Visual Abstract
Keywords: nephrolithiasis, kidney stones, urine calcium, prevention
Abstract
Key Points
Thiazide treatment successfully lowered urine calcium and both calcium oxalate and calcium phosphate supersaturations in both types of stone formers (SFs).
Alkali therapy may not confer the same benefits on calcium phosphate SFs as it does on calcium oxalate SFs.
Background
Randomized controlled trials have shown that both thiazide diuretics and potassium citrate (K-Cit) can prevent calcium stone recurrence, but most participants formed calcium oxalate (CaOx) stones. While thiazides are expected to lower risk of calcium phosphate (CaP) stone formation, the effect of K-Cit on risk of CaP stone formation is unclear.
Methods
To study the effect of common calcium stone treatments, we analyzed the 24-hour urines of CaOx and CaP stone formers (SFs) by four treatment types: Lifestyle, K-Cit, Thiazide, or Both medications.
Results
Patients treated with thiazides reduced urine calcium in both CaOx (M=−74.4, SD=94.6 mg/d) and CaP (M=−102, SD=99.7 mg/d) SFs while those on K-Cit had no change in urine calcium. Among CaOx SFs, urine citrate rose in patients administered K-Cit with or without thiazide, but citrate did not rise significantly in CaP SFs. Urine pH rose in all CaOx SFs, but among CaP SFs, only rose in patients receiving K-Cit. CaOx supersaturation (SS) decreased in all patients who received Thiazide, and decreased among CaOx SFs treated with K-Cit. CaP SS decreased in both CaOx SFs (M=−0.46, SD=0.86) and CaP SFs (M=−0.76, SD=0.85) treated with Thiazide, except CaOx SFs who received Both. Patients treated with K-Cit alone increased CaP SS in CaOx SFs (M=0.25, SD=0.79).
Conclusions
Patients treated with Thiazide lowered urine calcium and SS in both stone groups. Patients treated with K-Cit had no significant changes in urine calcium and had a decrease in CaOx SS in CaOx SFs. The study raises questions about the best preventive treatment for patients with CaP stones and suggests that K-Cit may not confer the same benefits on CaP SFs as it does on CaOx SFs.
Introduction
Kidney stones affect approximately one in ten people in the United States; the overall prevalence is 9.4% among women and 10.9% among men and has been increasing steadily.1 Idiopathic calcium stones are the most common, with a majority composed primarily of calcium oxalate (CaOx).2,3 Calcium phosphate (CaP) stones are less common than CaOx, but have been increasing as well, and are particularly common among women of childbearing age.4–6 After an initial episode of nephrolithiasis, up to 50% of patients form at least one recurrent stone within the first 5 years if left untreated.7
Hypercalciuria is the most common metabolic abnormality in patients who form calcium kidney stones.8–10 Elevated levels of urine calcium increase both CaOx and CaP supersaturations (SSs),11 which are the driving force of stone formation. Treatment of kidney stones is often aimed at decreasing SS.11
Strategies to decrease stone recurrence generally include lifestyle and dietary changes,12,13 but many patients require pharmaceutical interventions as well. The two most commonly prescribed medications are thiazide-type diuretics and potassium alkali, commonly in the form of potassium citrate (K-Cit).14 Both drug classes have shown effectiveness in randomized placebo-controlled trials, with reductions in recurrence rates of 50% or more.15,16 However, treatment trials have often been limited to CaOx stone formers (SFs), and others have not explicitly included CaP SFs, so it is unknown how many have participated in such trials. The need for surgical treatment in CaP SFs exceeds that of CaOx SFs, emphasizing their need for stone prevention.5
Thiazide-type diuretics lower stone risk by decreasing urinary calcium, primarily by increasing proximal tubule calcium reabsorption.17 K-Cit treatments may lower stone risk by several proposed mechanisms. Some studies have shown that K-Cit may lower urine calcium excretion.18 In addition, increased urine citrate will chelate calcium which lowers its ability to complex with oxalate or phosphate.19,20 Both mechanisms would decrease urine SS for CaOx or CaP SFs. A third mechanism, not reflected in SS, is the ability of citrate to act as an inhibitor of crystal growth in urine.20
Because K-Cit treatment will raise urine pH and, therefore, increase CaP SS at any level of calcium excretion, it will have contrasting effects on stone risk, some beneficial and others not.21 We present clinical data concerning the effects of K-Cit, thiazide, or both on the full range of stone risk factors in clinical use in both CaOx and CaP SFs. Although thiazide appears equally effective in both types of SFs, K-Cit may be less effective in CaP compared with CaOx SFs.
