Treating Metabolic Acidosis in Chronic Kidney Disease to Prevent Adverse Kidney and Cardiovascular Outcomes

Upon completion, this project will determine if treatment of metabolic acidosis in non-diabetic study participants with reduced kidney function (chronic kidney disease \[CKD\] stage 3) associated with high blood pressure (hypertension) and macroalbuminuria, the latter indicating pronounced kidney injury, using either base-producing fruits and vegetables (F+V) or standard therapy for treatment of metabolic acidosis with the medication sodium bicarbonate (NaHCO3) 1) slows progression of CKD toward end-stage renal disease \[ESRD\]; 2) improves indices of cardiovascular disease (CVD) risk; and 3) better preserves plasma acid-base parameters. These studies are designed to compare the differential effects of treating the metabolic acidosis of CKD with F+Vs or NaHCO3 on kidney outcomes, including progression to ESRD, on indices of CVD risk and on plasma acid-base parameters.

The long-term objective of this study is to determine if treatment of metabolic acidosis in study participants with chronic kidney disease (CKD), reduced estimated glomerular filtration rate (eGFR), and very high levels of urine albumin excretion (macroalbuminuria) reduces risk for further eGFR decline and/or for subsequent development of cardiovascular disease (CVD). The specific aims of this study are to determine if metabolic acidosis treatment with either base-producing fruits and vegetables (F+V) in amounts calculated to reduce participant dietary acid content by half, or sodium bicarbonate (NaHCO3, 0.3 mEq/kg body weight, an amount designed to match the alkali content of provided F+V) in participants with stage 3 CKD (eGFR 30 to 59 ml/min/1.73 m2) compared with Usual Care 1) slows CKD progression; 2) improves indices of cardiovascular risk; and 3) better preserves plasma acid-base parameters. Despite blood pressure control with "kidney protective" drugs like angiotensin converting enzyme (ACE) inhibitors, many patients with CKD and reduced eGFR have progressive eGFR decline toward end-stage renal disease (ESRD) with need for dialysis or kidney transplant to maintain life. They also have increased risk to die of CVD. Studies from our laboratory and those of other investigators support that treatment of metabolic acidosis slows GFR decline in animal models of CKD. Many patients with CKD stage 3 have metabolic acidosis that might exacerbate eGFR decline and its treatment might slow or stop it. This study will recruit participants with hypertension-associated CKD stage 3 (eGFR 30-59 ml/min/1.73 m2) without diabetes to avoid contribution of diabetes to eGFR decline. They will have macroalbuminuria (urine albumin \[mg\]-to-creatinine \[g\] ratio \> 200 mg/g) that increases their CKD progression risk to optimize the chance to see benefits of metabolic acidosis treatment. They will have plasma total CO2 (PTCO2) \< 24 but \> 22 millimolar (mM) to recruit participants with metabolic acidosis that is not severe enough to warrant treatment by current guidelines (with oral NaHCO3) to ethically randomize participants to received non-recommended treatment for metabolic acidosis (F+V) or no treatment (Usual Care). Participants whose PTCO2 decreases to 22 mM or below during follow up will be treated with oral NaHCO3 tablets with the goal to maintain their PTCO2 \> 22 mM. All will undergo blood pressure control to target systolic blood pressure \< 130 mm Hg (millimeters of mercury) with regimens including ACE inhibition and will receive atorvastatin because their macroalbuminuria puts them at increase CVD risk. At study entry and yearly for 10 years, all participants will have 10 ml of blood drawn from an antecubital vein for measurement of the negative log of free hydrogen ion concentration (pH), partial pressure of carbon dioxide gas (PCO2), PTCO2, creatinine, LDL cholesterol, HDL cholesterol, Lp(a) cholesterol, sodium, potassium, and chloride. They will have 20 ml of urine collected for measurement of creatinine, albumin, N-acetyl-D-glucosaminidase, angiotensinogen, and isoprostane 8-isoprostaglandin F2 alpha. They will also have an 8-hour urine collection at a Texas Tech University Health Sciences Center (TTUHSC) clinic at baseline, 3 years, 5 years, and 10 years for PTCO2, pH, ammonium, titratable acidity, creatinine, sodium, and potassium after fasting after midnight. The course of plasma and urine parameters over the 10 years of follow up in those randomized to F+V or NaHCO3 compared to Usual Care will help determine the effect(s) treatment of metabolic acidosis on CKD progression (change in urine indices of kidney injury and eGFR), indices of CVD risk (change in LDL, HDL, and Lp(a) cholesterol), and on participant acid-base status (serum acid-base parameters \[pH, PCO2, bicarbonate concentration \[HCO3\], and PTCO2). These studies will also determine differences in metabolic acidosis treatment with F+V vs. NaHCO3. We hypothesize that metabolic acidosis treatment with F+V or NaHCO3 will 1) slow CKD progression indicated by lower urine kidney injury indices and slower eGFR decline; 2) improve indices of cardiovascular risk indicated by lower LDL, lower Lp(a), and higher HDL cholesterol; and 3) improve plasma acid-base status indicated by higher PTCO2. Excretion of urine acid-base parameters will help determine effects of these treatments on urine acid excretion. Blood pH and PCO2 will be measured using the Immediate Response Mobile Analysis (IRMA) blood analysis system and blood and urine concentrations of albumin and creatinine will be measured with standard techniques. Blood and urine PTCO2 will be measured as done previously with fluorimetry in the PI's laboratory. Urine ammonium, titratable acidity, N-Acetyl-beta-D-glucosaminidase, angiotensinogen, and isoprostane 8-isoprostaglandin F2 alpha will be measured as done previously in the laboratory of the Co-PI.

Eligibility Criteria:
Inclusion Criteria:

1. Non-malignant high blood pressure or hypertension
2. 18-70 yrs old
3. urine albumin-to-creatine ratio \> 200 mg/g creatinine
4. estimated glomerular filtration rate (eGFR) 30 to 59 ml/min/1.73 m2
5. Plasma total CO2 (PTCO2) \> 22 but \< 24 mmol/l
6. able to tolerate angiotensin converting enzyme \[ACE\] inhibition drug therapy because guidelines recommend it for patients with albuminuric CKD
7. non-smoking
8. greater than or equal to 2 primary care visits in the preceding year, indicating compliance
9. Able to provide informed consent.

Exclusion Criteria:

1. Malignant hypertension or history thereof
2. primary kidney disease or findings consistent thereof such as \> 3 red blood cells per high powered field of urine or urine cellular casts
3. history of diabetes or fasting glucose greater than or equal to 110/mg/dl
4. history of hematologic disorders, malignancies, chronic infections, current pregnancy, history or clinical evidence of CVD
5. peripheral edema or diagnosis associated with edema such as heart/liver failure or nephrotic syndrome because of the sodium load that accompanies NaHCO3 therapy
6. baseline plasma potassium concentration \> 4.6 mmol/l to reduce the risk for hyperkalemia in those participants randomized to F+Vs which increases dietary potassium intake
7. taking, or unable to stop taking, drugs other than ACE inhibitors that limit urine potassium excretion
8. Unable to provide informed consent.