mL) and DCE (13.70 mL), resulting in a 1:6 bead to DCE mass/volume ratio). The beads were dispersed in the DCE using mechanical agitation (˜150 rpm stirring). Water (3.00 mL, resulting in a 1:1 water to bead mass ratio) was added directly to the dispersion, and stirring was continued for 30 minutes. After 30 minutes, the flask was immersed into an oil bath held at 70° C. The reaction was held in the oil bath and agitated using mechanical stirring under a nitrogen atmosphere for 16 hours. Methanol (60 mL) was added to the reaction and, solvent was removed by decanting. The beads were then filtered, and then purified by washing (MeOH two times, H 2 O once, 1N HCl two times, H 2 O once, 1N NaOH three times, and then H 2 O until the pH of solution after washing was 7). The purified beads were then dried by lyophilization for 48. Swelling ratio, chloride binding capacity in SGF and chloride binding capacity (SIB-CI) and phosphate binding capacity (SIB-P) in SIB are presented in Table S-4. 
     
       
         
           
               
               
               
               
             
               
                 TABLE S-4 
               
             
            
               
                   
               
               
                   
                   
                   
                 Binding  
               
               
                   
                 Vol % 
                   
                 (mmol/g dry weight) 
               
            
           
           
               
               
               
               
               
               
            
               
                 Unique ID 
                 DCE 
                 Swelling 
                 SGF 
                 SIB-Cl 
                 SIB-P 
               
               
                   
               
               
                 019031-B1 FA 
                 100 
                 1.1 
                 11.3 
                 5.2 
                 1.3 
               
               
                 019031-B2 FA 
                  92 
                 1.0 
                 11.2 
                 5.2 
                 1.4 
               
               
                 019031-B3 FA 
                  84 
                 0.9 
                 11.3 
                 4.9 
                 1.7 
               
               
                 019031-B4 FA 
                  76 
                 1.0 
                 11.3 
                 4.8 
                 1.8 
               
               
                 019031-B5 FA 
                  68 
                 1.0 
                 11.4 
                 4.6 
                 1.9 
               
               
                 019031-B6 FA 
                  0 
                 1.1 
                 11.2 
                 3.1 
                 3.5 
               
               
                   
               
            
           
         
       
     
     Exemplary Synthesis G 
     Polyallylamine hydrochloride is dissolved in water. Sodium hydroxide is added to partially deprotonate the polyallylamine hydrochloride (preferably 50 mol %). The aqueous phase generated has a water content (by weight) 2.42 times the weight of the polyallyamine hydrochloride. A baffled 3 necked flask, equipped with an overhead mechanical stirrer, nitrogen inlet, Dean Stark apparatus with condenser is set up to conduct the suspension reaction. A dichloroethane heptane mixture is prepared, such that there is 3 times by weight dichloroethane to heptane. This dichloroethane, heptane mixed solvent is added to the baffled 3 neck flask. The aqueous solution is added to the flask, such that the ratio is 6.4 dichloroethane to one water by volume. The reaction mixture is stirred and heated to 70° C. for 16 hours. At this point beads are formed. The Dean Stark step is initiated to remove all the water from the beads, while returning the dichloromethane and heptane back to the reaction mixture. Once no more water is removed the reaction mixture is cooled. Water and sodium hydroxide is added back to the reaction mixture at a ratio of 0.25 water to polyallylamine and up to 1 equivalent of sodium hydroxide per chloride on allylamine added (both calculated from polyallylamine hydrochloride added at the beginning of the reaction). The reaction is heated for a further 16 hours at 70° C. The reaction is cooled to room temperature. The beads are purified using a filter frit with the following wash solvents; methanol, water, aqueous solution of HCl, water, aqueous solution of sodium hydroxide and 3 water washes or until the filtrate measures a pH of 7. 
     Example 1 
     Efficacy of TRC101 in the Treatment of Acidosis in an Adenine-Induced Model of Nephropathy in Rats 
     The drug substance, TRC101, is a non-absorbed free-flowing powder composed of low-swelling, spherical beads, approximately 100 micrometers in diameter; each bead is a single crosslinked, high molecular weight molecule. TRC101 is a highly crosslinked aliphatic amine polymer that is synthesized by first copolymerizing two monomers, allylamine hydrochloride and N,N′-diallyl-1,3-diaminopropane dihydrochloride, followed by crosslinking the polymer with 1,2-dichloroethane as described in Exemplary Synthesis A and in WO2016/094685 A1. TRC101 is the polymer with unique ID 019070-A3 FA in Table S-1 of Exemplary Synthesis A. 
     TRC101 is administered as a free-amine polymer and contains no counterion. TRC101 is insoluble in aqueous and non-aqueous solvents. TRC101 has both high proton and chloride binding capacity and chloride binding selectivity. The high amine content of the polymer is responsible for the high proton and chloride binding capacity of TRC101; the polymer&#39;s extensive crosslinking provides size exclusion properties and selectivity over other potential interfering anions, such as phosphate, citrate, bile acids, and short-chain and long-chain fatty acids. 
     TRC101 was evaluated in vivo in an adenine-induced rat model of chronic kidney disease (CKD) and metabolic acidosis. The study was designed in two parts. In both parts, male Sprague-Dawley rats weighing 260-280 g (10 per group) were first administered adenine (0.75 wt % in casein diet) for 2 weeks to induce nephropathy. Study Part 1 investigated the effect of early treatment with TRC101 administered in a casein diet with 0.25 wt % adenine for the 4 weeks following the 2-week nephropathy induction period. In contrast, study Part 2 assessed the effect of TRC101 administered after animals had been kept on casein diet with 0.25 wt % adenine for 5 weeks following the induction period, before the 4-week TRC101 treatment period was started. The dose levels of TRC101 were 0, 1.5, 3.0, and 4.5 wt % in the diet. Both study parts assessed the effect of withdrawing TRC101 after the end of the Treatment Phase with a 2-week Withdrawal Phase, in which TRC101 was discontinued in the low (1.5 wt %) and high (4.5 wt %) TRC101 dose groups, while dosing of TRC101 was continued in the mid dose group (3.0 wt %). All animals received casein diet with 0.25 wt % adenine during the Withdrawal Phase. 
     In both study parts, blood samples were taken from the tail vein of animals before treatments started and weekly during the Treatment and Withdrawal Periods for measurement of blood bicarbonate (SBC) using a HESKA Element POC™ blood gas analyzer. Animals were randomized based on SBC levels at baseline (i.e., following adenine induction of nephropathy and before initiation of the dosing period) so that mean baseline SBC levels were comparable across all dose groups. In addition, 24-h fecal collections were performed for the untreated and 4.5 wt % TRC101 groups. Collected fecal samples were stored at −20° C. before drying in a lyophilizer for 3 days followed by homogenization with a mortar and pestle. Anions (Cl, SO 4 , and PO 4 ) were extracted from lyophilized, homogenized fecal samples by incubating the samples with NaOH for 18 hours. Sample supernatants were analyzed for by ion chromatography (IC). 
     In Part 1, early treatment with TRC101 resulted in a significant, dose-dependent increase in SBC in all treated groups, relative to the untreated controls ( FIG. 2 ; statistical analysis: 2-way ANOVA with Dunnett&#39;s multiple comparisons test vs. untreated group; horizontal dotted lines marke the nomal SBC range for male Sprague-Dawley rates of the same age). In contrast to the control group, which had a progressive decline in mean SBC due to adenine-induced renal insufficiency over the 4-week treatment period, mean SBC levels increased and remained in the normal range for low, mid and high treatment groups. Upon withdrawal of TRC101, mean SBC levels fell below the normal range in the low and high treatment groups and were similar to the untreated controls at the end of the withdrawal period; whereas, continued treatment with TRC101 (3.0 wt %) maintained SBC levels within the normal range, with the mean value significantly higher than that of the untreated controls. 
     Consistent with the results observed on SBC, recovered fecal samples from animals treated with 4.5 wt % TRC101 in Part 1 of the study demonstrated a significant 15-fold increase in fecal Cl relative to untreated controls ( FIGS. 3A-3C ). TRC101 also significantly increased fecal SO 4  and PO 4  excretion, but the effect was much less (3- and 2-fold increase, respectively, compared to untreated controls) than that observed for Cl. 
     In Part 2 of the study, maintaining rats for a total of 7 weeks on adenine-containing diet prior to the start of the Treatment Phase resulted in mean baseline SBC values that were below the normal range in all treatment groups at a mean of approximately 20 to 21 mEq/L. Treatments with TRC101 resulted in a significant, dose-dependent increase in SBC in all treated groups, relative to the untreated controls. At the end of the 4-week treatment period, mean SBC levels in control animals remained below the normal range. The mean SBC level at the low dose (1.5 wt % TRC101) was only marginally below normal range. At the mid (3.0 wt %) and high (4.5 wt %) doses of TRC101, mean SBC values remained within the normal range ( FIG. 4 ; 2-way ANOVA with Dunnett&#39;s multiple comparisons test vs. untreated group; horizontal dotted lines marke the nomal SBC range for male Sprague-Dawley rates of the same age). Similar to the results observed in Part 1 of the study, withdrawal of TRC101 administration in Part 2 resulted in a decrease in mean SBC to below the normal range in the low and high doses treatment groups; whereas, continued treatment with 3.0 wt % TRC101 maintained mean SBC levels within the normal range ( FIGS. 5A-5C ). The mean SBC level in the 3.0 wt % TRC101 group remained significantly higher than that of the untreated control group throughout the study. 
     Consistent with the results observed on SBC, recovered fecal samples from animals treated with 4.5 wt % TRC101 in Part 2 of the study demonstrated a significant 10-fold increase in fecal Cl relative to controls, but only a 2-fold increase in fecal SO 4  and PO 4  excretion ( FIGS. 5A-5C ). 
     Example 2 
     In Vivo Anion Binding of Polymers in a Pig with Normal Renal Function 
     The anion binding capacities of TRC101 (as described in Example 1) was evaluated in vivo in a female Yorkshire pig with normal renal function. A comparative experiment was conducted using the free amine form of bixalomer (approved in Japan), an anion-binding resin designed to bind phosphate and available commercially to treat hyperphosphatemia. TRC101 and the free amine form of bixalomer were each individually sealed in nylon sachets (with a 64 micrometer mesh size and differentiated for each polymer by sachet shape), fed to a single pig at a total dose of 2 g for each polymer (i.e., 10 sachets each), and then the polymers were recovered from the sachets collected in the feces over a 10-day period (seven and six sachets were recovered from feces for bixalomer and TRC101, respectively). Bound anions were extracted from the polymers by incubating with NaOH for 18 hours. The anion concentrations in the samples were determined in supernatant by IC. 
     Analysis of the anions bound to the polymers after recovery from the feces revealed in vivo average binding of 2.62 and 0.50 mEq of chloride, 0.46 and 0.11 mmol of sulfate, and 0.37 and 0.95 mmol of phosphate per gram of TRC101 and bixalomer, respectively ( FIGS. 6A-6C  statistical analysis unpaired T test; Mean±standard deviation; N=7 and 6 sachests for Bixalomer and TRC101, respectively). Therefore, TRC101 removed 5- and 4-fold more chloride and sulfate, respectively, than bixalomer removed from the GI tract of the pig. On the other hand, bixalomer, a phosphate binder, removed 2.5-fold more phosphate than TRC101 removed from the GI tract of the pig. 
     Example 3 
     Efficacy of TRC101 in Subjects with Chronic Kidney Disease and Low Serum Bicarbonate Levels 
     Part 1 
     TRC101 (as described in Example 1) was studied in a double-blind, placebo-controlled, parallel-design, 4-arm, fixed dose study to evaluate the ability of TRC101 to control serum bicarbonate (SBC) in human subjects with marked metabolic acidosis. A total of 101 subjects with chronic kidney disease (CKD) and low SBC values were randomized into one of the four arms in an approximately 1:1:1:1 ratio (total daily doses of 3, 6 or 9 g/day TRC101 or 3 g/day placebo [microcrystalline cellulose], administered twice daily [BID]). 
     Subjects were eligible for inclusion in the study if they were 18 to 80 years of age, had Stage 3 or 4 CKD (estimated glomerular filtration rate [eGFR], 20 to &lt;60 mL/min/1.73 m 2  of body surface area) and SBC levels of 12 to 20 mEq/L (inclusive) at both Screening and study Day −1, had systolic blood pressure (SBP) at Screening &lt;170 mmHg, had a hemoglobin A1c (HbA1c) value of s 9.0% and a fasting serum glucose (FSG) value of s 250 mg/dL (13.9 mmol/L) at Screening. Key exclusion criteria were history of anuria, dialysis, acute kidney injury, acute renal insufficiency or &gt;30% increase in serum creatinine or 30% decrease in eGFR in the past 3 month, severe comorbid conditions (other than CKD) such as congestive heart failure with maximum New York Heart Association (NYHA) Class III or IV symptoms, unstable angina or acute coronary syndrome, dementia, hypertensive urgency or emergency, transient ischemic attack, stroke, or use of home oxygen during the 6 months prior to Screening. Other exclusion criteria were serum potassium values of &lt;3.8 mEq/L or &gt;5.9 mEq/L at Screening, Type 1 diabetes or chronic obstructive pulmonary disease, history or current diagnosis of heart or kidney transplant, clinically significant diabetic gastroparesis, bariatric surgery, bowel obstruction, swallowing disorders, severe gastrointestinal disorders, severe recurrent diarrhea or severe recurrent constipation. 
     At the time of Screening, subjects who met all the entry criteria were admitted to the Clinical Research Unit (CRU) on Day −1 and placed on a study diet controlled for protein, caloric content, anions, cations and fiber, in accordance with dietary recommendations for patients with CKD (KDOQI, 2003). The potential renal acid load (i.e., PRAL value) (Scialla, 2013) was calculated for the daily meal plans to ensure that the study diet was neither acidic nor basic; PRAL values for the four daily meal plans ranged from −1.71 to +1.92 and averaged 0.82. The PRAL is calculated as follows: 
       PRAL(mEq/d)=(0.49*protein[g/d])+(0.037*phosphorus[mg/d])−(0.21*potassium[mg/d])−(0.26*magnesium[mg/d])−0.013*(calcium[mg/d])
 
     Four detailed meal plans were developed that specified the foods (including measured quantities) provided at breakfast, lunch, dinner and two light snacks each day (Table S-5). Care was taken to ensure the diet closely approximated the subjects&#39; typical diet so that perturbations in serum bicarbonate related to a sudden change in diet would be minimized. The dietary sources of protein were predominantly plant-based. Meat (i.e., pork, fish) was served once per day on two of the four meal plans. The sites rotated among the four daily meal plans over the course of the treatment period. The mean (±standard deviation) serum bicarbonate level in the placebo group was 17.6 (±1.43) mEq/L at baseline and remained constant during the 14-day treatment period (17.5 [±1.87] mEq/L at Day 15), demonstrating that the study diet did not change the level of serum bicarbonate. 
     