Methods
Patient Selection
Patients were evaluated at the University of Chicago Kidney Stone Evaluation and Treatment Program between 1989 and 2020 by one of four nephrologists. Any changes in practice patterns during this time were reflective of the nationwide changes because more research proved the futility of low-calcium diets and citrate became a more common form of treatment. Patients were included in the study according to the following set of criteria1: had formed a CaOx or CaP stone defined as a stone containing ≥50% of that component according to stone analysis completed prior and most recent to baseline urine collection2; had completed at least two baseline 24-hour urine collections with serum panels while off medications, which were then analyzed in the University of Chicago Kidney Stone Laboratory before an initial visit where they were evaluated and counseled; and 3 had completed at least one follow-up 24-hour urine. All patients were advised to adhere to a low-sodium diet and to increase fluid intake to facilitate 2.5 L urine volume per day. Patients with systemic disease potentially leading to stone formation (e.g., primary hyperparathyroidism, bowel disease, diabetes, distal renal tubular acidosis), missing laboratory data, on treatment before entry, younger than 18 years, or with >5-year difference between laboratory test results were excluded. This study was approved by the Institutional Review Board at the University of Chicago (11943A).
Laboratory Methods and Data Extraction
For each patient, 24-hour urine and serum samples were analyzed using methods previously published.22 Data regarding new prescriptions of thiazide and/or K-Cit at the initial visit were collected. Patients on neither medication were placed in the lifestyle treatment–only group. Each patient was retrospectively categorized into one of four treatment groups: Lifestyle, K-Cit, Thiazide, or Both.
Statistical Analyses
Pre-treatment values were averaged for each patient. CaOx and CaP SSs were calculated using EQUIL2.23 gastrointestinal (GI) anion, net acid excretion, and titratable acidity (TA) were calculated as previously shown.24 Descriptive statistics including pairwise Wilcoxon tests were performed between pre- and post-treatment laboratory measurements to assess the significance of the changes within each treatment group. Notch box plots of the differences were generated for each of the treatment groups and stone types and significance tested with pairwise Wilcoxon rank-sum tests. All analyses were completed in R statistical software.25
Results
This study includes a total of 836 idiopathic calcium SFs. Of these, 693 formed CaOx stones (205 female) and 143 formed CaP stones (77 female). Table 1 presents the pre-treatment baseline values for all patient groups by treatment type and stone type. It is against this that we present changes observed in each treatment group.
Table 1.
