Pharmacological Therapy for Calcium Phosphate Urolithiasis
Phase: PHASE2
Conditions: Calcium Phosphate Kidney Stones
Sponsor: University of Texas Southwestern Medical Center

STUDY PROTOCOL AND STATISTICAL ANALYSIS PLAN 
 
Official title: Pharmacological Therapy for Calcium Phosphate 
Urolithiasis 
NCT number: NCT01754779 
Document date: Version 2.0 – February 21, 2018 

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                                                                                      IRB # 032012-058 
IRB Protocol #: 032012-058 
Title of Project: Pharmacological Therapy for Calcium Phosphate Urolithiasis 
Principal Investigator: Naim Maalouf, MD (Center for Mineral Metabolism & Clinical Research) 
Co-Investigators: Khashayar Sakhaee, MD (CMMCR) 
 
Version 2.0 – February 21, 2018 
 
Background & Significance 
The incidence of calcium phosphate (CaP) kidney stone disease has increased significantly over the last three 
decades. Patients suffering from CaP urolithiasis often experience stone recurrence despite pharmacological 
interventions, an indication to the suboptimal nature of the current medical regimen.  
The major metabolic risk factors predisposing to CaP stone formation are hypercalciuria (60-80% of CaP stone 
formers), high urine pH (50-60%), and hypocitraturia (30-50%). While both CaP and calcium oxalate stone 
formers frequently exhibit hypercalciuria and hypocitraturia, a notable distinction between these two groups is 
the significantly higher urine pH among CaP stone formers. This is pathogenetically important because urine pH 
above 6.0 is essential for crystallization of CaP driven by the higher concentration of divalent phosphate ion.  
Currently, there is no proven countermeasure for treatment and prevention of recurrent CaP stone disease. 
Raising fluid intake, protein and sodium restriction, and thiazide are all likely to reduce stone recurrence in CaP 
stone formers by decreasing urine calcium concentration and CaP supersaturation. However, many CaP stone 
formers often experience stone recurrence despite compliance with these measures, suggesting the need to 
evaluate additional therapies.  
One frequently prescribed medication for calcium stone formers is potassium citrate, which has proven efficacy 
against calcium oxalate stones. Potassium citrate increases urine citrate and lowers urine calcium, which in turn 
reduce CaP crystallization. However, a concern is that, in CaP stone formers, these beneficial effects may be 
negated by a further rise in urine pH induced by potassium citrate, thus promoting CaP crystallization. No study 
has directly assessed the role of potassium citrate as a countermeasure to stone recurrence in CaP stone 
formers. An alternative strategy that is physiologically-based but not clinically-tested is citric acid administration 
that can potentially increase urine citrate without raising urine pH. 
 
Effects of potassium citrate and citric acid in vitro and in vivo: We conducted in vitro experiments in which KCit 
and CitA were added in increasing concentration to filtered aliquots of urines from healthy individuals. CaP 
(brushite) crystals were added, and urines incubated for 3 hours at 37°C then filtered to remove any crystals 
formed. [Ca][Phos] in filtrate was compared to that in original urine. 
  
We also tested the effects of KCit and CitA administration to a small number of CaP stone formers: In 4 CaP 
stone formers, administration of KCit 20 mEq BID increased urine citrate and pH in all patients, and lowered 
urine calcium and saturation of CaP as brushite. The decline in brushite saturation is likely due to the combined 
effect of a rise in urine citrate, slight reduction in calciuria, and formation of pH-dependent calcium citrate-
phosphate soluble complexes1, 2. This encouraging result was obtained while patients were in an outpatient 
setting in which environmental factors may confound/attenuate some of the findings. We feel that KCit needs to 
be studied further and in a more controlled setting, especially in view of it reducing stone recurrence in patients 
with dRTA3, 4 or MSK5, conditions that present with CaP stones. 
 