       
         
           
               
             
               
                 TABLE S-5 
               
             
            
               
                   
               
               
                 Composition of Study Treatment Period Diet 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
            
               
                   
                   
                 Protein  
                 Ca  
                 Mg  
                   
                   
                 Na  
                   
                   
               
               
                 Parameter 
                 Calories 
                 (g) 
                 (mg) 
                 (mg) 
                 P (mg) 
                 K (mg) 
                 (mg) 
                 Fiber (g) 
                 PRAL 
               
               
                   
               
               
                 Mean 
                 2209.25 
                 52.32 
                 810 
                 232.5 
                 1008.125 
                 2171.375  
                 2249.5 
                 27.022 
                 0.82 
               
               
                 Range 
                 2129- 
                 50.6- 
                 778- 
                 210- 
                 991- 
                 2048- 
                 2076- 
                 22.9- 
                 −1.71- 
               
               
                   
                 2246 
                 53.4 
                 849 
                 235 
                 1060 
                 2277 
                 2370 
                 32.1 
                 +1.92 
               
               
                   
               
               
                 Ca = calcium; K = potassium; Mg = magnesium; Na = sodium; P = phosphate 
               
            
           
         
       
     
     Enrolled subjects were randomized to one of three TRC101 doses or placebo on Day −1 and dosing was initiated in the morning on Day 1 (next day) in accordance with the randomization assignment. 101 subjects were randomized in an approximately 1:1:1:1 ratio to one of the following groups: Group 1. 3 g/day of placebo administered in equally divided doses BID (twice daily) for 14 days (n=25); Group 2. 3 g/day of TRC101 administered in equally divided doses BID for 14 days (n=25); Group 3. 6 g/day of TRC101 administered in equally divided doses BID for 14 days (n=25); Group 4. 9 g/day of TRC101 administered in equally divided doses BID for 14 days (n=26). TRC101 or placebo were administered orally as an aqueous suspension BID, with breakfast and dinner. The first dose of study drug was taken with breakfast. One hour prior to the administration of the study drug, venous blood was drawn for a pre-dose SBC (contributing to the baseline SBC value) and safety laboratory measurements. Subjects remained in the CRU and continued BID dosing with study drug (at breakfast and dinner) for 14 days. On Day 15, subjects were discharged from the CRU. All subjects who completed the study had a discharge assessment on Day 15 and returned to the CRU on Day 17 and Day 21 for AE collection, blood draws and safety assessments. A subset of patients (n=41) also returned to the CRU on Day 28 for AE collection, blood draws and safety assessments. 
     No subject was withdrawn early from the study for any reason. The majority of subjects were male (65%), all subjects were white, and the median age was 61 years (range: 30 to 79 years). 
     Subjects in the study had Stage 3-4 CKD (39% with Stage 4) with a mean baseline eGFR of 36.4 mL/min/1.73 m 2  (range 19.0 to 66.0 mL/min/1.73 m 2 ) and metabolic acidosis characterized by a mean SBC level of 17.6 mEq/L (range 14.1-20.4 mEq/L). At baseline, 60% of subjects had an SBC value of 12-18 mEq/L and 40% had an SBC value of &gt;18-20 mEq/L. 
     Subjects had baseline comorbidities common in CKD patients including hypertension (93%), diabetes (73%), left ventricular hypertrophy (30%), and congestive heart failure (21%). As would be expected in a CKD Stage 3-4 population, nearly all study subjects had indications for sodium restriction: hypertension (93%), congestive heart failure (21%), peripheral edema (15%) and use of diuretics (41%). 
     Over a 2-week treatment period, TRC101 significantly increased SBC levels in the study population of CKD patients with baseline SBC levels ranging from 14 to 20 mEq/L. At Day 15, all three doses tested (3, 6 and 9 g/day TRC101 BID) significantly (p&lt;0.0001) increased mean SBC levels from baseline and each dose increased SBC levels to a significantly (p&lt;0.0001) greater extent than placebo. 
       FIG. 7  illustrates the steady increase in mean SBC observed in all three TRC101 dose groups during the 14-day treatment period with a mean increase at the end of treatment of approximately 3-4 mEq/L across all three active dose groups. Serum bicarbonate levels in the placebo group remained essentially unchanged throughout the study, suggesting that the diet with a controlled protein and cation/anion content administered in the clinical research unit matched well with what the subjects ate at home and, therefore, had no significant impact on their SBC values. 
     TRC101 had a rapid onset of action (i.e., statistically significant increase in mean within group change from baseline in SBC; p&lt;0.0001) within the first 24-48 hours following the initiation of treatment for all three TRC101 dose groups combined. The onset of action for between-group differences (active vs. placebo) appear to occur between 48-72 hours after the initiation of treatment with TRC101. At Day 4 (72 hours after the first dose of TRC101), the mean increase in SBC from baseline for each TRC101 group was 1-2 mEq/L: 3 g/day (p=0.0011); 6 g/day (p=0.0001); 9 g/day (p&lt;0.0001). 
     Each of the TRC101 dose groups showed a statistically significant (p&lt;0.0001) increase from baseline in SBC of approximately 3-4 mEq/L after 2 weeks of treatment (see Table 1). 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Change from Baseline in SBC at Day 15 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                 TRC101 
                 TRC101 
                 TRC101 
                 TRC101 
               
               
                   
                 Placebo 
                 3g/d BID 
                 6g/d BID 
                 9g/d BID 
                 Combined 
               
               
                   
                 (N = 25) 
                 (N = 25) 
                 (N = 25) 
                 (N = 26) 
                 (N = 76) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Baseline 
                   
                   
                   
                   
                   
               
               
                 n 
                 25 
                 25 
                 25 
                 26 
                 76 
               
               
                 Mean (SD) 
                 17.30 
                 18.02 
                 17.77 
                 17.48 
                 17.75 
               
               
                   
                 (1.338) 
                 (1.009) 
                 (1.212) 
                 (1.282) 
                 (1.180) 
               
               
                 Median 
                 17.40 
                 17.90 
                 17.80 
                 17.73 
                 17.83 
               
               
                 Min, Max 
                 14.1, 19.6 
                 15.6, 20.4 
                 15.4, 19.9 
                 14.5, 19.2 
                 14.5, 20.4 
               
               
                 Day 15 
                   
                   
                   
                   
                   
               
               
                 n 
                 25 
                 25 
                 25 
                 26 
                 76 
               
               
                 Mean (SD) 
                 17.35 
                 21.08 
                 20.72 
                 21.30 
                 21.04 
               
               
                   
                 (1.958) 
                 (1.960) 
                 (2.423) 
                 (2.977) 
                 (2.475) 
               
               
                 Median 
                 17.00 
                 21.30 
                 20.50 
                 21.45 
                 21.20 
               
               
                 Min, Max 
                 14.1, 21.7 
                 17.3, 24.8 
                 15.4, 25.9 
                 15.1, 27.0 
                 15.1, 27.0 
               
               
                 Day 15 Change  
                   
                   
                   
                   
                   
               
               
                 from Baseline (CFB) 
                   
                   
                   
                   
                   
               
               
                 n 
                 25 
                 25 
                 25 
                 26 
                 76 
               
               
                 Mean (SD) 
                 0.05 (1.955) 
                 3.06 (2.209) 
                 2.95 (2.625) 
                 3.83 (2.372) 
                 3.29 (2.408) 
               
               
                 Median 
                 −0.10 
                 3.55 
                 2.40 
                 3.23 
                 3.07 
               
               
                 Min, Max 
                 −3.5, 4.6 
                 −1.6, 7.5 
                 −1.5, 8.6 
                 −0.4, 9.2 
                 −1.6, 9.2 
               
               
                 Within Group CFB 
                   
                   
                   
                   
                   
               
               
                 LS Mean (SEM) 
                 −0.10 (0.414) 
                 3.21 (0.415) 
                 3.04 (0.414) 
                 3.74 (0.406) 
                 3.33 (0.237) 
               
               
                 95% CI of LS Mean 
                 −0.91, 0.71 
                 2.39, 4.02 
                 2.23, 3.85 
                 2.95, 4.54 
                 2.86, 3.80 
               
               
                 p-value 
                 0.8109 
                 &lt;.0001 
                 &lt;.0001 
                 &lt;.0001 
                 &lt;.0001 
               
               
                 Between Group CFB  
                   
                   
                   
                   
                   
               
               
                 Difference  
                   
                   
                   
                   
                   
               
               
                 (TRC101-Placebo) 
                   
                   
                   
                   
                   
               
               
                 LS Mean (SEM) 
                 NA 
                 3.31 (0.588) 
                 3.14 (0.587) 
                 3.84 (0.579) 
                 3.43 (0.478) 
               
               
                 95% CI of LS Mean 
                 NA 
                 2.15, 4.46 
                 1.99, 4.29 
                 2.70, 4.98 
                 2.49, 4.37 
               
               
                 p-value 
                 NA 
                 &lt;.0001 
                 &lt;.0001 
                 &lt;.0001 
                 &lt;.0001 
               
               
                   
               
               
                 Note: 
               
               
                 baseline serum bicarbonate (SBC) is defined as an average of two SBC values from samples collected on Day −1 and at Day 1 pre-dose. Change from baseline (CFB) is defined as post-baseline value minus baseline value. 
               
               
                 Note: 
               
               
                 Least squares (LS) mean, standard error of LS mean (SEM), 95% CI of LS mean, and p-values are based on the mixed-effect repeated measures model with the CFB in SBC value as the dependent variable; treatment (placebo, 3 g/d BID, 6 g/d BID, and 9 g/d BID), time point (Days 2 through 15), and treatment by time point as fixed effects; subject as a random effect; and baseline estimated glomerular filtration rate (eGFR) and baseline SBC as continuous covariates. Within-subject correlations are modeled assuming a first-order autoregressive covariance structure. 
               
            
           
         
       
     
     There appeared to be little difference in efficacy between the 3 g/day and 6 g/day TRC101 doses; however, subjects in the 9 g/day TRC101 dose group demonstrated a more rapid and larger increase in SBC. For example, the mean increases in SBC at Day 8 were 1.82, 2.00, and 2.79 mEq/L in the 3, 6 and 9 g/day TRC101 dose groups respectively (i.e., ˜0.8-1.0 mEq/L difference between the 9 g/day dose group and the other two TRC101 dose groups). At Day 15, the comparable SBC increases were 3.21, 3.04, and 3.74 mEq/L, respectively (i.e., ˜0.5-0.7 mEq/L difference between the 9 g/day dose group and the other two TRC101 dose groups) ( FIG. 8 )). 
     Statistically significant between-group (active vs. placebo) differences in SBC change from baseline to Day 15 ranged from 3.14 to 3.84 mEq/L across the TRC101 treatment groups, with a combined mean difference of 3.43 mEq/L between TRC101 and placebo (p&lt;0.0001) (see Table 1). 
     As shown in Table 2, after 2 weeks of treatment, SBC levels increased by ≥3 mEq/L in over half of subjects (52.6%) in the combined TRC101 group compared to 8.0% of subjects in the placebo group (p&lt;0.0001). In addition, 22.4% of all TRC101-treated subjects had increases in SBC≥5 mEq/L compared to 0 subjects in the placebo group. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Change in SBC by Category over Time 
               
            
           
           
               
               
               
               
               
               
            
               
                 Subjects  
                   
                 TRC101 
                 TRC101 
                 TRC101 
                 TRC101 
               
               
                 with Post 
                 Placebo 
                 3 g/d 
                 6 g/d 
                 9 g/d 
                 Combined 
               
               
                 Baseline SBC 
                 N = 25 
                 N = 25 
                 N = 25 
                 N = 26 
                 N = 76 
               
               
                   
               
            
           
           
               
            
               
                 Day 15 Increase from Baseline 
               
            
           
           
               
               
               
               
               
               
            
               
                 ≥2 mEq/L 
                 4 (16.0%) 
                 18 (72.0%) 
                 14 (56.0%) 
                 19 (73.1%) 
                  1 (67.1%) 
               
               
                 ≥3 mEq/L 
                 2 (8.0%)  
                 14 (56.0%) 
                 10 (40.0%) 
                 16 (61.5%) 
                 40 (52.6%) 
               
               
                 ≥4 mEq/L 
                 1 (4.0%)  
                  8 (32.0%) 
                 10 (40.0%) 
                 11 (42.3%) 
                 29 (38.2%) 
               
               
                 ≥5 mEq/L 
                 0 
                  3 (12.0%) 
                  6 (24.0%) 
                  8 (30.8%) 
                 17 (22.4%) 
               
               
                 ≥6 mEq/L 
                 0 
                  3 (12.0%) 
                  3 (12.0%) 
                  4 (15.4%) 
                 10 (13.2%) 
               
               
                 ≥7 mEq/L 
                 0 
                 1 (4.0%) 
                 2 (8.0%) 
                 2 (7.7%) 
                 5 (6.6%) 
               
               
                   
               
            
           
         
       
     
     In the combined TRC101 treatment group, 35.5% of subjects had their SBC corrected into the normal range (22-29 mEq/L) after 2 weeks of treatment, and at the end of the treatment period, 64.5% of TRC101-treated subjects had SBC levels that were above the upper limit of the baseline range (&gt;20 mEq/L) (Table 3). The proportion of subjects achieving an SBC&gt;22 mEq/L was similar in the 3, 6 and 9 g/day TRC101 dose groups (40.0%, 28.0%, and 38.5%, respectively). At Day 8 of the treatment period, only about half of the treatment effect was seen, again suggesting that the SBC increase has not yet plateaued by the end of the 2-week treatment period. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Change in SBC by Category over Time 
               
            
           
           
               
               
               
               
               
               
            
               
                 Subjects  
                   
                 TRC101 
                 TRC101 
                 TRC101 
                 TRC101 
               
               
                 with Post 
                 Placebo 
                 3 g/d 
                 6 g/d 
                 9 g/d 
                 Combined  
               
               
                 Baseline SBC 
                 N = 25 
                 N = 25 
                 N = 25 
                 N = 26 
                 N = 76 
               
               
                   
               
            
           
           
               
            
               
                 Day 8 SBC Values 
               
            
           
           
               
               
               
               
               
               
            
               
                 &gt;20 mEq/L 
                 3 (12.0%) 
                 9 (36.0%) 
                  7 (28.0%) 
                 12 (46.2%) 
                 28 (36.8%) 
               
               
                 &gt;22 mEq/L 
                 2 (8.0%)  
                 2 (8.0%)  
                  5 (20.0%) 
                  6 (23.1%) 
                 13 (17.1%) 
               
               
                 &gt;27 mEq/L 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                 &gt;29 mEq/L 
                 0 
                 0 
                 0 
                 0 
                 0 
               
            
           
           
               
            
               
                 Day 15 SBC Values 
               
            
           
           
               
               
               
               
               
               
            
               
                 &gt;20 mEq/L 
                 2 (8.0%)  
                 16 (64.0%)  
                 14 (56.0%) 
                 19 (73.1%) 
                 49 (64.5%) 
               
               
                 &gt;22 mEq/L 
                 0 
                 10 (40.0%)  
                  7 (28.0%) 
                 10 (38.5%) 
                 27 (35.5%) 
               
               
                 &gt;27 mEq/L 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                 &gt;29 mEq/L 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
            
           
         
       
     