Pre-treatment 24-hour serum and urine values by treatment group and stone type
| Variable | Lifestyle | K-Cit | Thiazide | Both | ||||
|---|---|---|---|---|---|---|---|---|
| CaOx (N=246) | CaP (N=42) | CaOx (N=170) | CaP (N=16) | CaOx (N=187) | CaP (N=65) | CaOx (N=90) | CaP (N=20) | |
| Age, yr | 44.8 (13.5) | 39.2 (12.3) | 45.8 (12.3) | 38.8 (16.0) | 46.1 (11.4) | 45.0 (12.9) | 47.6 (10.4) | 40.7 (14.7) |
| Sex (male), N (%) | 174 (70.7%) | 20 (47.6%) | 117 (68.8%) | 6 (37.5%) | 131 (70.1%) | 31 (47.7%) | 66 (73.3%) | 9 (45.0%) |
| Serum | ||||||||
| Potassium (mmol/L) | 4.28 (0.33) | 4.18 (0.39) | 4.31 (0.29) | 4.14 (0.35) | 4.28 (0.32) | 4.25 (0.28) | 4.30 (0.32) | 4.44 (0.24) |
| Calcium (mg/dl) | 9.62 (0.34) | 9.58 (0.37) | 9.67 (0.31) | 9.58 (0.31) | 9.55 (0.28) | 9.51 (0.33) | 9.56 (0.33) | 9.71 (0.27) |
| CO2 (mmol/L) | 27.1 (1.98) | 26.7 (2.38) | 26.8 (2.11) | 26.6 (1.79) | 27.3 (1.64) | 26.2 (2.13) | 27.1 (1.80) | 27.1 (1.15) |
| Urine | ||||||||
| Volume (L/d) | 1.73 (0.80) | 2.26 (0.98) | 1.66 (0.70) | 1.66 (0.97) | 2.05 (0.83) | 2.23 (0.94) | 1.81 (0.59) | 1.56 (0.56) |
| Creatinine (mg/d) | 1670 (453) | 1540 (445) | 1600 (464) | 1330 (419) | 1730 (464) | 1650 (581) | 1830 (414) | 1450 (373) |
| Sodium (mmol/d) | 177 (61.7) | 175 (49.9) | 171 (71.3) | 164 (70.4) | 191 (65.0) | 189 (73.2) | 189 (59.8) | 149 (46.5) |
| Calcium (mg/d) | 213 (108) | 222 (103) | 160 (80.6) | 187 (80.4) | 283 (104) | 312 (135) | 283 (108) | 265 (84.9) |
| Potassium (mmol/d) | 64.0 (23.8) | 75.5 (40.7) | 60.3 (27.4) | 48.2 (14.3) | 63.7 (24.2) | 72.6 (33.3) | 59.6 (17.9) | 48.9 (14.6) |
| Citrate (mg/d) | 575 (267) | 442 (237) | 415 (302) | 399 (390) | 627 (279) | 562 (305) | 529 (305) | 416 (220) |
| Magnesium (mg/d) | 106 (37.8) | 103 (36.7) | 99.3 (38.3) | 76.7 (30.3) | 110 (37.0) | 123 (55.0) | 112 (37.9) | 106 (21.6) |
| Ammonium (mEq/d) | 31.2 (15.2) | 31.3 (16.7) | 32.2 (23.2) | 22.4 (10.6) | 33.5 (15.7) | 34.5 (18.6) | 31.5 (21.3) | 13.2 (16.8) |
| pH | 6.06 (0.40) | 6.54 (0.36) | 5.74 (0.49) | 6.26 (0.45) | 6.14 (0.40) | 6.32 (0.35) | 5.85 (0.36) | 6.11 (0.36) |
| Sulfate (mEq/d) | 46.3 (19.0) | 42.1 (14.9) | 45.1 (20.1) | 31.5 (10.1) | 47.3 (18.1) | 52.1 (18.9) | 50.6 (18.8) | 42.7 (11.5) |
| Phosphorous (mEq/d) | 67.5 (26.9) | 53.2 (26.8) | 71.6 (28.0) | 70.0 (25.8) | 57.8 (24.3) | 58.3 (19.1) | 64.2 (21.1) | 68.9 (21.4) |
| Oxalate (mg/d) | 42.7 (16.5) | 43.6 (14.4) | 41.6 (15.5) | 36.7 (13.0) | 44.2 (14.9) | 45.8 (16.8) | 47.9 (21.1) | 37.2 (14.0) |
| GI anion (mEq/d) | 22.2 (14.4) | 23.9 (11.0) | 18.0 (14.8) | 23.3 (15.8) | 21.1 (11.4) | 22.0 (8.30) | 18.9 (12.5) | 17.9 (13.4) |
| TA (mEq/L) | 18.0 (11.2) | 9.37 (6.43) | 20.4 (8.99) | 15.5 (9.73) | 14.3 (8.59) | 13.2 (8.83) | 18.0 (11.4) | 15.6 (6.57) |
| Net acid (mEq/L) | 46.6 (19.0) | 40.9 (17.9) | 49.6 (20.1) | 36.0 (14.3) | 47.7 (17.3) | 43.6 (15.7) | 48.3 (22.9) | 27.2 (16.5) |
| CaOx SS | 8.64 (3.96) | 7.21 (3.64) | 7.81 (4.31) | 9.37 (4.64) | 9.22 (3.74) | 8.74 (3.71) | 11.0 (4.99) | 10.5 (3.50) |
| CaP SS | 1.40 (0.94) | 1.75 (1.07) | 0.79 (0.76) | 1.83 (1.04) | 1.58 (0.860) | 1.98 (0.910) | 1.25 (0.749) | 2.27 (1.37) |
Values are expressed as mean (SD) or N (%) as indicated. CaOx, calcium oxalate; CaP, calcium phosphate, GI, gastrointestinal; K-Cit, potassium citrate; SS, supersaturation; TA, titratable acidity.