Specific Aims 
Based on the knowledge and rationale stated above and our preliminary results, we submit the following 
hypothesis: 
 
Potassium citrate and/or citric acid are potential countermeasures that attenuate the risk of 
recurrent stone formation in CaP stone formers. 

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                                                                                      IRB # 032012-058 
 
 
To test this hypothesis, we will pursue the following objectives: 
We will examine in two short-term placebo-controlled cross-over metabolic studies whether citric acid or 
potassium citrate can reduce calcium phosphate saturation in urine of CaP stone formers. In the first study (Aims 
1 &1a) that was recently conducted in hypocitraturic CaP stone formers without hypercalciuria, and we compared 
the effects of potassium citrate, citric acid and placebo. The results of the study showed that the rise in urinary 
citrate (an inhibitor of CaP crystallization) with potassium citrate supplementation was negated with a significant 
elevation in urinary pH resulting in increased urinary supersaturation with CaP salts. (In this revised version of 
the protocol we are adding a pilot project as another aim to the first study (Aim 1c), in which we are proposing a 
lower dose of potassium citrate sufficient enough to raise the urinary citrate modestly, without altering the urinary 
pH to negate the protective inhibitory effect of urinary citrate.  Aim 1c will recruit up to five patients with calcium 
phosphate stones CaP regardless of being hypercalciuric or not, and five normal healthy subjects without kidney 
stones.) 
The second study will be conducted in hypercalciuric CaP stone formers on a thiazide diuretic who require 
potassium supplementation, and will compare the effects of potassium chloride alone, potassium chloride + citric 
acid, and potassium citrate alone. Physicochemical assays will be applied in addition to computer-based stone 
risk prediction programs to assess risk of stone recurrence. 
The proposed small scale clinical pilot studies will use surrogate measures to test two simple interventions. They 
address a clinical question of utmost importance as we are in dire need of an effective therapy for patients with 
recurrent CaP stones, a group of stone formers that have not been specifically evaluated in past clinical trials. 
Results from these studies are likely to lead to full-scale randomized clinical trials with clinical outcomes for the 
prevention and treatment of recurrent CaP urolithiasis, an increasingly encountered condition in clinical practice.  
Rationale and overall strategy: We will examine whether CitA and/or KCit can reduce the risk of recurrent 
nephrolithiasis in CaP stone formers. Subjects will be equilibrated on a fixed metabolic diet prior to urine 
collection for measurement of outcomes. Use of metabolic diet in this pilot study is essential to eliminate potential 
confounders from differences in dietary intake across phases. Physicochemical assays will be used in addition 
to computer-based stone risk prediction programs to determine stone risk. Once a regimen is identified, a trial 
with clinical outcomes can be designed in the future. Inclusion of patients without hypercalciuria will provide a 
cleaner sample to examine urine pH and citrate. However, since a large portion of CaP formers are 
hypercalciuric, we need to include these subjects to build a foundation for future trials. Based on the presence 
or absence of hypercalciuria, CaP stone formers will be included into 2 separate Aims.  
 
Study Protocol:  
Study Design & Methods: 
Aim 1: Calcium phosphate stone formers without hypercalciuria 
Subjects: 25 hypocitraturic stone formers without hypercalciuria will participate in this 3-phase cross-over 
metabolic study. Subjects will be recruited from the UTSW Mineral Metabolism and Urology clinics. 
Inclusion criteria: Hypocitraturic CaP stone formers with elevated urine pH will be >21 years, of either gender, 
any race and ethnicity. Hypocitraturia will be defined as 24-hr urine citrate < 320 mg/d and elevated pH as 24-hr 
urine pH above 6.406, 7 in the absence of urinary tract infection. CaP stone disease will be defined based on most 
recent available stone composition with CaP constituting over 70% of overall stone components. 
Exclusion criteria: History of recurrent urinary tract infections, conditions that predispose to acid-base disorders 
such as chronic diarrhea, estimated GFR<60 ml/min, chronic use of non-steroidal anti-inflammatory drugs, 
angiotensin 2 receptor blockers, ACE-inhibitors, diuretics, antacids or alkali treatment, and carbonic anhydrase 
inhibitors. Patients with hypercalciuria (24-hr urine calcium > 250 mg/day) will be allocated to Aim 2. 