     The 2-week treatment period in the study was followed by a 2-week follow-up period in which subjects were off treatment. At the end of the 2-week follow-up period, a withdrawal effect of approximately 3 mEq/L was observed in the combined TRC101 group, with SBC levels returning nearly to baseline ( FIG. 9 ). These results underscore the chronic nature of the underlying metabolic acidosis in these CKD patients, and suggest that continued treatment with TRC101 is needed to maintain elevated SBC levels. 
     There were no mean changes in serum parameters (sodium, calcium, potassium, phosphate, magnesium, low density lipoprotein) observed in the study that would indicate off-target effects of TRC101; there were also no mean changes in serum chloride. 
     Part 2 
     The double-blind, placebo-controlled, parallel-design, fixed dose study of Part 1 was extended by the introduction of two additional arms: a total of 34 subjects with chronic (CKD) and low SBC values were randomized into one of two additional arms: total daily dose of 6 g/day TRC101 (28 subjects) or 3 g/day placebo (6 subjects) [microcrystalline cellulose], administered once daily [QD]). All subjects who completed Part 2 of the study had a discharge assessment on Day 15 and returned to the CRU on Day 17, Day 21, and Day 28 for AE collection, blood draws and safety assessments. Part 2 of the study was otherwise unchanged from Part 1. 
     Discussion of Part 1 and Part 2 Study Results 
     There were no significant differences between the TRC101 and placebo treatment groups with respect to demographics, baseline eGFR or serum bicarbonate, or comorbidities (Table 4). Patients had a mean baseline eGFR of 34.8 mL/min/1.73 m 2  and a mean baseline serum bicarbonate level of 17.7 mEq/L. Study participants had conditions common to CKD patients, including patients with hypertension (93.3%), diabetes (69.6%), left ventricular hypertrophy (28.9%), congestive heart failure (21.5%), peripheral edema (14.1%) and stable diuretic use (42.2%). 
     Analysis of the mean serum bicarbonate level in the placebo group over the course of the in-unit treatment period and out-patient follow-up period demonstrated that the study diet did not change the level of serum bicarbonate. The mean (±standard deviation) serum bicarbonate level in the placebo group was 17.6 (±1.43) mEq/L at baseline and remained constant during the 14-day treatment period (17.5 [±1.87] mEq/L at Day 15). 
     There was a significant increase in mean serum bicarbonate in all groups treated with TRC101 within the first 24-48 hours compared to placebo ( FIGS. 10 &amp; 11 ). Within 72 hours after the first dose of TRC101, the mean increase in serum bicarbonate from baseline for each TRC101 group was 1-2 mEq/L 
     Over the 2-week treatment period, TRC101 increased serum bicarbonate values over the respective baseline values for each group, while placebo-treated patients had no change in serum bicarbonate ( FIGS. 10 &amp; 11 ). At day 15, the between group difference of serum bicarbonate versus placebo was 3.31 mEq/L (95% CI of LS mean 2.15 to 4.46; p&lt;0.0001), 3.14 mEq/L (95% CI of LS mean 1.99 to 4.29; p&lt;0.0001), 3.84 mEq/L (95% CI of LS mean 2.70 to 4.98; p&lt;0.0001), and 3.72 mEq/L (95% CI of LS mean 2.70 to 4.74; p&lt;0.0001), for TRC101 dose groups 1.5 g, 3.0 g, 4.5 g BID and 6 g QD, respectively. By comparison, the placebo within group change from baseline to day 15 was −0.21 mEq/L (95% CI of LS mean −0.91 to 0.49; p=0.56). The mean increase in the combined TRC101 dose groups was 3.57 mEq/L higher than in the placebo group at the end of the 14-day treatment period (95% CI of LS mean 2.75 to 4.38; p&lt;0.0001). At day 15 there was no significant difference in the mean serum bicarbonate increase when TRC101 was given as a dose of 6.0 g once daily versus 3.0 g twice daily (˜0.53 mEq/L; 95% CI of LS mean −1.61 to 0.56; p=0.34). 
     Treatment with TRC101 caused a steady increase in mean serum bicarbonate in all TRC101 dose groups during the 14-day treatment period. The slope of serum bicarbonate increase remained constant, with no evidence of a plateau at the end of treatment, indicating that the maximal increase in serum bicarbonate using the study doses of TRC101 was not established. The change in serum bicarbonate was similar in all groups treated with TRC101 at the end of the treatment period ( FIGS. 10 &amp; 11 ). 
     After 2 weeks of treatment with TRC101, serum bicarbonate increased by ≥3 mEq/L in over half of the patients (51.9%) in the combined TRC101 dose group, compared to 6.5% of patients in the placebo group (Table 5). In addition, 38.5% and 22.1% of all TRC101-treated patients, compared to 3.2% and 0% of placebo-treated patients, had increases in serum bicarbonate of ≥4 mEq/L and ≥5 mEq/L, respectively. 
     At the end of TRC101 treatment, 34.6% of patients in the combined TRC101 group had a serum bicarbonate in the normal range (22-29 mEq/L) compared to no patients in the placebo group. At the end of TRC101 dosing, the proportion of patients with a normal serum bicarbonate was similar in the four TRC101 dose groups (40.0%, 28.0%, and 38.5%, 32.1% for 1.5 g BID, 3.0 g BID, 4.5 g BID, and 6.0 g QD, respectively) while none of the patients in the placebo group had a normal serum bicarbonate (Table 6). 
     At the end of the 2-week, off-treatment, follow-up period, a decrease in serum bicarbonate of approximately 3.0-3.5 mEq/L from the end-of-treatment value was observed in all TRC101 dose groups, with serum bicarbonate levels returning nearly to baseline value in each respective group ( FIGS. 10, 11 and 12 ). 
     In contrast to serum bicarbonate, serum potassium, serum sodium and serum chloride levels did not significantly change over the course of the study ( FIGS. 13A-13D ), yielding a change in the serum anion gap in excess of 2 mEq/l ( FIG. 14 ) over the course of the study. 
     All 135 randomized patients received TRC101 or placebo daily for 14 consecutive days and were included in the safety analysis population. No patients died during the study, or had any adverse events resulting in treatment discontinuation, and no patients suffered serious or severe adverse events. Gastrointestinal adverse events were the most commonly reported events in TRC101-treated patients, and all events were mild or moderate in severity (Table 7). Diarrhea was the most common adverse event; all diarrhea events were mild, self-limited, of short duration, and none required treatment. There were no trends suggesting an off-target effect of TRC101 on electrolytes (i.e., sodium, potassium, magnesium, calcium or phosphate). There were also no trends suggesting an effect of TRC101 on vital signs or ECG intervals. No subject experienced increases in serum bicarbonate that resulted in metabolic alkalosis (i.e., serum bicarbonate &gt;29 mEq/L). 
     This two-part, double-blind, placebo-controlled, parallel-design, 6-arm, fixed dose clinical study demonstrates that ingestion of TRC101 highly significantly increases serum bicarbonate level in patients with Stage 3 or 4 CKD and low SBC as assessed both by change from baseline within group and by comparisons between active and placebo groups. The rapid onset of action (within 24-72 hours) and efficacy (&gt;3.0 mEq/L increase in SBC) observed in the study suggests that TRC101 is an effective agent in controlling SBC level in the target patient population. Unlike sodium bicarbonate, TRC101 does not introduce cations, such as sodium or potassium, which are deleterious to sodium-sensitive patients with common CKD comorbidities (e.g. hypertension, edema and heart failure). Therefore, TRC101 is expected to provide a safe treatment to control SBC in CKD patients with low SBC, including those who are sodium-sensitive. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Baseline demographics, dietary intake, renal function, serum bicarbonate and co-morbidities ( a  median values) 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 Placebo 
                 TRC101  
                 TRC101 
                 TRC101  
                 TRC101  
                 TRC101 
                   
               
               
                   
                 Combined 
                 1.5 g BID 
                 3.0 g BID 
                 6 g QD 
                 4.5 g BID 
                 Combined 
                 Total 
               
               
                   
                 N = 31 
                 N = 25 
                 N = 25 
                 N = 28 
                 N = 26 
                 N = 104 
                 N = 135 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Age a  (years) 
                 65.0 
                 59.0 
                 61.0 
                 65.0 
                 66.0 
                 62.5 
                 63.0 
               
               
                 Gender 
                 19 (61.3%)/ 
                 19 (76.0%)/ 
                 17 (68.0%)/ 
                 16 (57.1%)/ 
                 15 (57.7%)/ 
                 68 (65.4%)/ 
                 87 (64.4%)/ 
               
               
                 (Male/Female) 
                 12 (38.7%) 
                 6 (24.6%) 
                 8 (32.0%) 
                 12 (42.9%) 
                 11 (42.3%) 
                 36 (34.6%) 
                 48 (35.6%) 
               
               
                 Weight a , kg 
                 81.0 
                 80.0 
                 84.70 
                 84.2 
                 81.2 
                 83.0 
                 82.0 
               
               
                 Average Daily  
                 0.64 
                 0.65 
                 0.61 
                 0.62 
                 0.64 
                 0.63 
                 0.63 
               
               
                 Protein 
                   
                   
                   
                   
                   
                   
                   
               
               
                 Intake a , g/kg/d 
                   
                   
                   
                   
                   
                   
                   
               
               
                 Diabetes Mellitus 
                 20 (64.5%)/ 
                 18 (72.0%)/ 
                 20 (80.0%)/ 
                 17 (60.7%)/ 
                 19 (73.1%)/ 
                 74 (71.2%)/ 
                 94 (69.6%)/ 
               
               
                 (Yes/No) 
                 11 (35.5%) 
                 7 (28.0%) 
                 5 (20.0%) 
                 11 (39.3%) 
                 7 (26.9%) 
                 30 (28.8%) 
                 41 (30.4%) 
               
               
                 Hypertension  
                 30 (96.8%)/ 
                 24 (96.0%)/ 
                 23 (92.0%)/ 
                 26 (92.9%)/ 
                 23 (88.5%)/ 
                 96 (92.3%)/ 
                 126 (93.3%)/ 
               
               
                 (Yes/No) 
                 1 (3.2%) 
                 1 (4.0%) 
                 2 (8.0%) 
                 2 (7.1%) 
                 3 (11.5%) 
                 8 (7.7%) 
                 9 (6.7%) 
               
               
                 Heart Failure  
                 7 (22.6%)/ 
                 5 (20.0%)/ 
                 7 (28.0%)/ 
                 5 (17.9%)/ 
                 5 (19.2%)/ 
                 22 (21.1%)/ 
                 29 (21.5%)/ 
               
               
                 (Yes/No) 
                 24 (77.4%) 
                 20 (80.0%) 
                 18 (72.0%) 
                 23 (82.1%) 
                 21 (80.8%) 
                 82 (78.9%) 
                 106 (78.5%) 
               
               
                 Left Ventricular 
                 8 (25.8%)/ 
                 7 (28.0%)/ 
                 7 (28.0%)/ 
                 8 (28.6%)/ 
                 9 (34.6%)/ 
                 31 (29.8%)/ 
                 39 (28.9%)/ 
               
               
                 Hypertrophy 
                 23 (74.2%) 
                 18 (72.0%) 
                 18 (72.0%) 
                 20 (71.4%) 
                 17 (65.4%) 
                 73 (70.2%) 
                 96 (71.1%) 
               
               
                 (Yes/No) 
                   
                   
                   
                   
                   
                   
                   
               
               
                 Peripheral Edema 
                 4 (12.9%)/ 
                 3 (12.0%)/ 
                 4 (16.0%)/ 
                 4 (14.3%)/ 
                 4 (15.4%)/ 
                 15 (14.4%)/ 
                 19 (14.1%)/ 
               
               
                 (Yes/No) 
                 27 (87.1%) 
                 22 (88.0%) 
                 21 (84.0%) 
                 24 (85.7%) 
                 22 (84.6%) 
                 89 (85.6%) 
                 116 (85.9%) 
               
               
                 SBP a , mmHg 
                 128.00 
                 132.00 
                 133.00 
                 130.00 
                 128.50 
                 131.50 
                 130.00 
               
               
                 eGFR a , 
                 29.0 
                 34.0 
                 35.0 
                 28.0 
                 34.0 
                 33.0 
                 32.0 
               
               
                 m&gt;/min/1.73m 2   
                   
                   
                   
                   
                   
                   
                   
               
               
                 SBC a , mEq/L 
                 17.6 
                 17.9 
                 17.8 
                 17.7 
                 17.7 
                 17.8 
                 17.7 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Proportion of Patients by Serum Bicarbonate Increase Category at Day 15 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Patients with 
                 Pooled 
                 TRC101 
                 TRC101 
                 TRC101 
                 TRC101  
                 TRC101 
               
               
                 Post-baseline 
                 Placebo 
                 1.5 g BID 
                 6 g QD 
                 3.0 g BID 
                 4.5 g BID 
                 Combined 
               
               
                 Serum Bicarbonate 
                 N = 31 
                 N = 25 
                 N = 28 
                 N = 25 
                 N = 26 
                 N = 104 
               
               
                   
               
               
                 ≥2 mEq/L 
                 4 (12.9%) 
                 18 (72.0%) 
                 23 
                 14 
                 19 (73.1%) 
                 74 (71.2%) 
               
               
                   
                   
                   
                 (82.1%) 
                 (56.0%) 
                   
                   
               
               
                 ≥3 mEq/L 
                 2 (6.5%)  
                 14 (56.0%) 
                 14 
                 10 
                 16 (61.5%) 
                 54 (51.9%) 
               
               
                   
                   
                   
                 (50.0%) 
                 (40.0%) 
                   
                   
               
               
                 ≥4 mEq/L 
                 1 (3.2%)  
                  8 (32.0%) 
                 11 
                 10 
                 11 (42.3%) 
                 40 (38.5%) 
               
               
                   
                   
                   
                 (39.3%) 
                 (40.0%) 
                   
                   
               
               
                 ≥5 mEq/L 
                 0 
                  3 (12.0%) 
                 6 (21.4%) 
                 6 (24.0%) 
                  8 (30.8%) 
                 23 (22.1%) 
               
               
                 ≥6 mEq/L 
                 0 
                  3 (12.0%) 
                 5 (17.9%) 
                 3 (12.0%) 
                  4 (15.4%) 
                 15 (14.4%) 
               
               
                 ≥7 mEq/L 
                 0 
                  1 (4.0%)  
                 1 (3.6%)  
                 2 (8.0%)  
                  2 (7.7%) 
                  6 (5.8%) 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Proportion of Patients by Serum Bicarbonate Category (Days 8 and 15) 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 Patients with 
                 Pooled 
                 TRC101 
                 TRC101 
                 TRC101 
                 TRC101 
                 TRC101 
               
               
                 Post-baseline  
                 Placebo 
                 1.5 g BID 
                 6 g QD 
                 3.0 g BID 
                 4.5 g BID 
                 Combined 
               
               
                 Serum Bicarbonate 
                 N = 31 
                 N = 25 
                 N = 28 
                 N = 25 
                 N = 26 
                 N = 104 
               
               
                   
               
            
           
           
               
            
               
                 Day 8 Serum Bicarbonate Values 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 &gt;20 mEq/L 
                 5 (16.1%) 
                 9 (36.0%) 
                 16 (57.1%) 
                 7 (28.0%) 
                 12 (46.2%) 
                 44 (42.3%) 
               
               
                 &gt;22 mEq/L 
                 2 (6.5%)  
                 2 (8.0%)  
                  5 (17.9%) 
                 5 (20.0%) 
                  6 (23.1%) 
                 18 (17.3%) 
               
               
                 &gt;27 mEq/L 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                 &gt;29 mEq/L 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
            
           
           
               
            
               
                 Day 15 Serum Bicarbonate Values 
               
            
           
           
               
               
               
               
               
               
               
            
               
                 &gt;20 mEq/L 
                 2 (6.5%) 
                 16 (64.0%) 
                 17 (60.7%) 
                 14 (56.0%) 
                 19 (73.1%) 
                 69 (66.3%) 
               
               
                 &gt;22 mEq/L 
                 0 
                 10 (40.0%) 
                  9 (32.1%) 
                  7 (28.0%) 
                 10 (38.5%) 
                 36 (34.6%) 
               
               
                 &gt;27 mEq/L 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                 &gt;29 mEq/L 
                 0 
                 0 
                 0 
                 0 
                 0 
                 0 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Treatment-Emergent Adverse Events Occurring in &gt;5% of Patients  
               