Changes by Treatment Group
Serum Values
Administration of K-Cit alone resulted in a significant rise in serum potassium in CaOx SFs, but not CaP SFs (Table 2). Conversely, a decrease in serum potassium was observed in all groups receiving thiazide. Unexpectedly, a decline in serum potassium was also observed in the lifestyle group. Patients receiving thiazide alone had an increase in serum calcium while only CaOx SFs saw an increase when taking K-Cit and thiazide concurrently. Serum CO2 increased in all patients treated with thiazide.
Table 2.
Unadjusted changes from pre-treatment to post-treatment in stone chemistries by treatment group and stone type
| Variable | Lifestyle | K-Cit | Thiazide | Both | ||||
|---|---|---|---|---|---|---|---|---|
| CaOx (N=246) | CaP (N=42) | CaOx (N=170) | CaP (N=16) | CaOx (N=187) | CaP (N=65) | CaOx (N=90) | CaP (N=20) | |
| Time to follow-up, yr | 0.57 (1.35) | 0.56 (1.24) | 0.42 (0.68) | 0.35 (0.36) | 0.31 (0.61) | 0.33 (0.53) | 0.34 (1.34) | 0.43 (0.98) |
| Serum | ||||||||
| Potassium (mmol/L) | −0.11 (0.44)a | −0.14 (0.42) | 0.12 (0.35)b | 0.10 (0.34) | −0.45 (0.40)b | −0.56 (0.41)b | −0.34 (0.48) | −0.44 (0.37) |
| Calcium (mg/dl) | 0.046 (0.29) | 0.11 (0.38) | 0.097 (0.26)a | 0.037 (0.27) | 0.17 (0.28)b | 0.20 (0.30)a | 0.20 (0.34)b | 0.18 (0.35) |
| CO2 (mmol/L) | 0.46 (2.06)a | 0.31 (1.83) | 0.76 (1.77)a | 0.11 (1.47) | 1.37 (2.08)b | 1.90 (2.55)b | 2.09 (2.13)b | 2.51 (1.30)a |
| Urine | ||||||||
| Volume (L/d) | 0.50 (0.84)b | 0.11 (0.82) | 0.44 (0.68)b | 0.23 (0.99) | 0.30 (0.77)b | 0.29 (0.80)a | 0.48 (0.75)b | 0.50 (0.77)a |
| Calcium (mg/d) | −6.88 (90.4) | −12.0 (94.9) | 0.56 (72.0) | −9.97 (76.6) | −74.4 (94.6)b | −102 (99.7)b | −99.7 (99.3)b | −64.0 (119)a |
| Citrate (mg/d) | 32.4 (282) | 26.0 (197) | 252 (306)b | 36.0 (353) | −28.5 (251) | −118 (249)a | 118 (264)b | 94.2 (217) |
| Potassium (mmol/d) | 9.21 (31.0)b | 6.04 (41.7) | 34.4 (31.6)b | 15.7 (28.5) | 4.16 (24.2) | 2.93 (25.1) | 44.7 (31.4)b | 38.4 (34.3)b |
| pH | 0.14 (0.49)b | 0.072 (0.36) | 0.62 (0.62)b | 0.34 (0.52)a | 0.12 (0.47)b | 0.12 (0.32) | 0.73 (0.59)b | 0.48 (0.52)b |