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                                                                                      IRB # 032012-058 
Study protocol: In this double-blind, placebo-
controlled, crossover study, each subject will 
undergo 3 phases, the order of which will be 
randomized by a simple randomization scheme. 
The 3 phases will be Placebo (PBO), Citric Acid 
(CitA), and Potassium Citrate (KCit). Each phase 
will be 1 week in duration, during which subjects will 
take assigned study medications. A 1-week 
washout period is imposed between phases (Figure 
1). During the first 2 days of each phase, subjects 
will be instructed to adhere to a diet at home with a 
daily composition of 800 mg calcium, 100 mEq 
sodium, 800 mg phosphorus, 50 mEq potassium 
and 2 liters of total fluids daily. On the last 5 days of each phase, subjects will be kept on a constant metabolic 
diet of the same composition provided by the Clinical Research Unit (CRU). During the final two study days (days 
6-7), subjects will be admitted to the CRU where a 22-hr urine and 2-hr fasting urine will be collected on day 6 
under mineral oil to measure urine chemistries (stone risk factors) and acid-base parameters, and on day 7 for 
crystallization studies. Fasting blood will be obtained at the end of each urine collection.   
Study Medications: Subjects will receive three 10 mEq tablets of CitA twice a day during the CitA phase (60 
mEq/day), two 10 mEq KCit tablets and one placebo tablet twice a day during the KCit phase (40 mEq/day), and 
3 tablets twice daily of matching placebo during the PBO phase. Study tablets are prepared by a compounding 
pharmacy, with placebo tablets similar in appearance and size to the active medication tablets. 
Sample size: This was calculated based on our preliminary studies. 20 subjects will provide a power of 0.80 at 
the 0.015 level of significance (to adjust for multiple comparisons of the three phases) to detect a difference of 
0.3 units in CPR brushite, between treatment and placebo phases (within subject standard deviation of 0.38). 
Assuming 20% withdrawal, 25 subjects will be enrolled with the expectation that 20 subjects will complete the 
entire study.  
Serum: Blood will be collected for measurement of serum sodium, potassium, chloride, CO2, glucose, BUN, 
creatinine, calcium, albumin, magnesium, phosphorus, and uric acid. These will be measured primarily to assure 
subject safety (e.g. hyperkalemia, renal insufficiency, metabolic acidosis/alkalosis). 
24-hr urine stone risk factors: These are well established at the UT Southwestern Mineral Metabolism 
Laboratories:8 urine pH, citrate, calcium, phosphorus, oxalate, uric acid, ammonium, sulfate, chloride, sodium, 
potassium, magnesium, total volume, creatinine, TA, HCO3-. These parameters will be combined to calculate 
saturation by JESS and compared individually across phases. 
Saturation: Urine saturation will be directly measured by CPR as previously described9, and will be calculated 
from the measured urinary parameters by JESS as Saturation Index1, 2, 10.  
Additional physicochemical measures: In addition to CPR, we will assess crystal growth (CG) of brushite after 
seeding urine with a small amount of brushite (0.25 mg/ml urine) as previously described11. We will also measure 
overall activity of urinary promoters and inhibitors to brushite crystallization as formation product (FP). This will 
be based on an established method to assess the limit of metastability of brushite12. FP is obtained by adding 
increasing amount of Ca to a series of aliquots of urine at constant pH for 2hrs, and is identified by the point at 
which visible brushite precipitation is elicited. Calculated SI using [Ca] and [P] at that point represents FP 
brushite. Measurement of CG and FP brushite will provide additional insights on the effects of KCit and CitA on 
CaP stone formation beside their effect on saturation, since the process of kidney stone formation depends on 
the complex interplay between these three factors.  
Statistical Analysis: For each phase, descriptive statistics will be computed for continuous variables. Data 
transformation or nonparametric tests will be utilized as 
needed to meet analysis assumptions. For this crossover 
design, repeated measures analysis will be implemented to 
assess treatment effects for biochemical parameters13. A 
Bonferroni-Hochberg adjustment will be used to adjust for 
multiple testing14. A mixed model approach will be used so 
that the covariance structure can be specified. If necessary, 
Table 1: Experimental groups and expected findings 
  