               
                 in any Treatment Group (Safety Analysis Set) 
               
            
           
           
               
               
               
               
            
               
                   
                   
                 TRC101 
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 Pooled 
                 1.5 g  
                   
                 3.0 g  
                 4.5 g  
                 TRC101 
                 Study 
               
               
                   
                 Placebo 
                 BID 
                 6 g QD 
                 BID 
                 BID 
                 Combined 
                 Total 
               
               
                   
                 (N = 31) 
                 (N = 25) 
                 (N = 28) 
                 (N = 25) 
                 (N = 26) 
                 (N = 104) 
                 (N = 135) 
               
               
                 Preferred Term 
                 n (%) 
                 n (%) 
                 n (%) 
                 n (%) 
                 n (%) 
                 n (%) 
                 n (%) 
               
               
                   
               
               
                 Patients reporting 
                 14 (45.2) 
                 13 (52.0) 
                 17 (60.7) 
                 9 (36.0) 
                 17 (65.4) 
                 56 (53.8) 
                 70 (51.9) 
               
               
                 any TEAE 
                   
                   
                   
                   
                   
                   
                   
               
               
                 Diarrhea 
                  4 (12.9) 
                  9 (36.0) 
                  3 (10.7) 
                 3 (12.0) 
                  6 (23.1) 
                 21 (20.2) 
                 25 (18.5) 
               
               
                 Headache 
                  1 (3.2)  
                  4 (16.0) 
                  1 (3.6)  
                 1 (4.0)  
                  2 (7.7) 
                  8 (7.7)  
                  9 (6.7)  
               
               
                 Constipation 
                 0 
                  1 (4.0)  
                  3 (10.7) 
                 1 (4.0)  
                  2 (7.7) 
                  7 (6.7)  
                  7 (5.2)  
               
               
                 Hyperglycemia 
                 0 
                 0 
                  3 (10.7) 
                 2 (8.0)  
                  2 (7.7) 
                  7 (6.7)  
                  7 (5.2)  
               
               
                 Hypoglycemia 
                  2 (6.5)  
                  2 (8.0)  
                 0 
                 1 (4.0)  
                  2 (7.7) 
                  5 (4.8)  
                  7 (5.2)  
               
               
                 Hypertension 
                  1 (3.2)  
                  1 (4.0)  
                  2 (7.1)  
                 0 
                  2 (7.7) 
                  5 (4.8)  
                  6 (4.4)  
               
               
                 Glomerular  
                  2 (6.5)  
                  2 (8.0)  
                 0 
                 1 (4.0)  
                  1 (3.8) 
                  4 (3.8)  
                  6 (4.4)  
               
               
                 filtration 
                   
                   
                   
                   
                   
                   
                   
               
               
                 rate decreased 
                   
                   
                   
                   
                   
                   
                   
               
               
                 Blood glucose 
                  2 (6.5)  
                  1 (4.0)  
                  1 (3.6)  
                 0 
                 0 
                  2 (1.9) 
                  4 (3.0)  
               
               
                 increased 
               
               
                   
               
               
                 BID = twice daily; GFR = glomerular filtration rate; QD = once daily; TEAE = treatment-emergent adverse event. 
               
            
           
         
       
     
     Example 4 
     Retrospective Analysis of the Benefit of Elevated Serum Bicarbonate Levels 
     The relationship between decreasing serum bicarbonate levels and worsening clinical outcomes is believed to be a continuum (i.e., as bicarbonate decreases from normal levels the risk of developing adverse outcomes associated with metabolic acidosis, such as death or progression of CKD, progressively increases). To develop a quantitative, predictive model of this relationship and to assess the influence of various CKD comorbidities, a longitudinal analysis using a population from the Optum, Inc. database including CKD patients with serum bicarbonate levels in the range of 12 to 29 mEq/L and eGFR 15 to 45 mL/min/1.73 m 2  was performed The key advantage of a large longitudinal dataset is the ability to designate a baseline period of significant duration (1 to 2 years) that establishes the presence (or absence) of metabolic acidosis and only then evaluates kidney disease progression ( FIG. 25 ). Since it can be difficult with retrospective database analyses to distinguish cause and effect (i.e., decreases in eGFR can cause decreases in serum bicarbonate and in turn metabolic acidosis can further cause decline in kidney function), all patients included in the analysis dataset were required to have at least two eGFR and serum bicarbonate measurements over a 1- to 2-year baseline period. Any renal progression events during this period were not counted and patients who died or progressed to dialysis/kidney transplant during the baseline period were excluded. Only after the end of the baseline period did we count the primary outcome event (i.e., death, progression to dialysis or kidney transplant, or ≥40% reduction from baseline in eGFR; hereafter, “DD40”). In addition, we mandated at least one additional confirmatory serum bicarbonate value in the observation period (i.e., the last available value in the patient&#39;s history). 
     To understand the quantitative relationship of increases in serum bicarbonate to the outcome of interest (i.e., DD40), three separate analyses were performed. These analyses evaluated: 1) the hazard ratio of DD40 in patients with metabolic acidosis (12 to &lt;22 mEq/L); 2) the hazard ratio of DD40 in patients with metabolic acidosis compared to those with normal serum bicarbonate levels (22 to 29 mEq/L); and 3) the benefit (i.e., reduction in hazard ratio of DD40) associated with different magnitudes of serum bicarbonate increase in the population of patients with serum bicarbonate 12 to 20 mEq/L (i.e., the population we intend to enroll in the TRCA-301 and TRCA-303 studies). These analyses are described in more detail below: 
     Analysis 1: In the subpopulation of acidotic patients with serum bicarbonate values between 12 and &lt;22 mEq/L (N=646), we evaluated the Cox proportional hazards model using baseline serum bicarbonate as a covariate to determine the effect of incremental changes in bicarbonate on the hazard ratio of DD40.
 
Analysis 2: The subpopulation of acidotic patients with serum bicarbonate values between 12 and &lt;22 mEq/L (N=646) was compared to the subpopulation of patients with normal serum bicarbonate (22 to 29 mEq/L; N=6,535) to quantify the hazard associated with having low serum bicarbonate.
 
Analysis 3: The subpopulation of patients with serum bicarbonate 12 to 20 mEq/L (i.e., the population to be enrolled in the TRCA-301 and TRCA-303 studies; N=351) was used as the reference group to evaluate the hazard reduction of the DD40 clinical outcome associated with an average 3 or 5 mEq/L increase in serum bicarbonate value. This analysis was performed to quantify the benefit of increases in serum bicarbonate of 2 to &lt;4 mEq/L or ≥4 mEq/L in the population to be enrolled in the TRCA-301 and TRCA-303 studies.
 
     The dataset used for this analysis is an extract of the Optum de-identified Electronic Health Record dataset (2007-2013), which contained longitudinal electronic health records for &gt;22 million unique patient lives. The source of the information in the database was approximately three dozen US health systems in 43 states covering approximately 200 hospitals and 1,800 outpatient clinics. The extract included patients with a documented diagnosis code or clinical evidence of Stage 3, 4, or 5 CKD (based on the Ninth Revision, International Classification of Diseases [ICD-9] code 585.4, 585.5) or an estimated glomerular filtration rate (eGFR)&lt;30 mL/min/1.73 m 2  at the start of the data period and with at least one serum bicarbonate (HCO 3 ) test result. The data period of the electronic health records is from January 2007 to July 2013. To exclude erroneous values, only serum bicarbonate values in the range 10 to 40 mEq/L and serum creatinine values in the range 0 to 20 mg/dL were included in the analysis dataset. 
     To assess the quantitative relationship between a death, dialysis or egfr decline of at least 40% (a “DD40” endpoint) and serum bicarbonate level, an analysis population was first defined that included only CKD patients with an eGFR value in the range of 15 to &lt;45 mL/min/1.73 m 2  and a serum bicarbonate level in the range of 12 to 29 mEq/L. Evidence of a Baseline Period of 1 to 2 years duration during which the patient had stable serum bicarbonate and eGFR values, prior to an up to 6.5-year Observation Period during which renal outcomes were assessed. 
     For inclusion in the analysis population, patients were required to have consistent evidence of the status of their acidosis by remaining in the same serum bicarbonate stratum (i.e., low [12 to 20 mEq/L], borderline [&gt;20 to &lt;22 mEq/L] or normal [22 to 29 mEq/L]) at the following three timepoints (with slightly wider ranges allowed for the second and third values to account for measurement variability):
         1. Baseline serum bicarbonate value, defined as the average of serum bicarbonate results collected within 30 days of the first date of collection from the records with serum bicarbonate results between 10 and 40 mEq/L;   2. First recorded serum bicarbonate value occurring at least 1 year but not more than 2 years after the Baseline HCO3 Date; and   3. Last recorded serum bicarbonate value.       

     Patients were required to have remained in the same serum bicarbonate stratum to which they were assigned at the beginning of the Baseline Period both at the end of the 1- to 2-year Baseline Period as well as at the end of the Observation Period. This approach was chosen to ensure that DD40 endpoints recorded during the Observation Period could be reliably associated with a particular serum bicarbonate stratum. One drawback of this approach is that the analysis population is likely to be somewhat healthier than the population that will be enrolled in the post-marketing study, TRCA-303. Since this is not expected to exaggerate differences in DD40 event rates observed between strata, the approach is considered reasonable. 
     Requirements for inclusion in the analysis population also mandated that the patient&#39;s eGFR must have remained in the target range of 15 to &lt;45 mL/min/1.73 m 2  at the beginning, and a target range of 10 to &lt;50 mL/min/1.73 m 2  at the end, of the 1- to 2-year Baseline Period. The eGFR at the end of the Baseline Period was used as the eGFR Baseline Value from which reductions in eGFR were calculated for the purposes of DD40 endpoint assessment. For a reduction in eGFR from the eGFR Baseline Value to have counted toward the DD40 endpoint, it must have been supported by a confirmatory eGFR value also occurring during the Observation Period that also represented at least a 40% reduction from Baseline. 
     The requirements for inclusion in the analysis population, and the resulting size of the analysis population after each requirement was implemented, are summarized in  FIGS. 15 and 16 , respectively. 
     Baseline Characteristics for the Analysis Population 
     The analysis population contained 7,181 CKD patients, which were divided into three strata based on their baseline serum bicarbonate level ( FIGS. 15 and 16 ): 351 patients with low bicarbonate levels (12 to 20 mEq/L), 295 patients with borderline acidosis (&gt;20 to &lt;22 mEq/L) and 6,535 patients with normal serum bicarbonate (22 to 29 mEq/L). Demographic and baseline information for the analysis population by serum bicarbonate stratum is provided in Table 400. 
     The analysis population was approximately 60% female, with an average age of approximately 74 years. Two-thirds (67%) of patients had a diagnosis of hypertension and 32% had a diagnosis of diabetes. A smaller proportion of patients (12%) had a history of cerebrovascular disease. Renin angiotensin aldosterone system (RAAS) inhibitor use prior to the beginning of the Observation Period was common in the analysis population (˜42% of patients). 
     Demographic and baseline characteristics were similar among the three serum bicarbonate strata, with the following exceptions: patients in the low serum bicarbonate stratum (12 to 20 mEq/L) were younger, had lower baseline eGFR, and were more often male than patients in the normal serum bicarbonate stratum (22 to 29 mEq/L). 
     At the time of the first qualifying eGFR value (i.e., at the beginning of the Baseline Period), the majority (79%) of patients in the analysis population had CKD stage 3b, with the remainder having more severe disease (CKD stage 4). The lowest serum bicarbonate stratum had a greater proportion of patients with CKD stage 4 (44%) than did the borderline acidotic and normal serum bicarbonate strata (26% and 20%, respectively). 
     
       
         
           
               
             
               
                 TABLE 400 
               
             
            
               
                   
               
               
                 Demographics and Baseline Characteristics of the Analysis Population 
               
            
           
           
               
               
               
               
            
               
                   
                 Serum Bicarbonate Stratum 
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 12 to 20 mEq/L 
                 &gt;20 to &lt;22 mEq/L 
                 22 to 29 mEq/L 
                 Total 
                   
               
               
                   
                 (N = 351) 
                 (N = 295) 
                 (N = 6,535) 
                 (N = 7,181) 
                 p-value 
               
               
                   
               
            
           
           
               
               
            
               
                 Age (years) a   
                 &lt;0.0001 
               
            
           
           
               
               
               
               
               
               
            
               
                 N 
                 351 
                 295 
                 6535 
                 7181 
                   
               
               
                 Mean (SD) 
                 69.4 (11.88) 
                 72.9 (9.31) 
                 74.1 (8.01) 
                 73.9 (8.36) 
                   
               
               
                 Median 
                 73.0 
                 77.0 
                 78.0 
                 78.0 
                   
               
               
                 Min, Max 
                 13, 83 
                 22, 83 
                 13, 83 
                 13, 83 
                   
               
               
                 &lt;18 years 
                  1 (0.3%) 
                 0 
                   2 (&lt;0.1%) 
                   3 (&lt;0.1%) 
                   
               
               
                 18 to &lt;65 years 
                  94 (26.8%) 
                  49 (16.6%) 
                  774 (11.8%) 
                  917 (12.8%) 
                   
               
               
                 ≥65 years 
                 256 (72.9%) 
                 246 (83.4%) 
                 5759 (88.1%) 
                 6261 (87.2%) 
                   
               
            
           
           
               
               
            
               
                 Sex 
                 0.0015 
               
            
           
           
               
               
               
               
               
               
            
               
                 Male 
                 155 (44.2%) 
                 145 (49.2%) 
                 2590 (39.6%) 
                 2890 (40.2%) 
                   
               
               
                 Female 
                 196 (55.8%) 
                 150 (50.8%) 
                 3945 (60.4%) 
                 4291 (59.8%) 
                   
               
            
           
           
               
               
            
               
                 Hypertension 
                 0.3615 
               
            
           
           
               
               
               
               
               
               
            
               
                 Yes 
                 225 (64.1%) 
                 190 (64.4%) 
                 4379 (67.0%) 
                 4794 (66.8%) 
                   
               
               
                 No 
                 126 (35.9%) 
                 105 (35.6%) 
                 2156 (33.0%) 
                 2387 (33.2%) 
                   
               
            
           
           
               
               
            
               
                 Cerebrovascular disease 
                 0.1622 
               
            
           
           
               
               
               
               
               
               
            
               
                 Yes 
                  40 (11.4%) 
                 25 (8.5%) 
                  791 (12.1%) 
                  856 (11.9%) 
                   
               
               
                 No 
                 311 (88.6%) 
                 270 (91.5%) 
                 5744 (87.9%) 
                 6325 (88.1%) 
                   
               
            
           
           
               
               
            
               
                 Diabetes 
                 0.0655 
               
            
           
           
               
               
               
               
               
               
            
               
                 Yes 
                 118 (33.6%) 
                 110 (37.3%) 
                 2042 (31.2%) 
                 2270 (31.6%) 
                   
               
               
                 No 
                 233 (66.4%) 
                 185 (62.7%) 
                 4493 (68.8%) 
                 4911 (68.4%) 
                   
               
            
           
           
               
               
            
               
                 Baseline ACEi or ARB Use 
                 0.1582 
               
            
           
           
               
               
               
               
               
               
            
               
                 Yes 
                 162 (46.2%) 
                 135 (45.8%) 
                 2704 (41.4%) 
                 3001 (41.8%) 
                   
               
               