| Ammonium (mEq/d) | 2.03 (12.6) | 0.67 (19.4) | −7.30 (18.9)b | −0.11 (12.0) | 6.04 (17.2)b | 5.03 (16.6)a | −5.52 (16.4) | −1.90 (8.35) |
| GI anion (mEq/d) | −0.47 (19.4) | −1.68 (18.0) | 14.7 (19.3)b | 8.46 (28.2) | −2.41 (14.0) | −2.54 (12.5) | 15.3 (20.5)b | 13.3 (21.1)a |
| Creatinine (mg/d) | 29.8 (262) | 44.6 (343) | 45.2 (200)b | 37.6 (220) | −2.13 (247) | −37.0 (281) | 4.67 (273) | 62.5 (383) |
| Sodium (mmol/d) | 1.50 (81.7) | 0.43 (62.7) | 11.2 (72.5)a | −15.3 (45.7) | −2.37 (83.9) | −21.0 (98.1) | 11.5 (77.4) | 23.2 (73.2) |
| Oxalate (mg/d) | 1.67 (19.0) | 0.58 (17.7) | 5.91 (21.5)b | 0.73 (16.7) | 0.21 (14.3) | −1.50 (15.7) | 4.30 (21.6)a | 6.04 (12.7) |
| Phosphorous (mg/d) | −18.2 (29.9)a | −7.96 (26.3) | −21.8 (24.7) | −25.6 (34.1)a | −10.4 (24.4) | −15.7 (21.7)a | −10.3 (25.8) | −23.5 (23.3) |
| Sulfate (mEq/d) | 3.86 (19.5)a | 1.09 (15.9) | 3.17 (17.9)a | 3.84 (13.9) | 2.84 (17.1)a | −1.97 (17.1) | 8.19 (66.4) | 6.28 (19.8) |
| TA (mEq/L) | −6.14 (12.0)b | −1.90 (5.93)a | −10.9 (8.55)b | −8.51 (12.0)a | −3.83 (8.71)b | −4.91 (6.06)b | −9.14 (11.3)b | −9.17 (6.80)b |
| Net acid (mEq/L) | −2.34 (16.8)a | 1.96 (23.7) | −16.0 (17.3)b | −0.12 (18.0) | 1.31 (19.1) | 2.24 (15.8) | −14.1 (21.6)b | −14.1 (13.2)a |
Deltas were calculated from post-treatment minus pre-treatment, and data are presented as mean (SD). CaOx, calcium oxalate; CaP, calcium phosphate; K-Cit, potassium citrate; TA, titratable acidity.
Pairwise t tests were used to compare pre- and post-treatment values.
P < 0.05.
P < 0.001.
Urine Volume, Potassium, and Sodium
Urine volume rose in all groups, with a significant increase observed in all CaOx SFs and CaP SFs on Thiazide and Both. Urine potassium rose significantly in CaOx SFs receiving K-Cit, but CaP SFs receiving K-Cit alone did not have a significant increase in urine potassium. Urine sodium did not decrease in any group (Table 2).
Urine Calcium
Thiazide administration reduced urine calcium in both CaOx and CaP SFs, whereas neither lifestyle modifications nor K-Cit alone decreased urine calcium (Figure 1, upper left and Table 2). The addition of K-Cit to thiazide had no additional effect on urine calcium compared with treatment with thiazide alone (Figure 1, upper left).
Figure 1.