Urine 
Brushite 
Cit 
pH 
Ca 
CPR / SI 
CG 
FP 
CitA 
 ↑ 
 ↔ 
↔ 
↓ 
↓ 
↑ 
KCit 
 ↑ 
 ↑ 
↓ 
↔/↓ 
↓ 
↑ 
Expected changes (↔, ↑, or ↓) compared with placebo 
 
Figure 1. Experimental design  

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                                                                                      IRB # 032012-058 
pairwise multiple comparisons will be made with with contrasts derived from the repeated measures models. 
Expected Findings, Data Interpretation: Table 1 shows the expected urinary and physicochemical findings based 
on published and preliminary studies15-18. We expect CitA to raise urine citrate without changing pH or Ca, and 
KCit to raise both urine pH and citrate while lowering urine Ca.   
 
Aim 1a Optional Outpatient Study:  
Subjects: Patients being enrolled into Aim 1 will be given the option to participate in the study as an outpatient if 
it is more convenient. 
Inclusion criteria: Same as above. 
Exclusion criteria: Same as above. 
Study protocol: In this double-blind, placebo-controlled, crossover study, each subject will undergo 3 phases, 
the order of which will be randomized by a simple randomization scheme. The 3 phases will be Placebo (PBO), 
Citric Acid (CitA), and Potassium Citrate (KCit). Each phase will be 1 week in duration, during which subjects will 
take assigned study medications. A 1-week washout period is imposed between phases (Figure 1). During the 
first 4 days of each phase, subjects will be instructed to adhere to a diet at home with a daily composition of 800 
mg calcium, 100 mEq sodium, 800 mg phosphorus, 50 mEq potassium and 2 liters of total fluids daily. On the 
last 3 days of each phase, subjects will be kept on a constant metabolic diet of the same composition provided 
by the Clinical Research Unit (CRU). During the final two study days (days 6-7), subjects will collect a 24 hour 
urine at home on day 6 for crystallization studies, and also under mineral oil on day 7 to measure urine 
chemistries (stone risk factors) and acid-base parameters. The subjects will bring the urine to the Mineral 
Metabolism Clinic at Aston on the morning of day 8.  Fasting blood will be obtained in the Mineral Metabolism 
Clinic on day 8 during this visit.    
 
Aim 1b Outpatient Study:  
Aim 1b of this protocol represents an extension of Aim 1.  Aim 1b will also be conducted in the same patient 
population as Aim 1, but will entail a change in the medication dose/frequency of citric acid and placebo. 
Subjects: - Hypocitraturic CaP stone formers without hypercalciuria. 
Inclusion criteria: Same as above. 
Exclusion criteria: Same as above. 
Study protocol: In this double-blind, placebo-controlled, crossover study, each subject will undergo 3 phases, 
the order of which will be randomized by a simple randomization scheme. In this aim we will utilize the following 
medications during the 3 phases:  
a. Placebo, 3 pills 3 times a day 
b. Citric Acid 10 mEq 2 pills + Placebo 1 pill, 3 times a day 
c. Citric Acid 10 mEq, 3 pills 3 times a day 
A 1-week washout period is imposed between phases (Figure 1). During the first 4 days of each phase, subjects 
will be instructed to adhere to a diet at home with a daily composition of 800 mg calcium, 100 mEq sodium, 800 
mg phosphorus, 50 mEq potassium and 2 liters of total fluids daily. On the last 3 days of each phase, subjects 
will be kept on a constant metabolic diet of the same composition provided by the Clinical Research Unit (CRU). 
During the final two study days (days 6-7), subjects will collect a 24 hour urine at home on day 6 for crystallization 
studies, and also under mineral oil on day 7 to measure urine chemistries (stone risk factors) and acid-base 
parameters. The subjects will bring the urine to the Mineral Metabolism Clinic at Aston on the morning of day 8.  
Fasting blood will be obtained in the Mineral Metabolism Clinic on day 8 during this visit.  
   