                 No 
                 150 (42.7%) 
                 118 (40.0%) 
                 2961 (45.3%) 
                 3229 (45.0%) 
                   
               
               
                 Missing 
                  39 (11.1%) 
                  42 (14.2%) 
                  870 (13.3%) 
                  951 (13.2%) 
                   
               
            
           
           
               
               
            
               
                 Baseline Serum Bicarbonate (HCO3) (mEq/L) b   
                 &lt;0.0001 
               
            
           
           
               
               
               
               
               
               
            
               
                 N 
                 351 
                 295 
                 6535 
                 7181 
                   
               
               
                 Mean (SD) 
                 18.3 (1.65)  
                 21.0 (0.26) 
                 25.3 (2.02) 
                 24.8 (2.59) 
                   
               
               
                 Median 
                 19.0 
                 21.0 
                 25.0 
                 25.0 
                   
               
               
                 Min, Max 
                 13, 20 
                 20, 22 
                 22, 29 
                 13, 29 
                   
               
            
           
           
               
               
            
               
                 First Qualifying eGFR (mL/min/1.73 m 2 ) 
                 &lt;0.0001 
               
            
           
           
               
               
               
               
               
               
            
               
                 N 
                 351 
                 295 
                 6535 
                 7181 
                   
               
               
                 Mean (SD) 
                 30.7 (7.86)  
                 33.7 (7.28) 
                 35.3 (6.56) 
                 35.0 (6.74) 
                   
               
               
                 Median 
                 31.0 
                 35.0 
                 36.0 
                 36.0 
                   
               
               
                 Min, Max 
                 15, 44 
                 15, 44 
                 15, 44 
                 15, 44 
                   
               
               
                 Stage 3b Moderate CKD 
                 197 (56.1%) 
                 217 (73.6%) 
                 5260 (80.5%) 
                 5674 (79.0%) 
                   
               
               
                 (30 to 44 mL/min/ 
                   
                   
                   
                   
                   
               
               
                 1.73 m 2 ) 
                   
                   
                   
                   
                   
               
               
                 Stage 4 Severe CKD 
                 154 (43.9%) 
                  78 (26.4%) 
                 1275 (19.5%) 
                 1507 (21.0%) 
                   
               
               
                 (15 to 29 mL/min/ 
                   
                   
                   
                   
                   
               
               
                 1.73 m 2 ) 
               
               
                   
               
               
                 ACEi = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; HCO3 = serum bicarbonate; SD = standard deviation 
               
               
                 Note: 
               
               
                 Race and urine albumin-to-creatinine ratio not included because &gt;95% and &gt;85% of patients, respectively, did not have this information recorded. 
               
               
                   a Age was calculated as the difference between date of birth and date of baseline bicarbonate, in years. All patients had their birth month and day set to June 1. Patients with no available birth date (i.e., no birth year) had their birth year set to the same year as the baseline serum bicarbonate measurement collection year (i.e., age = 0 years). Patients with birth year of 1928 or earlier had their birth year set to 1928 (i.e., age = 85 years). 
               
               
                   b Baseline serum bicarbonate calculated as average of all HCO 3  values within 30 days of first HCO 3  value. 
               
            
           
         
       
     
     Qualifying Serum Bicarbonate and eGFR Values for the Analysis Population 
     Because patients were required to remain in the same serum bicarbonate stratum to which they were assigned at the beginning of the Baseline Period, there was little difference in the mean serum bicarbonate values in a particular stratum over the course of the Baseline and Observation Periods. For example, patients in the low serum bicarbonate stratum had an average serum bicarbonate level of 18.3 mEq/L at the beginning of the Baseline Period, 18.5 mEq/L at the end of the Baseline Period (which is also the beginning of the Observation Period), and 18.5 mEq/L at the end of the Observation Period. Similarly, patients in the borderline and normal serum bicarbonate strata had serum bicarbonate values across the analysis periods that did not vary significantly (Table 500). The length of the Baseline Period varied among patients because it was determined by the time of the first serum bicarbonate record occurring at least 1 year but not more than 2 years after the patient&#39;s first recorded serum bicarbonate value. The average duration of the Baseline Period, determined by the second qualifying serum bicarbonate value, was 15.2 months in the analysis population overall, and it was similar among the three serum bicarbonate strata (Table 500). 
     To ensure that we were assessing the effects of various levels of acidosis in CKD patients who represent our intended TRCA-303 population, patients in the analysis population were required to have an eGFR value at least 1 year but not more than 2 years after the patient&#39;s first recorded serum bicarbonate value that was in the range between 10 and 50 mL/min/1.73 m 2 . The patient&#39;s Baseline eGFR Value was calculated from the average of all serum creatinine values recorded in the 90 days prior to this second qualifying eGFR value. The mean Baseline eGFR Values were 29.6, 32.8 and 35.4 mL/min/1.73 m 2  in the low, borderline and normal serum bicarbonate groups, respectively. The duration of the Baseline Period, as defined by the time between the first and second qualifying eGFR values, was 15.06 months in the analysis population overall, and it was similar among the three serum bicarbonate strata (Table 500). A patient&#39;s Baseline eGFR Value was used for assessment of all DD40 endpoint events occurring during the Observation Period. Reductions in eGFR sufficiently large to contribute to the DD40 event rate (i.e., 40%) were calculated as reductions from this eGFR value, not the eGFR at the beginning of the Baseline Period. All reductions in eGFR contributing to the DD40 event rate were also confirmed by a second eGFR value that confirmed magnitude of the reduction. 
     The average duration of the Observation Period, as defined by the time from the Baseline eGFR Date to the last recorded patient contact, was 34.9 months in the analysis population overall, and ranged from 32.9 to 35.0 months among the three serum bicarbonate strata. 
     
       
         
           
               
             
               
                 TABLE 500 
               
             
            
               
                   
               
               
                 Serum Bicarbonate and eGFR Values of the Analysis Population 
               
            
           
           
               
               
               
            
               
                   
                 Serum Bicarbonate Stratum 
                   
               
            
           
           
               
               
               
               
               
            
               
                   
                 12 to 20 mEq/L 
                 &gt;20 to &lt;22 mEq/L 
                 22 to 29 mEq/L 
                 Total 
               
               
                 All Patients 
                 (N = 351) 
                 (N = 295) 
                 (N = 6,535) 
                 (N = 7,181) 
               
               
                   
               
            
           
           
               
            
               
                 Baseline Serum Bicarbonate (mEq/L; First HCO3 Value) 
               
            
           
           
               
               
               
               
               
            
               
                 Mean (SD) 
                 18.3 (1.65) 
                 21.0 (0.26) 
                 25.3 (2.02) 
                 24.8 (2.59) 
               
               
                 Median (Min, Max) 
                 19.0 (13, 20) 
                 21.0 (20, 22) 
                 25.0 (22, 29) 
                 25.0 (13, 29) 
               
            
           
           
               
            
               
                 First Qualifying eGFR (mL/min/1.73 m 2 ) 
               
            
           
           
               
               
               
               
               
            
               
                 Mean (SD) 
                 30.7 (7.86) 
                 33.7 (7.28) 
                 35.3 (6.56) 
                 35.0 (6.74) 
               
               
                 Median (Min, Max) 
                 31.0 (15, 44) 
                 35.0 (15, 44) 
                 36.0 (15, 44) 
                 36.0 (15, 44) 
               
            
           
           
               
            
               
                 Second Qualifying Serum Bicarbonate (mEq/L; i.e., End of 1- to 2-year Baseline Period) 
               
            
           
           
               
               
               
               
               
            
               
                 Mean (SD) 
                 18.5 (2.37) 
                 21.2 (1.50) 
                 25.0 (2.29) 
                 24.5 (2.75) 
               
               
                 Median (Min, Max) 
                 19.0 (10, 22) 
                 21.0 (18, 24) 
                 25.0 (20, 29) 
                 25.0 (10, 29) 
               
            
           
           
               
            
               
                 Baseline eGFR Value (mL/min/1.73 m 2 ; i.e., End of 1-to 2-year Baseline Period) 
               
            
           
           
               
               
               
               
               
            
               
                 Mean (SD) 
                 29.6 (9.25) 
                 32.8 (8.93) 
                 35.4 (7.98) 
                 35.0 (8.20) 
               
               
                 Median (Min, Max) 
                 30.0 (10, 49) 
                 34.0 (10, 49) 
                 36.0 (10, 49) 
                 36.0 (10, 49) 
               
            
           
           
               
            
               
                 Last Serum Bicarbonate (mEq/L) 
               
            
           
           
               
               
               
               
               
            
               
                 Mean (SD) 
                 18.5 (2.51) 
                 21.0 (1.61) 
                 24.9 (2.40) 
                 24.4 (2.85) 
               
               
                 Median (Min, Max) 
                 19.0 (10, 22) 
                 21.0 (18, 24) 
                 25.0 (20, 29) 
                 25.0 (10, 29) 
               
            
           
           
               
            
               
                 Time (months) from First HCO3 to Second Qualifying Serum Bicarbonate Value (i.e., length of Baseline Period) 
               
            
           
           
               
               
               
               
               
            
               
                 Mean (SD) 
                 15.35 (3.283) 
                 14.95 (2.851) 
                 15.21 (3.149) 
                 15.20 (3.144) 
               
               
                 Median (Min, Max) 
                 14.10 (12.0, 24.0) 
                 13.90 (12.0, 23.9) 
                 14.10 (12.0, 24.0) 
                 14.10 (12.0, 24.0) 
               
            
           
           
               
            
               
                 Time (months) from First Qualifying eGFR to Baseline eGFR Date (i.e., length of Baseline Period) 
               
            
           
           
               
               
               
               
               
            
               
                 Mean (SD) 
                 14.90 (3.016) 
                 14.83 (2.847) 
                 15.08 (3.081) 
                 15.06 (3.069) 
               
               
                 Median (Min, Max) 
                 13.80 (12.0, 23.8) 
                 13.80 (12.0, 23.9) 
                 14.00 (12.0, 24.0) 
                 13.90 (12.0, 24.0) 
               
            
           
           
               
            
               
                 Time (months) from Baseline eGFR Date to Last Contact Date (i.e., length of Observation Period) 
               
            
           
           
               
               
               
               
               
            
               
                 Mean (SD) 
                 32.92 (19.80) 
                 34.74 (20.61) 
                 35.02 (19.47) 
                 34.90 (19.53) 
               
               
                 Median (Min, Max) 
                 32.30 (0.0, 73.0) 
                 33.60 (0.4, 72.2) 
                 35.30 (0.0, 77.1) 
                 35.20 (0.0, 77.1) 
               
               
                   
               
               
                 eGFR = estimated glomerular filtration rate; HCO 3  = serum bicarbonate; SD = standard deviation 
               
            
           
         
       
     
     Analysis Results 
     Frequency of Endpoint Events by Serum Bicarbonate Stratum 
     During the almost 6.5-year follow up of the 7,181 patients in the analysis population, 572 patients experienced the DD40 endpoint (Table 600). Of these patients, 50 died, 60 initiated dialysis or received renal transplantation and 462 had a 40% decline from baseline in eGFR. The incidence rate of each of the individual endpoint events, as well as of the DD40 composite endpoint, was 2.4- to 6.7-fold higher in the group of patients with low baseline serum bicarbonate than in the patients with normal serum bicarbonate. 
     
       
         
           
               
             
               
                 TABLE 600 
               
             
            
               
                   
               
               
                 Frequency and Incidence Rates of Endpoint Events by  
               
               
                 Serum Bicarbonate Stratum 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                 12 to 20 
                 &gt;20 to &lt; 22 
                 12 to &lt; 22 
                 22 to 24 
                 22 to 29 
                   
               
               
                   
                 mEq/L 
                 mEq/L 
                 mEq/L 
                 mEq/L 
                 mEq/L 
                 Total 
               
               
                 Endpoint Event 
                 (N = 351) 
                 (N = 295) 
                 (N = 646) 
                 (N = 1,572) 
                 (N = 6,535) 
                 (N = 7,181) 
               
               
                   
               
               
                 DD40 
                 71 (20.2%) 
                 35 (11.9%) 
                 106 (16.4%) 
                 110 (7.0%) 
                 466 (7.1%) 
                 572 (8.0%) 
               
               
                 Death 
                  7 (2.0%)  
                  5 (1.7%)  
                  12 (1.9%)  
                   9 (0.6%) 
                  38 (0.6%) 
                  50 (0.7%) 
               
               
                 Dialysis or  
                 14 (4.0%)  
                  6 (2.0%)  
                  20 (3.1%)  
                   9 (0.6%) 
                  40 (0.6%) 
                  60 (0.8%) 
               
               
                 kidney 
                   
                   
                   
                   
                   
                   
               
               
                 transplant 
                   
                   
                   
                   
                   
                   
               
               
                 ≥40% decline  
                 50 (14.2%) 
                 24 (8.1%)  
                  74 (11.5%) 
                  92 (5.9%) 
                 388 (5.9%) 
                 462 (6.4%) 
               
               
                 from baseline  
                   
                   
                   
                   
                   
                   
               
               
                 in eGFR 
               
               
                   
               
               
                 Number (%) of patients are reported. 
               
               
                 DD40 = the composite of death, dialysis or kidney transplant, and ≥40% decline from baseline in eGFR; 
               
               
                 eGFR = estimated glomerular filtration rate 
               
            
           
         
       
     
     Cox Regression Analyses 
     To understand the impact of each 1 mEq/L increase in serum bicarbonate on the hazard reduction of DD40, three separate analyses were performed (17). These analyses evaluated: 1) the hazard ratio of DD40 in patients with metabolic acidosis (12 to 22 mEq/L); 2) the hazard ratio of DD40 in patients with metabolic acidosis compared to those with normal serum bicarbonate levels (22 to 29 mEq/L); and 3) the benefit (i.e., reduction in hazard ratio of DD40) associated with different magnitudes of serum bicarbonate increase compared with the population of patients with serum bicarbonate 12 to 20 mEq/L ( FIG. 17 ). 
     (A) Analysis 1: Effect of Incremental Changes in Serum Bicarbonate on the Hazard of DD40 
     For the subpopulation of patients with below-normal serum bicarbonate, we evaluated the Cox proportional hazards model for the hazard ratio of the DD40 clinical endpoint adjusted for the following covariates: baseline bicarbonate, age, sex, hypertension, cerebrovascular disease, diabetes, baseline angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) use, and initial eGFR. Stepwise model selection using the backward-forward method was applied. A variable had to be significant at the 0.3 level before it could be entered into the model, and the variable had to be significant at the 0.21 level for it to remain in the final Cox proportional-hazards regression model. The significance level for entry into and staying in the model was intentionally conservative to allow variables to be included in the final model, even if all were not significant at the 0.05 level. 
     As shown in Table 401, each 1 mEq/L increase in baseline serum bicarbonate was associated with a reduction in the DD40 hazard of approximately 12%. 
     