Box plots of changes in urine calcium, citrate, pH, and GI anion by treatment group and stone type. The four treatment groups include patients who did not receive any pharmaceutical intervention (Lifestyle), those who received an alkali (K-Cit), those who received thiazide (Thiazide), and those who received both K-Cit and thiazide (Both). The top left panel shows changes in urine calcium excretion for CaOx and CaP SFs. The top right panel shows changes in urine citrate for CaOx and CaP SFs. The bottom left panel shows changes in urine pH for CaOx and CaP SFs. The bottom right panel shows changes in GI anion for CaOx and CaP SFs. Each box plot displays the results of the Wilcoxon rank-sum test to compare the treatment groups. CaOx, calcium oxalate; CaP, calcium phosphate; GI, gastrointestinal; K-Cit, potassium citrate; SF, stone former. *<0.05; **<0.01; ***<0.001; ****<0.0001.
Urine Citrate
Urine citrate excretion increased among all patients treated with K-Cit, but this was not statistically significant for CaP SFs. Conversely, urine citrate excretion significantly decreased in CaP SFs treated with thiazide but not CaOx SFs (Table 2). Concurrent administration of K-Cit and thiazide prevented the drop in citrate excretion seen with thiazide alone and led to an increase in citrate excretion among CaOx and CaP SFs (Figure 1, upper right and Table 2).
Urine pH
Urine pH rose in CaOx SFs across all groups. Among CaP SFs, urine pH rose only in groups receiving K-Cit (Table 2). Among CaOx SFs, patients receiving K-Cit had a significantly greater increase in pH compared with those who did not receive K-Cit (Figure 1, lower left). There is a similar pattern among CaP SFs, where patients receiving K-Cit differed from those on thiazide, but only those on Both differed from Lifestyle (Figure 1, lower left).
GI Anion
Urine gastrointestinal (GI) anion rose in all CaOx SFs receiving K-Cit and among CaP SFs receiving both K-Cit and thiazide (Table 2). For both CaOx and CaP SFs, the differences between groups for GI anion were the same as pH, which is physiologically rational26 (Figure 1, lower right).
TA, Ammonium, and Net Acid Excretion
Urine TA decreased in all patients (Table 2). Urine ammonium decreased in CaOx SFs treated with K-Cit alone and rose in CaOx SFs treated with thiazide alone. Among CaOx SFs, urine net acid decreased in patients treated with K-Cit with or without thiazide (Table 2). A similar pattern is observed in CaP SFs, but does not reach significance for those receiving K-Cit alone (Table 2).
Urine SS
Among CaOx SFs in the Lifestyle group, there were significant decreases in both CaOx and CaP SSs (Table 3). Patients treated with K-Cit significantly lowered CaOx SS and raised CaP SS (Table 3); however, the drop in CaOx SS did not differ from that in the Lifestyle group (Figure 2, left). Among CaOx SFs treated with Thiazide, both CaOx and CaP SSs decreased. The addition of K-Cit to Thiazide decreased CaOx SS further (Figure 2, left), but increased CaP SS compared with thiazide alone.
Table 3.
Unadjusted changes from pre-treatment to post-treatment in calcium oxalate and calcium phosphate supersaturations by treatment group and stone type
| Variable | Lifestyle | K-Cit | Thiazide | Both | ||||
|---|---|---|---|---|---|---|---|---|
| CaOx (N=246) | CaP (N=42) | CaOx (N=170) | CaP (N=16) | CaOx (N=187) | CaP (N=65) | CaOx (N=90) | CaP (N=20) | |
| CaOx SS | −2.13 (3.96)a | −0.93 (3.0) | −1.97 (3.86)a | −1.71 (4.09) | −3.30 (3.54)a | −3.13 (2.87)a | −5.09 (4.50)a | −3.51 (4.67)b |
| CaP SS | −0.27 (0.95)a | −0.34 (0.85) | 0.25 (0.79)a | −0.16 (1.18) | −0.46 (0.86)a | −0.76 (0.85)a | 0.12 (0.83) | −0.77 (1.32)b |
Deltas were calculated from post-treatment minus pre-treatment, and data are presented as mean (SD). CaOx, calcium oxalate; CaP, calcium phosphate; K-Cit, potassium citrate; SS, supersaturation.