The rationale for the adjustment in medication dose/frequency is that the data we have so far collected in the 
pilot study seems to suggest that the dose of citric acid used previously in Aim 1 does not significantly raise urine 
citrate as we had hypothesized. Some of the possibilities are:  1. medication doses given twice a day are not 
frequent enough (hence looking at the scheme in b. above) or, 2. the total dose given was not sufficient (hence 
the scheme c above), or that patients with Calcium Phosphate stones do not respond to Citric Acid the same 
way that healthy individuals without stones respond. 

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                                                                                      IRB # 032012-058 
Aim 1c Outpatient Study:  
Aim 1c of this protocol also represents an extension of Aim 1.  Aim 1c is a pilot project which proposes a lower 
dose of potassium citrate over the three phases of the study.   
Subjects: - Aim 1c will recruit up to five patients with calcium phosphate stones CaP with or without 
hypercalciuria, and five normal healthy subjects without kidney stones. 
Inclusion criteria: CaP Stone Former with elevated urinary pH will be >25 years, of either gender and any race 
and ethnicity. CaP stone disease will be defined based on the most recent available stone composition with CaP 
constituting over 70% of overall stone components. 
Exclusion criteria: History of recurrent urinary tract infections, chronic diarrhea, estimated eGFR <60 ml/min and 
chronic use of non-steroidal anti-inflammatory drugs, angiotensin 2 receptor blocker, ACE-inhibitors, diuretics, 
antacids, alkali treatment and carbonic anhydrase inhibitors.  
Study protocol: In this double-blind, placebo-controlled, crossover study, each subject will undergo 3 phases, 
the order of which will be randomized by a simple randomization scheme. In this aim, we will utilize the following 
medications during the 3 phases:  
a. Control, no medication 
b. Potassium Citrate 5mEq 1 pill, 2 times a day 
c. Potassium Citrate 10mEq, 1 pill, 2 times a day 
In each phase, the subjects will be instructed to adhere to a diet on a instructed diet consisting of 800 mg calcium, 
800 mg phosphorus, 100 mEq of sodium, 50 mEq of potassium and 2 liters of fluids daily at home. On the third 
day of the study, while on the instructed diet the subjects will collect 24-hour urine at home for the kidney stone 
risk profiles. The subjects will bring the urine to the Mineral Metabolism Clinic at Aston, 9th floor on the morning 
of day 4.   
The rationale for the adjustment in medication dose/frequency of the Potassium Citrate is evidenced in the 
recently completed three phases of the study control, potassium citrate and citric acid in calcium phosphate 
stone formers. The results of the study showed that the rise in urinary citrate (an inhibitor of CaP crystallization) 
with potassium citrate supplementation was negated with a significant elevation in urinary pH resulting in 
increased urinary supersaturation with CaP salts. In this aim, we are proposing a lower dose of potassium citrate 
sufficient enough to raise the urinary citrate modestly, while does not alter the urinary pH to negate the protective 
inhibitory effect of urinary citrate. 
 