       
         
           
               
             
               
                 TABLE 401 
               
             
            
               
                   
               
               
                 Cox Regression Model for DD40  
               
               
                 (Patients with Serum Bicarbonate 12 to 22 mEq/L) 
               
            
           
           
               
               
               
            
               
                   
                 Hazard Ratio  
                   
               
               
                   
                 (95% CI) 
                   
               
               
                 Covariate a   
                 (N =646) 
                 p-value 
               
               
                   
               
               
                 Baseline HCO 3    
                 0.88 (0.80, 0.97) 
                 0.0084 
               
               
                 increases of 1 mEq/L b   
                   
                   
               
               
                 Sex (Male/Female) 
                 1.33 (0.90, 1.94) 
                 0.1492 
               
               
                 Diabetes (Yes/No) 
                 1.63 (1.11, 2.40) 
                 0.0125 
               
               
                 Cerebrovascular disease  
                 1.55 (0.88, 2.74) 
                 0.1307 
               
               
                 (Yes/No) 
                   
                   
               
               
                 Initial qualifying eGFR  
                 1.04 (1.02, 1.07) 
                 0.0013 
               
               
                 decreases of 1 
                   
                   
               
               
                 (mL/min/1.73 m 2 ) 
               
               
                   
               
               
                 ACEi = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; CI = confidence interval; eGFR = estimated glomerular filtration rate; HCO 3  = serum bicarbonate 
               
               
                   a Cox proportional hazard model used stepwise selection for baseline HCO 3  value, age (&lt;65 or ≥65), sex (Male or Female), hypertension (Yes, No), cerebrovascular disease (Yes, No), diabetes (Yes, No), initial qualifying eGFR value, and baseline ACEi/ARB use (Yes, No). 
               
               
                   a Baseline serum bicarbonate was calculated as the average of measurements within 30 days of first measurement of HCO 3 . 
               
            
           
         
       
     
     (B) Analysis 2: Effect of Low Serum Bicarbonate on DD40 
     A Cox regression analysis adjusted for multiple covariates (i.e., age, sex, hypertension, cerebrovascular disease, diabetes, baseline ACE inhibitor or ARB use, and initial eGFR) was performed with two serum bicarbonate strata: patients with baseline serum bicarbonate in the ranges of 12 to &lt;22 mEq/L and 22 to 29 mEq/L. 
     The results demonstrate that the hazard ratio of the DD40 endpoint is higher in the group of patients with low serum bicarbonate compared with those with normal serum bicarbonate. The adjusted hazard ratio was 1.79 (95% confidence interval [CI]: 1.31, 2.43; p=0.0002; Table 501;  FIG. 26 ). 
     We also explored the potential impact of factors other than serum bicarbonate level on the DD40 hazard ratio in our analysis population. The factors investigated included demographic factors (age, sex), comorbidities common in the CKD population (hypertension, diabetes, cerebrovascular disease), use of an ACE inhibitor or ARB at baseline and the patient&#39;s initial eGFR value as a measure of the severity of their renal disease. The hazard ratios (95% CI) for each factor, while adjusting for the other factors, are provided in Table 501. 
     
       
         
           
               
             
               
                 TABLE 501 
               
             
            
               
                   
               
               
                 Cox Model Hazard Ratios (95% CI) for DD40 by Serum Bicarbonate Stratum 
               
            
           
           
               
               
               
               
               
            
               
                   
                 12 to &lt;22 mEq/L 
                 22 to 29 mEq/L 
                   
                   
               
               
                   
                 (N = 646) 
                 (N = 6,535) 
                 Covariate 
                 p-value 
               
               
                   
               
            
           
           
               
            
               
                 Baseline serum bicarbonate (mEq/L) a   
               
            
           
           
               
               
               
               
               
            
               
                 Mean (SD) 
                 19.6 (1.82)   
                 25.3 (2.02) 
                   
                   
               
            
           
           
               
            
               
                 Number (%) patients 
               
            
           
           
               
               
               
               
               
            
               
                 With Event during 
                 106 (16.4%) 
                 466 (7.1%) 
                   
                   
               
               
                 Observation Period 
                   
                   
                   
                   
               
            
           
           
               
            
               
                 Model without adjustment a   
               
            
           
           
               
               
               
               
               
            
               
                 Hazard Ratio (95% CI) 
                 2.50 (2.02, 3.09) 
                 Reference 
                 None 
                   
               
               
                 p-value 
                 &lt;0.0001 
                 Reference 
                   
                   
               
            
           
           
               
            
               
                 Model with adjustment b   
               
            
           
           
               
               
               
               
               
            
               
                 Hazard Ratio (95% CI) 
                 1.79 (1.31, 2.43) 
                 Reference 
                   
                   
               
               
                 p-value 
                 0.0002 
                 Reference 
                   
                   
               
            
           
           
               
               
               
            
               
                 Age (≥65 years/&lt;65 years) 
                 0.68 (0.51, 0.91) 
                 0.0091 
               
               
                 Diabetes (Yes/No) 
                 1.57 (1.23, 2.00) 
                 0.0002 
               
               
                 Hypertension (Yes/No) 
                 0.77 (0.56, 1.07) 
                 0.1163 
               
               
                 Cerebrovascular disease (Yes/No) 
                 1.83 (1.38, 2.43) 
                 &lt;0.0001 
               
               
                 Initial qualifying eGFR  
                 1.06 (1.04, 1.08) 
                 &lt;0.0001 
               
               
                 value by decreases of 1 mL/min/1.73 m 2   
                   
                   
               
               
                   
               
               
                 ACEi = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; CI = confidence interval; eGFR = estimated glomerular filtration rate; SD = standard deviation 
               
               
                   b COX proportional hazard model without adjustment for covariates. 
               
               
                   c Cox proportional hazard model stepwise selection for age (&lt;65 or ≥65), sex (male or female), hypertension (Yes, No), cerebrovascular disease (Yes, No), diabetes (Yes, No), initial qualifying eGFR value, and baseline ACEi/ARB use (Yes, No). The p-value for these covariates must be &lt;0.3 to be included in the model. 
               
            
           
         
       
     
     (C) Analysis 3: Effect of Incrementally Higher Serum Bicarbonate Levels on DD40 
     As shown in Table 700, the hazard ratio of the DD40 endpoint is reduced with both moderate and large increases in serum bicarbonate. This analysis used the low serum bicarbonate (12 to 20 mEq/L) stratum as Reference for comparison with two strata with higher average serum bicarbonate levels. The average baseline serum bicarbonate level in the Reference stratum was 18.3 mEq/L. The Test strata had average baseline serum bicarbonate levels of 21.0 and 23.1 mEq/L, representing increases in serum bicarbonate of approximately 3 and 5 mEq/L. A 3 mEq/L higher average serum bicarbonate level resulted in an adjusted hazard ratio of 0.60 (95% CI: 0.40, 0.91; p=0.0153), indicating that moderately higher serum bicarbonate levels significantly reduce the hazard of the DD40 endpoint. A 5 mEq/L higher average serum bicarbonate level resulted in an adjusted hazard ratio of 0.39 (95% CI: 0.29, 0.53; p&lt;0.0001). 
     
       
         
           
               
             
               
                 TABLE 700 
               
             
            
               
                   
               
               
                 Hazard Ratios and 95% Confidence Intervals for DD40 from Cox Model 
               
               
                 (10&lt; = Baseline eGFR &lt;50 mL/min/1.73 m 2 ) 
               
               
                 Patients a  with Baseline SBC &gt; = 12 mEq/L and &lt; = 29 mEq/L and First Qualifying eGFR &gt; = 15 and &lt;45 mL/min/1.73 m 2   
               
            
           
           
               
               
               
               
            
               
                   
                 Baseline Serum Bicarbonate 
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                 &gt;27-29 mEq/L 
                 &gt;24-27 mEq/L 
                 22-24 mEq/L 
                 &gt;20-&lt;22 mEq/L 
                 12-20 mEq/L 
                   
                   
               
               
                   
                 (N = 612) 
                 (N = 2413) 
                 (N = 1572) 
                 (N = 295) 
                 (N = 351) 
                 Covariate 
                 p-value e   
               
               
                   
               
            
           
           
               
            
               
                 Baseline serum bicarbonate (mEq/L) 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 n 
                 612 
                 2413 
                 1572 
                 295 
                 351 
                   
                   
               
               
                 Mean (SD) 
                 28.4 (0.54) 
                 25.9 (0.82) 
                 23.1 (0.79) 
                 21.0 (0.26) 
                 18.3 (1.65) 
                   
                   
               
               
                 Median 
                 28.0 
                 26.0 
                 23.0 
                 21.0 
                 19.0 
                   
                   
               
               
                 Min, Max 
                 27, 29 
                 24, 27 
                 22, 24 
                 20, 22 
                 13, 20 
                   
                   
               
            
           
           
               
            
               
                 1st qualifying estimated glomerular filtration rate (eGFR) (mL/min/1.73 m 2 ) 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 n 
                 612 
                 2413 
                 1572 
                 295 
                 351 
                   
                   
               
               
                 Mean (SD) 
                 36.7 (5.91) 
                 35.5 (6.44) 
                 34.9 (6.81) 
                 33.7 (7.28) 
                 30.7 (7.86) 
                   
                   
               
               
                 Median 
                 38.0 
                 36.0 
                 36.0 
                 35.0 
                 31.0 
                   
                   
               
               
                 Min, Max 
                 17, 44 
                 15, 44 
                 15, 44 
                 15, 44 
                 15, 44 
                   
                   
               
            
           
           
               
            
               
                 Length of observation period (months) 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 n 
                 612 
                 2413 
                 1572 
                 295 
                 351 
                   
                   
               
               
                 Mean (SD) 
                 33.25 (19.62) 
                 34.15 (19.67) 
                 34.54 (19.86) 
                 34.74 (20.61) 
                 32.92 (19.80) 
                   
                   
               
               
                 Median 
                 33.02 
                 33.91 
                 34.30 
                 33.58 
                 32.30 
                   
                   
               
               
                 Min, Max 
                 0.1, 71.3 
                 0.0, 77.1 
                 0.1, 71.0 
                 0.4, 72.2 
                 0.0, 73.0 
                   
                   
               
            
           
           
               
            
               
                 Number (%) patients 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Had Event  
                 23 (3.8%) 
                 154 (6.4%) 
                 110 (7.0%) 
                 35 (11.9%) 
                 71 (20.2%) 
                   
                   
               
               
                 (New DD40 &gt; 1 Year 
                   
                   
                   
                   
                   
                   
                   
               
               
                 (baseline eGFR 
                   
                   
                   
                   
                   
                   
                   
               
               
                 date 1 to 2 years)) 
                   
                   
                   
                   
                   
                   
                   
               
               
                 Censored 
                 589 (96.2%) 
                 2259 (93.6%) 
                 1462 (93.0%) 
                 260 (88.1%) 
                 280 (79.8%) 
                   
                   
               
            
           
           
               
            
               
                 Model without adjustment b   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Hazard Ratio (95% Cl) 
                 0.17 (0.10, 0.27) 
                 0.28 (0.21, 0.37)  
                 0.31 (0.23, 0.42) 
                 0.54 (0.36, 0.81) 
                 Reference 
                 None 
                   
               
               
                 p-value c   
                 &lt;.0001 
                 &lt;.0001 
                 &lt;.0001 
                 0.0027 
                 Reference 
                   
                   
               
            
           
           
               
            
               
                 Model with adjustment d   
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Hazard Ratio (95% Cl) 
                 0.25 (0.16, 0.41) 
                 0.41 (0.31, 0.55)  
                 0.43 (0.32, 0.59) 
                 0.66 (0.44, 0.99) 
                 Reference 
                   
                   
               
               
                 p-value c   
                 &lt;.0001 
                 &lt;.0001 
                 &lt;.0001 
                 0.0452 
                 Reference 
                   
                   
               
               
                 Age (&gt; = years/&lt;65 years) 
                   
                   
                   
                   
                   
                 0.69 (0.54, 0.89) 
                 0.0046 
               
               
                 Sex (Male/Female) 
                   
                   
                   
                   
                   
                 1.24 (1.01, 1.51) 
                 0.0367 
               
               
                 Diabetes (Yes/No) 
                   
                   
                   
                   
                   
                 1.68 (1.36, 2.06) 
                 &lt;.0001 
               
               
                 Cerebrovascular disease  
                   
                   
                   
                   
                   
                 1.76 (1.35, 2.28) 
                 &lt;.0001 
               
               
                 (Yes/No) 
                   
                   
                   
                   
                   
                   
                   
               
               
                 Initial qualifying eGFR  
                   
                   
                   
                   
                   
                 1.06 (1.04, 1.07) 
                 &lt;.0001 
               
               
                 decreases of 1 
                   
                   
                   
                   
                   
                   
                   
               
               
                 (mL/min/1.73 m 2 ) 
                   
                   
                   
                   
                   
                   
                   
               
               
                 Baseline ACEi or ARB use 
                   
                   
                   
                   
                   
                 1.24 (1.01, 1.53) 
                 0.0366 
               
               
                   
               
               
                 Note: Events are counted when occurred &gt; = 365 days after the first recorded HCO3 value. 
               
               
                   a Baseline serum bicarbonate was calculated as the average of measurements within 30 days of first measurement of HCO3 (between 10 and 40 mEq/L). 
               
               
                   b Cox proportional hazard model stepwise selection for age (&lt;65 or &gt; = 65), sex (Male or Female), hypertension (Yes, No), cerebrovascular disease (Yes, No), diabetes (Yes, No), initial qualifying eGFR value, and baseline ACEi/ARB use (Yes, No). The p-value for these covariates must be &lt;0.3 to be included in the model. 
               
               
                   c p-value is testing for the hazard ratio for eGFR deline &gt; = 40% in patients with a baseline SBC category over the reference category. 
               
               
                   d Cox proportional hazard model stepwise selection for age (&lt;65 or &gt; = 65), sex (Male or Female), hypertension (Yes, No), cerebrovascular disease (Yes, No), diabetes (Yes, No), initial qualifying eGFR value, baseline proteinuria (Moderate or Severe), baseline proteinuria (Servere), and baseline ACEi/ARB use (Yes, No). The p-value for these covariates must be &lt;0.3 to be included in the model. 
               
               
                   e The p-value is testing effect of covariates. 
               