Pairwise t tests were used to compare pre- and post-treatment values.
P < 0.001.
P < 0.05.
Figure 2.
Box plots of change in urine CaOx and CaP SSs by treatment groups and stone types. The four treatment groups include patients who did not receive any pharmaceutical intervention (Lifestyle), those who received an alkali (K-Cit), those who received thiazide (Thiazide), and those who received both K-Cit and thiazide (Both). The left panel shows changes in CaOx SS for CaOx and CaP SFs and calcium. The right panel shows changes in CaP SS for CaOx and CaP SFs. Each box plot displays the results of the Wilcoxon rank-sum test to compare treatment groups. SS, supersaturation. *<0.05; **<0.01; ***<0.001; ****<0.0001.
Among CaP SFs, patients in the Lifestyle and K-Cit groups did not have a significant change in SS (Table 3). In all patients treated with thiazide, there was a significant decrease in CaOx and CaP SSs with or without K-Cit (Table 3).
Supplemental Table 1 presents the post-treatment baseline values for all patient groups by treatment type and stone type.
Discussion
Idiopathic calcium kidney stones are frequently associated with hypercalciuria27 and hypocitraturia, which are graded risk factors of stone formation and may occur within the same patients.28,29 In a prior study, we have shown that in our practice, treatment selection is influenced by baseline 24-hour urine parameters.22 This is likely true in this patient population as well. However, although hypocitraturia is more common among CaP SFs than CaOx SFs,30 whether treatment with K-Cit is indicated is unclear. Randomized double-blind trials showing that K-Cit can effectively reduce new stone formation have included few, if any, CaP SFs.14,15,20,31–33 Given concerns about the possibility of increased CaP SS and worsening stone formation in CaP SFs,21 we have been cautious in its use, which explains why fewer CaP SFs were treated with K-Cit compared with CaOx SFs.
As expected, patients who received thiazide treatment successfully lowered urine calcium and both CaOx and CaP SSs. These effects would be expected to lower stone formation risk for either stone type.11 Patients treated with thiazide also lowered serum potassium and decreased citrate excretion in CaP SFs.
A consistent effect of K-Cit to raise urine pH was observed among CaOx SFs and CaP SFs. This was accompanied by an increase in CaP SS in CaOx SFs who received K-Cit alone. Surprisingly, CaP SS did not change significantly among CaP SFs who received K-Cit alone; however, this might be because of the small population size.
Citrate has complex effects on urine determinants of calcium stone risk, some of which could lower urine SS. Some studies have shown that K-Cit treatment can lower urine calcium excretion18,34,35 while others have not.15,36,37 In this study, we did not see a significant decrease in urine calcium excretion in patients treated with K-Cit alone. It is unclear why our results differ from some prior studies; however, two of the studies showing a decrease were completed under controlled conditions with metabolic diets, whereas patients in this study and others without a change were on free-choice diets. Our patients were also encouraged to eat adequate amounts of calcium.12,38 Interestingly, citrate trials by Ettinger et al. and Doizi et al. did not find a significant decrease in urine calcium excretion in CaOx SFs and CaP SFs, respectively.15,37 This suggests that this is not an anomalous finding.
If citrate does not lower urine calcium excretion, then the main benefits of citrate on stone prevention require delivery of citrate into urine. Urine citrate can chelate calcium in the urine, thereby lowering free calcium concentration.21 Among CaOx SFs, we observed a modest decrease in CaOx SS in those taking K-Cit alone, but the change did not differ from SFs getting lifestyle modification alone. CaP SS increased modestly in CaOx patients treated with K-Cit alone. Ettinger et al. did not find any significant changes in urine SS for CaOx or CaP, suggesting that the beneficial effect of citrate treatment for these patients may be mediated mainly by the inhibitory activity of citrate on crystal formation and growth15,19 rather than by changes in SS.