 
Aim 2: Calcium phosphate stone formers with hypercalciuria 
Rationale: Since the majority of CaP stone formers are hypercalciuric (60-80%), we will separately study this 
group with a similar 3-phase design. In our practice, these patients are all prescribed a thiazide diuretic (generally 
indapamide due to its long half-life, allowing once a day dosing) to reduce hypercalciuria along with a potassium 
supplement to avert thiazide-induced hypokalemia19.  However, it is unclear whether KCl or KCit is the optimal 
K supplement for CaP stone formers on a thiazide diuretic.  
Study protocol: In this 
double-blind, placebo-
controlled 
crossover 
study, 
each 
hypercalciuric 
CaP 
stone 
former 
will 
undergo 3 phases, the 
order of which will be 
randomized 
by 
a 
simple randomization 
scheme.  
Study 
medications: 
The 
3 
phases 
will 
be 
Indapamide+KCl+PBO, 
Indapamide+KCl+CitA, 
and 
Indapamide+KCit+PBO. The dose of indapamide will be fixed at 1.25 mg/day in each subject, the amount of 
potassium provided as KCit or KCl will be kept constant at 20 mEq BID, and the amount of Citrate provided either 
 Phase 
Ind+KCl+PBO 
Ind+KCl+CitA 
Ind+KCit+PBO 
Potassium dose  
20 mEq BID KCl 
20 mEq BID KCl 
20 mEq BID KCit 
Citrate dose 
None 
20 mEq BID CitA 
Expected effect on urine pH 
↔ 
↔ 
↑ 
Expected effect on urine citrate 
↔ 
↑ 
↑ 
Expected effect on urine calcium  
↔ 
↔ 
↓ 
Expected effect on CPR(brushite) 
↔ 
↓ 
↓ 
Table 2. Experimental design and expected findings in Aim 2. Ind: Indapamide; PBO: Placebo. 
Note that “Expected effects” in this table represent the expected effects of KCl vs. KCl+CitA vs 
KCit beyond effect of indapamide which will be fixed throughout the study 

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                                                                                      IRB # 032012-058 
as KCit or CitA will be 20 mEq BID (Table 2). This will allow for direct assessment of effects of KCl vs. KCl+CitA 
vs. KCit. Subjects will be studied in the same experimental protocol described in Figure 1.  
Inclusion criteria: Hypercalciuric CaP stone formers with elevated urine pH will be >21 years, of either gender, 
any race and ethnicity. Hypercalciuria will be defined as 24-hr urine calc ium > 250 mg/d in women and > 300 
mg/d in men prior to indapamide use, and high pH as >6.40 in the absence of urinary tract infection. CaP stone 
disease will be defined based on most recent available stone composition with CaP constituting over 70% of 
overall stone components. Subjects will be included irrespective of urinary citrate 
Exclusion criteria: Same as in Aim 1 except for hypercalciuria.   
Analyses: Analyses will be conducted in a similar fashion to those described under Aim 1.  
 
Aim 2a Optional Outpatient Study: 
Subjects: Patients being enrolled into Aim 2 will be given the option to participate in the study as an outpatient if 
it is more convenient. 
Inclusion criteria: Same as above. 
Exclusion criteria: Same as above. 
Study protocol: In this double-blind, placebo-controlled crossover study, each hypercalciuric CaP stone former 
will undergo 3 phases, the order of which will be randomized by a simple randomization scheme. The 3 phases 
will be Indapamide+KCl+PBO, Indapamide+KCl+CitA, and Indapamide+KCit+PBO. The dose of indapamide will 
be fixed at 1.25 mg/day in each subject, the amount of potassium provided as KCit or KCl will be kept constant 
at 20 mEq BID, and the amount of Citrate provided either as KCit or CitA will be 20 mEq BID (Table 2). This will 
allow for direct assessment of effects of KCl vs. KCl+CitA vs. KCit. During the first 4 days of each phase, subjects 
will be instructed to adhere to a diet at home with a daily composition of 800 mg calcium, 100 mEq sodium, 800 
mg phosphorus, 50 mEq potassium and 2 liters of total fluids daily. On the last 3 days of each phase, subjects 
will be kept on a constant metabolic diet of the same composition provided by the Clinical Research Unit (CRU). 
During the final two study days (days 6-7), subjects will collect a 24 hour urine at home on day 6 for crystallization 
studies, and also under mineral oil on day 7 to measure urine chemistries (stone risk factors) and acid-base 
parameters. The subjects will bring the urine to the Mineral Metabolism Clinic at Aston on the morning of day 8.  
Fasting blood will be obtained in the Mineral Metabolism Clinic on day 8 during this visit.    
 