            
           
         
       
     
     CONCLUSION 
     The subpopulations of patients that represent increases in serum bicarbonate of 2 to &lt;4 mEq/L or 4 mEq/L in the acidotic (serum bicarbonate 12 to 20 mEq/L) population have a 40% and 61% reduced hazard of DD40, respectively. This result suggests that each 1 mEq/L increase of serum bicarbonate reduces hazard of DD40 by ˜12 to 13%. 
     Example 5 
     Description and Analysis of Results from Clinical Trial 
     A double blind, randomized, placebo-controlled study that enrolled 217 subjects with Stage 3b or 4 CKD (an estimated glomerular filtration rate [eGFR] of 20 to 40 mL/min/1.73 m 2 ) and low blood bicarbonate levels (between 12 mEq/L and 20 mEq/L) was conducted. At the beginning of the 12-week treatment period, subjects were randomized in a 4:3 ratio to receive once-daily, or QD, a pharmaceutical composition according to the present invention, e.g., TRC101, or placebo. Subjects in the active group initially received a QD dose of 6 grams of TRC101 (2 sachets). After week 4, bi-directional blinded dose adjustments to 3 grams/day (1 sachet) or 9 grams/day (3 sachets) were allowed in order to maintain blood bicarbonate in the normal range. Subjects in the placebo group initially received 2 sachets of placebo, with the same ability for bi-directional dose adjustments after 4 weeks. The dose titration algorithm required down-titration at blood bicarbonate values of 27 to 30 mEq/L. Subjects with a blood bicarbonate level greater than 30 underwent an interruption of the study drug in accordance with the titration algorithm. Subjects were permitted to continue their existing oral alkali supplement during the trial, provided that dosing remained stable. The trial was conducted at 47 sites in the United States and Europe. 
     Eligible patients were aged 18 to 85 years and had systolic blood pressure &lt;170 mmHg and hemoglobin A1c&lt;9%. During the up to 2-week Screening Period, three qualifying fasting serum bicarbonate values over 14 days were required to establish eligibility; the first two values and the average of all three were required to be within the range 12-20 mmol/L. Two qualifying eGFR values not different by &gt;20% and in the range 20-40 mL/min/1-73 m 2  were required during screening. Patients were excluded if their serum bicarbonate level was low enough to need emergency intervention or evaluation for an acute acidotic process, or if in the 3 months prior to the first Screening Visit they had anuria, dialysis, or acute or chronic worsening renal function (e.g., 30% decline in eGFR). Patients with recent history of chronic obstructive pulmonary disease, heart failure with New York Heart Association Class IV symptoms, stroke, transient ischemic attack, cancer, cardiac event, diabetic gastroparesis, bariatric surgery, bowel obstruction, swallowing disorders, severe gastrointestinal disorders, or hospitalization other than for pre-planned diagnostic or minor invasive procedures, those who had a heart or kidney transplant, and those who planned initiation of renal replacement therapy within 12 weeks were also excluded. Eligible patients did not have liver enzyme levels &gt;3 times the upper limit of normal, serum calcium levels ≤2 mmol/L or serum potassium levels &lt;3.8 mmol/L or &gt;5.9 mmol/L. Concomitant medication requirements for study participation precluded use of any other investigational medication as well as other binder drugs (except for short-term use of potassium binders for treatment of hyperkalemia) and required stable doses (whenever possible) of the following if they were used: calcium-containing supplements; antacids; H2-blockers; proton pump inhibitors; oral alkali; diuretics; renin-angiotensin-aldosterone system inhibitors; and non-ophthalmic carbonic anhydrase inhibitors. Dosing of oral concomitant medications and study drug was separated by &gt;4 hours. 
     The starting study drug dose was 6 grams/day TRC101 (2 packets/day) or placebo (2 packets/day) administered orally as a suspension in water with lunch. The first dose was administered in the clinic on the day of randomisation, after which, patients self-administered the study drug for 12 weeks and recorded the dose in a diary, which was reviewed, together with used and unused study drug returned at each visit. Beginning at Week 4, the study drug dose was algorithmically titrated by the interactive response technology system in the range from 0-9 grams/day (or equivalent number of packets of placebo) to a target bicarbonate of 22-29 mmol/L based on the bicarbonate measurement at each visit. The dose was down-titrated if bicarbonate was high-normal (27-30 mmol/L) and interrupted if it was &gt;30 mmol/L (Table 800). 
     
       
         
           
               
             
               
                 TABLE 800 
               
             
            
               
                   
               
               
                 Dose Titration Algorithm 
               
            
           
           
               
               
               
            
               
                 Serum  
                   
                   
               
               
                 Bicarbonate 
                   
                   
               
               
                 (mmol/L) 
                 Before Week 4 Visit 
                 Week 4 through Week 11 
               
               
                   
               
               
                 &lt;12* 
                 Evaluate for new  
                 Evaluate for new  
               
               
                   
                 acute acidotic 
                 acute acidotic 
               
               
                   
                 process, contact  
                 process, contact  
               
               
                   
                 Medical Monitor. 
                 Medical Monitor. 
               
               
                   
                 Maintain dose  
                 Maintain dose  
               
               
                   
                 pending discussion 
                 pending discussion 
               
               
                   
                 with Medical  
                 with Medical  
               
               
                   
                 Monitor 
                 Monitor. 
               
               
                 12 to &lt;22 
                 Maintain dose until  
                 Increase the study  
               
               
                   
                 next scheduled 
                 drug dose by 1 
               
               
                   
                 visit. 
                 packet/day  
               
               
                   
                   
                 (maximum dose is  
               
               
                   
                   
                 3 packets/day). 
               
               
                   
                   
                 Only increase the  
               
               
                   
                   
                 dose if NO dose 
               
               
                   
                   
                 changes have been  
               
               
                   
                   
                 made during the 
               
               
                   
                   
                 previous 14 days. 
               
               
                   
                   
                 Retest serum  
               
               
                   
                   
                 bicarbonate at next 
               
               
                   
                   
                 scheduled visit. 
               
               
                 22 to &lt;27 
                 Maintain dose until  
                   
               
               
                   
                 next scheduled visit. 
                   
               
               
                 27 to 30 
                 Decrease the study  
                   
               
               
                   
                 drug dose by  
                   
               
               
                   
                 1 packet/day 
                   
               
               
                   
                 (minimum dose is 0  
                   
               
               
                   
                 packets/day). 
                   
               
               
                   
                 Invite subject for a  
                   
               
               
                   
                 visit in approximately 
                   
               
               
                   
                 1 week to retest  
                   
               
               
                   
                 serum bicarbonate. 
                   
               
               
                   
                 Only decrease the  
                   
               
               
                   
                 dose if NO dose  
                   
               
               
                   
                 changes have been  
                   
               
               
                   
                 made during the  
                   
               
               
                   
                 previous 14 days. 
                   
               
               
                 &gt;30* 
                 Interrupt (hold)  
                   
               
               
                   
                 study drug. 
                   
               
               
                   
                 Invite subject for a  
                   
               
               
                   
                 visit in approximately  
                   
               
               
                   
                 1 week to retest  
                   
               
               
                   
                 serum bicarbonate. 
                   
               
               
                   
                 If serum bicarbonate  
                   
               
               
                   
                 at that visit is: 
                   
               
               
                   
                 &lt;27 mmol/L, restart  
                   
               
               
                   
                 study drug at a lower  
                   
               
               
                   
                 dose  
                   
               
               
                   
                 (1 packet/day less than 
                   
               
               
                   
                 before dose  
                   
               
               
                   
                 interruption). 
                   
               
               
                   
                 ≥27 mmol/L, continue  
                   
               
               
                   
                 to hold the dose and  
                   
               
               
                   
                 retest again in  
                   
               
               
                   
                 approximately 
                   
               
               
                   
                 1 week. 
               
               
                   
               
               
                 *Serum bicarbonate value of &lt;12 mmol/L or &gt;30 mmol/L confirmed by a repeated measurement from a separate blood draw. 
               
            
           
         
       
     
     Comorbid conditions between treated and placebo subjects entering the trial were equally balanced and included: 97% with hypertension, 65% with type 2 diabetes, 44% with left ventricular hypertrophy, and 31% with congestive heart failure; during the three months prior to baseline, 12% of subjects had shortness of breath with exertion and 9% had recurrent or continuous signs/symptoms of edema or fluid overload. Nine percent of the total patient population in the trial reported the use of oral alkali therapy at baseline. 
     The blood bicarbonate levels of subjects were measured on day 1, week 1, week 2, and bi-weekly thereafter, up to and including week 14 (see, e.g.,  FIG. 18 ). The primary efficacy endpoint of the trial was an increase in blood bicarbonate level of at least 4 mEq/L or achieving a blood bicarbonate level in the normal range of 22 to 29 mEq/L at the end of the 12-week treatment period. The secondary efficacy endpoint of the trial was the change from baseline in blood bicarbonate at the end of treatment. 
     The study was conducted according to the principles of the Declaration of Helsinki and according to Good Clinical Practice guidelines. The study protocol was approved by each site&#39;s relevant institutional review board or ethics committee and appropriate competent authorities in accordance with applicable laws and regulations. Prior to enrollment, all patients provided written informed consent. An unblinded, independent Data Monitoring Committee performed scheduled reviews of safety data during the study. 
     Procedures 
     During the Screening Period, the Screening 1 and Screening 2 Visits were ≥5 days apart, and Screening 1 and Baseline Visits were ≤14 days apart. Following randomisation, patients attended scheduled visits at Weeks 1, 2, 4, 6, 8, 10, and 12 during which serum bicarbonate was measured using an i-STAT® Handheld Blood Analyzer (Abbott Point of Care) and safety assessments were conducted ( FIG. 18 : eGFR, estimated glomerular filtration rate; n, number of patients in each treatment group; QD, once daily; R, randomization; W, week). 
     Patients fasted for ≥4 hours (other than water) prior to measurements of bicarbonate levels to reduce the indirect effect of food-induced secretion of bicarbonate into the bloodstream. Venous blood for bicarbonate measurement was drawn into a 2 mL lithium heparin tube and transferred with a mini-pipette as soon as possible (within 10 minutes) into an i-STAT G3+ cartridge for assessment of bicarbonate with the i-STAT device. Tubes were capped until blood was transferred into the cartridge, and strict adherence to blood drawing and transfer techniques were required. The i-STAT devices were calibrated prior to and during the study according to the manufacturer&#39;s recommendations. The Kidney Disease and Quality of Life (KDQOL) Short Form-36, Question 3 (Physical Functioning Domain) ( FIG. 21 ) and standardized repeated chair stand test ( FIGS. 22A &amp; 22B ) were administered at baseline and Week 12. The KDQOL was forward and backwards translated, linguistically validated, culturally adapted, reviewed by clinicians, and cognitively debriefed in CKD patients. Following completion of study treatment at Week 12, patients either rolled over into a 40-week extension study or underwent two follow-up visits (Week 13 and Week 14) after the last dose of study drug. 
     Serum Bicarbonate 
     A total of 71 of 120 (59%) TRC101-treated patients and 20 of 89 (22%) placebo-treated patients met the primary endpoint responder definition (p&lt;0.0001 for the comparison), with a treatment difference (TRC101−placebo) of 37% (95% CI, 23%-49%). A similar placebo-subtracted treatment difference was observed for each of the two components of the primary endpoint. Compared with the placebo group, a higher percentage of patients in the TRC101 group had increases in serum bicarbonate at all pre-defined thresholds (≥2 through ≥7 mmol/L). 
     The serum bicarbonate curves for the TRC101 and placebo groups separated over time starting at Treatment Week 1 and maintained separation through the end of treatment ( FIG. 19C ). At Week 12, the mean change from baseline in the TRC101 and placebo groups was 4-5 (95% CI, 3-9 to 5-1) mmol/L and 1-7 (95% CI, 1-0 to 2-3) mmol/L, respectively (p&lt;0·0001). The LS mean (SEM) change from baseline to Week 12, the secondary endpoint, was 4-4 (3-5) mmol/L and 1-8 (3-1) mmol/L in the TRC101 and placebo groups, respectively (p&lt;0·0001). ( FIG. 19A-C : Change in Serum Bicarbonate— FIG. 19A : The composite primary endpoint, the placebo-subtracted percentage of patients achieving a ≥4 mmol/L increase from baseline in serum bicarbonate or a serum bicarbonate in the normal range (22-29 mmol/L) at Treatment Week 12 (37%, 95% CI: 23%, 49%), is depicted as the top line. The two lower lines depict each component of the primary endpoint. The individual primary endpoint component analyses were pre-specified but were not adjusted for multiple comparisons. P-values are for the difference in proportions between TRC101 and placebo groups (Fisher&#39;s exact test).  FIG. 19B : The percentage of patients in the TRC101 (circles) and placebo (squares) groups whose serum bicarbonate level increased from baseline to Week 12 by pre-specified thresholds. Achieving a ≥4 mmol/L increase was a component of the primary endpoint.  FIG. 19C : The baseline bicarbonate (Treatment Week 0), the mean of the Screening 1, Screening 2, and Baseline Day 1 values, was 17-3 mmol/L in both treatment groups. Values depicted are the means (±95% CI) change from baseline in serum bicarbonate (mmol/L). At Week 12, the mean serum bicarbonate increase was 4-5 (95% CI, 3-9 to 5-1) mmol/L in the TRC101 group (circles) vs. 1-7 (95% CI, 1-0 to 2-3) mmol/L in the placebo group (squares). 
     Results from post-hoc analyses using a rank-based model were consistent with those from the pre-specified MMRM model (p&lt;0·0001 for treatment effect). 
     Other than in subgroups with &lt;8 patients, the lower-bound of the 95% confidence interval for the treatment difference exceeded 0 within all pre-specified subgroups, including age, gender, geographical region, baseline bicarbonate, screening eGFR, and baseline alkali use. Other than in subgroups with &lt;8 patients, the lower-bound of the 95% confidence interval for the treatment difference exceeded 0 within all pre-specified subgroups, including age, gender, geographical region, baseline alkali use, baseline bicarbonate and screening eGFR. P-values for the interaction between treatment and each subgroup were obtained from logistic regression models, where treatment, subgroup, and interaction of treatment×subgroup were included as predictors. However, these should be interpreted with caution given the post-hoc nature of the analysis and multiple comparisons.) 
     Physical Functioning 
     Metabolic acidosis has been implicated as an important factor contributing to reduced muscle mass, manifested in decreases in lean body mass and muscle strength as well as increased protein catabolic rate. Prior to a measurable decrease in blood bicarbonate, the body adapts, in part, to the increasing acid load by using intracellular buffers in muscle (primarily proteins and organic phosphates). 
     The two exploratory endpoints in this study were included to assess whether improvement in muscle function and patient quality of life could be demonstrated in the patient population through the treatment of metabolic acidosis. The first exploratory endpoint examined the effect of treatment with TRC101 on self-reported responses to the physical functioning subpart of the Kidney Disease and Quality of Life Short Form, or the KDQOL-SF, survey. The KDQOL-SF survey is a validated questionnaire designed to assess health-related quality of life, or HRQOL, in kidney disease patients. Subjects in the trial responded to 10 questions related to physical function during daily activities, or KDQOL-SF Physical Function Survey (Question 3) (see, e.g.,  FIG. 21 ). The score conversion for the Survey is as follows: 1 (limited a lot)=0; 2 (limited a little)=50; 3 (not limited)=100. Total score=sum of all 10, divided by 10. The second exploratory endpoint objectively measured physical function derived from a repeated chair stand test, or Repeated Chair Stand Test. In the Repeated Chair Stand Test, subjects were asked to fold their arms across their chests and to stand up from a sitting position once; if they successfully rose from the chair, they were asked to stand up and sit down five times as quickly as possible, and the time for these five repetitions was recorded (see, e.g.,  FIG. 22 ). The KDQOL-SF Physical Function Survey and Repeated Chair Stand Test were administered and scored in a blinded fashion, and a change in Physical Function Survey score and Repeated Chair Stand Test time from baseline at week 12 were pre-defined as exploratory endpoints. 
     At the end of 12 weeks of treatment, physical functioning, as measured by the KDQOL Physical Function Domain, which quantifies patients&#39; self-reported degree of limitation in performing daily activities such as climbing stairs and walking ( FIG. 21 ), increased significantly in TRC101-treated patients compared to placebo-treated patients (p=0·0122) ( FIG. 20A ). The LS mean (95% CI) change within the TRC101 group (6.3 [3.7, 8.9]) and the placebo-subtracted treatment effect (5.2 [1.1, 9.2]) both exceeded the minimal clinically important difference in KDQOL subscales as reported in the literature (Clement, F M et al., 2009, The Impact of Selecting a High Hemoglobin Target Level on Health-Related Quality of Life for Patients with Chronic Kidney Disease: A Systematic Review and Meta-Analysis, Arch. Intern. Med. 169 (12): 1104-1112; Collister, D et al., 2016, The Effect of Erythropoietin-Stimulating Agents on Health-Related Quality of Lide in Anemia of Chronic Kidney Disease: A Systematic Review and Meta-Analysis, Ann. Intern. Med. 164(7): 472-478; Leaf, D E et al., 2009, Interpretation and Review of Health-Related Quality of Life Data in CKD Patients Receiving Treatment for Anemia, Kidney Int. 75(1): 15-24; Samsa, G et al., Determining Clinically Important Differences in Health Status Measures: A General Approach with Illustration to the Health Utilities Index Mark II, Pharmacoeconomics, 15(2): 141-155). Physical function, as measured by the repeated chair stand test, numerically improved in the TRC101 group (p=0.0249) and numerically worsened (p=0.5727) in the placebo group: on average (LS mean [95% CI]), the chair stand time increased by 0.35 (˜0.9, 1.6) seconds in the placebo group and declined by 1.17 (0.2, 2.2) seconds in the TRC101 group ( FIG. 20B ). The between-group difference was not statistically significant (p=0.0630). ( FIGS. 20A-20B —Changes in Physical Functioning.) ( FIG. 20A : Patients reported how limited they were on the 10 items of the Physical Functioning Domain of the Kidney Disease and Quality of Life (KDQOL) at Baseline and at Treatment Week 12 (see  FIG. 21 ). The least squares mean and 95% CI of the change from baseline to Week 12 in total score is presented for each group. The range for the minimal clinically important differences reported for the KDQOL subscales is 3-5 points.) ( FIG. 20B : Patients were timed on the speed with which they could repeatedly stand from a chair five times at baseline and at Treatment Week 12. Least squares mean and 95% CI of the change from baseline to Week 12 in the time to perform the repeated chair stand test is presented for each group. Not all patients were able to perform the test. Data are presented for patients who performed the test at both baseline and Week 12. (TRC101, n=109; Placebo, n=76).) 
     Post-hoc rank-based analyses of physical function showed consistent results for patient-reported physical function (p=0·0117) and a stronger association for the between-group difference in the time to complete the repeated chair stand test (p=0·0027), both favoring TRC101. 
     Safety 
     TRC101 was well-tolerated. In total, over 95% of subjects in each of the groups completed the trial. Overall treatment-related adverse events occurred in 9.7% of subjects in the placebo group and 13.7% of TRC101-treated subjects. The most common treatment-related adverse events were mild to moderate GI disorders, which occurred in 5.4% of subjects in the placebo group and 12.9% of TRC101-treated subjects. The GI adverse events that occurred in more than one subject in the trial included diarrhea, flatulence, nausea and constipation. The only other treatment-related adverse event that occurred in more than one subject was paresthesia (1.1% of subjects in the placebo group and 0.8% of TRC101-treated subjects). There were no apparent effects of TRC101 on serum parameters, such as sodium, calcium, potassium, phosphate, magnesium, or low-density lipoprotein observed in the trial that would indicate off-target effects of TRC101. A high blood bicarbonate level, defined as greater than 30 mEq/L, was observed transiently in 2 subjects, or 0.9%. Discontinuation of TRC101 per the protocol-defined dosing algorithm resulted in normalization of blood bicarbonate in these subjects. 
     There were no apparent effects of TRC101 on vital signs, ECG intervals, renal function, hematology parameters, liver function tests, lipids, or urinalyses (Table 806). 
     