Protection of Human Subjects    
1. 1.  Risks to the Subjects 
Human Subjects Involvement and Characteristics 
 
Aim 1  
3-phase, double-blind, cross-over metabolic study examining the effects of potassium citrate and citric acid on 
urinary predictors of stone formation in calcium phosphate stone formers without hypercalciuria 
 
Disease State 
Subject Number 
Inclusion Criteria 
Exclusion Criteria 
Calcium 
phosphate stone 
formers without 
hypercalciuria 
25 
 ≥ 21 years of age for 
all subjects 
 Stone 
analysis 
showing 
calcium 
phosphate as major 
component of stone 
(>70%) 
 Hypocitraturia (urine 
citrate < 320 mg/d) 
 24hr urine pH>6.40 
 Hypercalciuria (24h urine 
calcium > 250 mg/day) 
 Recurrent urinary tract infections 
 Chronic diarrhea 
 Endogenous creatinine 
clearance < 70ml/minute by 
eGFR 
 Chronic use of non-steroidal 
anti-inflammatory drugs, 
angiotensin 2 receptor blockers, 
ACE inhibitors, diuretics, 
antacids/alkali treatment, or 
carbonic anhydrase inhibitors 

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                                                                                      IRB # 032012-058 
 
Aim 2  
3-phase, double-blind, cross-over metabolic study examining the effects of potassium citrate and citric acid on 
urinary predictors of stone formation in calcium phosphate stone formers with hypercalciuria 
 
Disease State 
Subject Number 
Inclusion Criteria 
Exclusion Criteria 
Calcium 
phosphate stone 
formers with 
hypercalciuria 
25 
 ≥ 21 years of age for 
all subjects 
 Stone 
analysis 
showing 
calcium 
phosphate as major 
component of stone 
(>70%) 
 Hypercalciuria (urine 
calcium > 250 mg/d in 
women 
and 
>300 
mg/d in men) 
 24hr urine pH>6.40 
 
 Recurrent urinary tract infections 
 Chronic diarrhea 
 Endogenous creatinine 
clearance < 70ml/minute by 
eGFR 
 Chronic use of non-steroidal 
anti-inflammatory drugs, 
angiotensin 2 receptor blockers, 
ACE inhibitors, diuretics, 
antacids/alkali treatment, or 
carbonic anhydrase inhibitors 
 
Prisoners, institutionalized individuals, children under the age of 21 and pregnant women will be excluded from 
all studies.  
 
Sources of Materials: Results from medical, diet history, pregnancy tests, blood and urine tests, physical 
examinations, medication and dietary compliance, and demographics will be used in this study and accessed by 
the study investigators, research coordinator and study nurses and the biostatistician.   
 
Research data recorded in this study will include:  
 Medical History: medications, surgeries, allergies, use of alcohol and/or tobacco,  
 Pregnancy test results 
 Blood tests:  Comprehensive metabolic panel (sodium, potassium, chloride, bicarbonate, glucose, BUN, 
creatinine, calcium, total protein, albumin, bilirubin, alkaline phosphatase, AST, ALT), magnesium, 
phosphorus and uric acid. 
 Urine tests: total volume, pH, creatinine, sodium, potassium, calcium, magnesium, phosphorus, oxalate, 
uric acid, sulfate, citrate, chloride and ammonium, spot urinalysis, pregnancy test, and physicochemical 
assays (concentration product ratio, crystal growth, formation product).  
 Physical examinations: diet history, height and weight, blood pressure 
 Assessments from clinic visits: adverse events, medication and dietary compliance 
 Demographics: name, date of birth, gender, and race/ethnic background  
 