       
         
           
               
             
               
                 TABLE 806 
               
             
            
               
                   
               
               
                 Change from Baseline in Laboratory Parameters and Blood 
               
               
                 Pressure after 12 Weeks of Treatment 
               
            
           
           
               
               
               
            
               
                   
                 Placebo 
                 TRC101 
               
               
                   
                 (N = 93) 
                 (N = 124) 
               
               
                   
               
            
           
           
               
            
               
                 Blood urea nitrogen—mmol/L 
               
            
           
           
               
               
               
            
               
                 no. 
                 89 
                 120 
               
               
                 Mean (SD) 
                 0.65 (3.96) 
                 −0.05 (4.02)  
               
               
                 Median (IQR) 
                 0.36 (3.21) 
                  0.00 (3.75)  
               
            
           
           
               
            
               
                 Serum creatinine—μmol/L 
               
            
           
           
               
               
               
            
               
                 no. 
                 89 
                 120 
               
               
                 Mean (SD) 
                 13.3 (49.4) 
                 11.1 (44.9) 
               
               
                 Median (IQR) 
                  6.2 (37.1) 
                  6.6 (40.2) 
               
            
           
           
               
            
               
                 Serum sodium—mmol/L 
               
            
           
           
               
               
               
            
               
                 no. 
                 89 
                 120 
               
               
                 Mean (SD) 
                 0.0 (2.9) 
                 0.3 (2.9) 
               
               
                 Median (IQR) 
                 0.0 (4.0) 
                 0.5 (3.0) 
               
            
           
           
               
            
               
                 Serum potassium—mmol/L 
               
            
           
           
               
               
               
            
               
                 no. 
                 89 
                 118 
               
               
                 Mean (SD) 
                 0.05 (0.63) 
                 0.03 (0.60) 
               
               
                 Median (IQR) 
                 0.00 (0.80) 
                 0.00 (0.80) 
               
            
           
           
               
            
               
                 Serum chloride—mmol/L 
               
            
           
           
               
               
               
            
               
                 no. 
                 89 
                 120 
               
               
                 Mean (SD) 
                 −0.1 (3.4)  
                 −0.2 (3.3)  
               
               
                 Median (IQR) 
                  0.0 (4.0)  
                  0.0 (5.0)  
               
            
           
           
               
            
               
                 Serum calcium—mmol/L 
               
            
           
           
               
               
               
            
               
                 no. 
                 89 
                 120 
               
               
                 Mean (SD) 
                 −0.02 (0.13)  
                 −0.02 (0.12)  
               
               
                 Median (IQR) 
                 −0.03 (0.13)  
                 −0.01 (0.15)  
               
            
           
           
               
            
               
                 Serum phosphate—mmol/L 
               
            
           
           
               
               
               
            
               
                 no. 
                 89 
                 120 
               
               
                 Mean (SD) 
                 0.03 (0.22) 
                 0.02 (0.19) 
               
               
                 Median (IQR) 
                 0.03 (0.23) 
                 0.03 (0.19) 
               
            
           
           
               
            
               
                 Serum magnesium—mmol/L 
               
            
           
           
               
               
               
            
               
                 no. 
                 89 
                 120 
               
               
                 Mean (SD) 
                 0.02 (0.09) 
                 0.02 (0.09) 
               
               
                 Median (IQR) 
                 0.04 (0.12) 
                 0.00 (0.12) 
               
            
           
           
               
            
               
                 Estimated glomerular filtration rate—mL/min/1.73 m 2   
               
            
           
           
               
               
               
            
               
                 no. 
                 89 
                 120 
               
               
                 Mean (SD) 
                 −0.8 (5.1)  
                 −0.8 (6.0)  
               
               
                 Median (IQR) 
                 −1.0 (6.0)  
                 −1.0 (5.0)  
               
            
           
           
               
            
               
                 Venous blood pH 
               
            
           
           
               
               
               
            
               
                 no. 
                 89 
                 120 
               
               
                 Mean (SD) 
                 0.03 (0.12) 
                 0.05 (0.10) 
               
               
                 Median (IQR) 
                 0.03 (0.10) 
                 0.05 (0.11) 
               
            
           
           
               
            
               
                 Venous blood base excess—mmol/L 
               
            
           
           
               
               
               
            
               
                 no. 
                 89 
                 120 
               
               
                 Mean (SD) 
                 2.1 (4.2) 
                 5.3 (4.3) 
               
               
                 Median (IQR) 
                 2.0 (6.0) 
                 5.0 (7.0) 
               
            
           
           
               
            
               
                 Cholesterol (total)—mmol/L 
               
            
           
           
               
               
               
            
               
                 no. 
                 89 
                 120 
               
               
                 Mean (SD) 
                 −0.16 (0.93)  
                 0.05 (0.99) 
               
               
                 Median (IQR) 
                 −0.08 (0.88)  
                 0.03 (1.03) 
               
            
           
           
               
            
               
                 Low-density lipoprotein cholesterol—mmol/L 
               
            
           
           
               
               
               
            
               
                 no. 
                 87 
                 115 
               
               
                 Mean (SD) 
                 −0.06 (0.81)  
                  0.02 (0.84)  
               
               
                 Median (IQR) 
                 −0.05 (0.85)  
                 −0.03 (0.93)  
               
            
           
           
               
            
               
                 High-density lipoprotein cholesterol—mmol/L 
               
            
           
           
               
               
               
            
               
                 no. 
                 89 
                 120 
               
               
                 Mean (SD) 
                 0.02 (0.29) 
                 0.04 (0.34) 
               
               
                 Median (IQR) 
                 0.03 (0.28) 
                 0.08 (0.25) 
               
            
           
           
               
            
               
                 Systolic blood pressure—mmHg 
               
            
           
           
               
               
               
            
               
                 no. 
                 89 
                 120 
               
               
                 Mean (SD) 
                 −1.1 (8.7)  
                 −2.4 (7.6)  
               
               
                 Median (IQR) 
                 −1.0 (6.0)  
                 −2.0 (7.5)  
               
            
           
           
               
            
               
                 Diastolic blood pressure—mmHg 
               
            
           
           
               
               
               
            
               
                 no. 
                 89 
                 120 
               
               
                 Mean (SD) 
                 −1.4 (7.4)  
                 −1.5 (6.6)  
               
               
                 Median (IQR) 
                 −1.0 (7.0)  
                 −1.0 (8.5)  
               
               
                   
               
            
           
         
       
     
     A high (&gt;30 mmol/L) serum bicarbonate level was observed transiently in two patients but normalized following interruption of study drug per the protocol titration algorithm. There were no apparent effects on serum electrolytes that would indicate off-target effects of TRC101 (Table 806). The incidence of serum potassium ≥5.0 or ≥6.0 mmol/L (Table 807), and mean serum potassium over time, were similar in both groups. 
     
       
         
           
               
             
               
                 TABLE 807 
               
             
            
               
                   
               
               
                 Proportion of Patients with Serum Potassium Exceeding 
               
               
                 Predefined Thresholds 
               
            
           
           
               
               
               
            
               
                   
                 Placebo 
                 TRC101 
               
               
                   
                 (N = 93) 
                 (N = 124) 
               
               
                   
               
            
           
           
               
            
               
                 Baseline 
               
            
           
           
               
               
               
            
               
                 no. 
                 92 
                 124 
               
               
                 &gt;5 mmol/L—no. (%) 
                 31 (34) 
                  41 (33) 
               
               
                 &gt;6 mmol/L—no. (%) 
                  2 (2) 
                  4 (3) 
               
            
           
           
               
            
               
                 Week 1 
               
            
           
           
               
               
               
            
               
                 no. 
                 88 
                 117 
               
               
                 &gt;5 mmol/L—no. (%) 
                 39 (44) 
                  51 (44) 
               
               
                 &gt;6 mmol/L—no. (%) 
                  7 (8) 
                  5 (4) 
               
            
           
           
               
            
               
                 Week 2 
               
            
           
           
               
               
               
            
               
                 no. 
                 87 
                 115 
               
               
                 &gt;5 mmol/L—no. (%) 
                 39 (45) 
                  46 (40) 
               
               
                 &gt;6 mmol/L—no. (%) 
                  3 (3) 
                  2 (2) 
               
            
           
           
               
            
               
                 Week 4 
               
            
           
           
               
               
               
            
               
                 no. 
                 87 
                 118 
               
               
                 &gt;5 mmol/L—no. (%) 
                 46 (53) 
                  53 (45) 
               
               
                 &gt;6 mmol/L—no. (%) 
                  5 (6) 
                  7 (6) 
               
            
           
           
               
            
               
                 Week 6 
               
            
           
           
               
               
               
            
               
                 no. 
                 91 
                 120 
               
               
                 &gt;5 mmol/L—no. (%) 
                 46 (51) 
                  52 (43) 
               
               
                 &gt;6 mmol/L—no. (%) 
                  6 (7) 
                  8 (7) 
               
            
           
           
               
            
               
                 Week 8 
               
            
           
           
               
               
               
            
               
                 no. 
                 89 
                 119 
               
               
                 &gt;5 mmol/L—no. (%) 
                 40 (45) 
                  54 (45) 
               
               
                 &gt;6 mmol/L—no. (%) 
                  6 (7) 
                  8 (7) 
               
            
           
           
               
            
               
                 Week 10 
               
            
           
           
               
               
               
            
               
                 no. 
                 87 
                 119 
               
               
                 &gt;5 mmol/L—no. (%) 
                 40 (46) 
                  45 (38) 
               
               
                 &gt;6 mmol/L—no. (%) 
                  2 (2) 
                  7 (6) 
               
            
           
           
               
            
               
                 Week 12 
               
            
           
           
               
               
               
            
               
                 no. 
                 89 
                 118 
               
               
                 &gt;5 mmol/L—no. (%) 
                 38 (43) 
                  43 (36) 
               
               
                 &gt;6 mmol/L—no. (%) 
                  5 (6) 
                  5 (4) 
               
               
                   
               
            
           
         
       
     
     DISCUSSION 
     In non-dialysis-dependent patients with CKD and chronic metabolic acidosis (mean serum bicarbonate 17-3 mmol/L), 12 weeks of treatment with TRC101 significantly increased serum bicarbonate, with 50% of patients achieving normalization, 56% achieving a ≥4 mmol/L increase, and 59% meeting the composite primary endpoint definition. The mean increase in serum bicarbonate at Week 12 in the TRC101 group was 4-5 mmol/L, and 39% and 26% of TRC101-treated patients had an increase in serum bicarbonate ≥6 and ≥7 mmol/L, respectively. The effect of TRC101 on serum bicarbonate was both rapid and sustained over 12 weeks in these outpatients whose dietary protein intake was not governed by the study protocol. 
     Accumulation of metabolically produced acid stimulates increases kidney production of endothelin, angiotensin II and aldosterone, substances that provide the short-term benefit of enhancing renal tubule acid excretion but are detrimental in the long term by promoting inflammation and fibrosis in the kidney interstitium that contributes to a progressive decline of kidney function. Similarly, in response to acid retention the kidney increases ammonia production per functioning nephron to facilitate acid excretion, however, the increased ammonia levels promote inflammation and activation of complement that also contributes to kidney fibrosis. 
     Metabolic acidosis in patients with CKD has traditionally been treated with sodium-based alkali supplements (sodium bicarbonate, sodium citrate) that enter the systemic circulation and neutralize accumulated acid. Potassium-based alkali therapies (e.g., potassium bicarbonate) are rarely used in patients with CKD because of the risk of life-threatening hyperkalemia. Alternative treatments for metabolic acidosis include vegetarian diets, but these limit patient choice and have low long-term adherence. An alternative treatment would remove, rather than neutralize, acid, without administering a sodium or potassium load. Removal of acid by binding to a non-absorbed polymer that is then excreted is a potential new mechanism for treating metabolic acidosis in patients with CKD. 
     The study described in this Example demonstrates that TRC101, a non-absorbed, counterion-free, polymeric drug that selectively binds and removes hydrochloric acid from the gastrointestinal tract, thus increasing systemic bicarbonate concentration, is effective in treating metabolic acidosis. These findings demonstrate that the effect of TRC101 on serum bicarbonate reaches a plateau after 4 to 8 weeks of treatment and the effect is sustained over 12 weeks in an outpatient CKD population eating a free choice diet. 
     The embodiments described in this disclosure can be combined in various ways. Any aspect or feature that is described for one embodiment can be incorporated into any other embodiment mentioned in this disclosure. While various novel features of the inventive principles have been shown, described and pointed out as applied to particular embodiments thereof, it should be understood that various omissions and substitutions and changes can be made by those skilled in the art without departing from the spirit of this disclosure. Those skilled in the art will appreciate that the inventive principles can be practiced in other than the described embodiments, which are presented for purposes of illustration and not limitation.