Potential Risks: Risks are enumerated in the consent form associated with the study that is explained to and 
signed by the participants.  Individual aims may include some or all of the risks listed below: 
 Blood Draws - Some common risks from venipuncture include discomfort, bleeding and/or bruising, 
dizziness or feeling faint.  On a rare occasion, an infection could develop at the site where blood was 
collected.   
 Potassium Citrate may cause diarrhea, nausea and abdominal cramping and a high blood potassium level. 
Signs of high potassium levels include feeling weak, lightheaded, dizzy, or having numbness or tingling.  
 Citric Acid is a weak organic acid found in a variety of citrus fruits and vegetables; it is commonly used as 
a natural preservative or to improve taste to foods and soft drinks. 
 
Subjects will be advised beforehand of the nature of potential side effects.  Those with an increased risk of 
injury or side effects will be excluded from the study.  If adverse symptoms appear, patients will be asked to 
contact the investigators.   
 
2. Adequacy of Protection Against Risks 

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                                                                                      IRB # 032012-058 
Recruitment and Informed Consent: Recruitment of subjects will be attempted via referral from the UT 
Southwestern Medical Center Urology and Mineral Metabolism Clinics. Consent of patients will be obtained prior 
to their involvement in the study by one of the investigators and will be witnessed by personnel not involved in 
the study. The subjects will receive a copy of the IRB-approved consent and a copy will be maintained in their 
research chart.  All efforts will be utilized to ensure subject privacy and all data will be held confidentially. HIPPA 
regulations will be discussed with all participants and HIPPA consent will be obtained concurrently with the study 
consent.  
 
Protection Against Risk: Subjects will be screened for any diseases that would increase the likelihood of side 
effects. Subjects will be closely monitored for any adverse effects and investigators will be alerted immediately 
in the case of any untoward outcomes. Participation in the study will be terminated if the subjects encounter any 
serious adverse effects. 
 
3. Potential Benefits of the Proposed Research to the Subjects and Others 
The immediate benefits to participants of the study will be limited. Subjects will receive the results of their 
laboratory work and will receive financial reimbursement for their time. The risks are minimal and are acceptable 
when the potential benefits are considered. The benefits mainly include the knowledge that may be gained 
regarding risk of recurrent urinary stones, which in the long-term could impact the care of the subjects 
themselves. 
 
4. Importance of the Knowledge to be Gained 
Calcium phosphate kidney stones are increasingly encountered in clinical practice, and are highly recurrent and 
difficult to treat. Currently, there is no proven measure for the prevention and treatment of recurrent calcium 
phosphate stones. This proposal will test whether pharmacological therapy with potassium citrate or citric acid 
reduces the risk of recurrent stone formation in calcium phosphate stone formers. Results from this pilot study 
will help identify options for the prevention and treatment of recurrent stones in this group of patients. 
 
Inclusion of Women, Minorities, and Pediatric Populations 
Inclusion of Women: The targeted/planned distribution of subjects by sex/gender and racial/ethnic groups is 
included. The study will include both men and women. There is no reason why either gender should be excluded 
from the investigation. The recruitment process will focus equally on obtaining both male and female participants.     
 
Inclusion of Minorities: All minorities will be included as there is no reason to exclude any individual based on 
ethnicity. Recruitment will be extended to all racial/ethnic groups. All subjects who meet inclusion/exclusion 
criteria to the target enrollment will be included.   
 
Inclusion of Children: The subject selection criteria include subjects age 21 years and above. Children will be 
excluded from this study because the investigative team does not include pediatricians with experience treating 
children. 
 
References 
 
1. 
Rodgers A, Allie-Hamdulay S, Jackson G. Therapeutic action of citrate in urolithiasis explained by 
chemical speciation: increase in pH is the determinant factor. Nephrol Dial Transplant. Feb 
2006;21(2):361-369. 
2. 
Pak CY, Moe OW, Maalouf NM, Zerwekh JE, Poindexter JR, Adams-Huet B. Comparison of semi-
empirical and computer derived methods for estimating urinary saturation of brushite. J Urol. Mar 
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