We, like others,15 found a significant increase in urine citrate in CaOx SFs given K-Cit. However, unlike others,37 we found that urine citrate did not rise significantly in CaP SFs treated with K-Cit. Possibly, this is due to lower doses of citrate or poorer compliance with medication in the CaP SFs, although urine potassium rose to the same extent in both CaP and CaOx SFs given K-Cit and thiazide. The lower numbers of CaP SFs treated also diminishes power to find a difference. However, it is possible that renal handling of citrate may differ between CaP and CaOx SFs. Others have found that the relationship between urine citrate excretion and net gastrointestinal alkali absorption was decreased in CaP SFs compared with CaOx SFs or non-SFs, suggesting abnormalities in renal citrate handling in CaP SFs.30 In a Clinical Research Center–based study where participants were fed a controlled diet, male CaP SFs had lower fractional excretions of citrate than CaOx SFs or female CaP SFs in both fasting and fed states, which suggests altered renal citrate handling in at least some CaP SFs.27
This raises the question whether CaP SFs will benefit from K-Cit if they do not raise urine citrate while having persistently high SS. In a hypercalciuric stone forming rat model, thiazide was a more effective form of treatment of CaP stones compared with K-Cit.39 This finding suggests the need for future studies of humans with CaP stones to determine whether K-Cit is effective for stone prevention. It is possible that a higher dosage of K-Cit is required for CaP SFs to provide sufficient transport of citrate into urine to achieve therapeutic benefit. Alternatively, K-Cit may be ineffective in at least some CaP SFs.
As expected, CaOx patients who received K-Cit had an increase in urine potassium and GI anion, as well as a decrease in ammonium, TA, and net acid excretion. There was a similar pattern among CaP SFs despite not reaching significance in those receiving K-Cit alone. This was possibly due to the small population of CaP SFs, which limited statistical power. By contrast, thiazide-treated patients had a decrease in serum potassium and urine citrate. In patients treated with both K-Cit and thiazide, the decrease in urine citrate otherwise seen after thiazide treatment was not observed although serum potassium decreased significantly in these patients as well. This suggests that the combination of K-Cit and thiazide might be more effective in stone prevention than either agent alone. This also requires further study.
Because this study is only evaluating the immediate effects of treatment on urine stone risk factors, we cannot evaluate the efficacy of these treatments on stone recurrence. A previous study from our clinic has shown that prevention of recurrence is equivalent in both CaOx and CaP SFs, confirming that effective treatment is possible.5 This study is not a randomized trial, but rather is a retrospective study looking at the effects seen in patients under ordinary clinical conditions. As a result, treatment choices were not random because treatment selection was likely influenced by baseline 24-hour urine results. There is also a discrepancy in the population sizes between CaOx and CaP SFs, which may limit statistical power.
To our knowledge, this is the first real-world study to detail the effects of these two common treatments on urine stone risk in CaOx and CaP SFs to assess whether there are differences in their response. It would appear that they respond similarly to thiazide, but the response to K-Cit may differ. Future studies should investigate the relative benefits of these treatments in both CaOx and CaP SFs.
Supplementary Material
Acknowledgments
Kristen Bergsland, PhD, Joan Parks, Fred Coe, MD.
Disclosures
E. Worcester reports the following: Patents or Royalties: BMA Biomedical; and Advisory or Leadership Role: Oxalosis and Hyperoxaluria Foundation. All remaining authors have nothing to disclose.
Funding
M. Prochaska: National Institute of Diabetes and Digestive and Kidney Diseases (DK127252). E. Worcester: National Institute of Diabetes and Digestive and Kidney Diseases (PO1 DK56788).
Author Contributions
Conceptualization: Elaine Worcester.
Data curation: Elaine Worcester.
Formal analysis: Audrey Steely.
Funding acquisition: Megan Prochaska, Elaine Worcester.
Methodology: Elaine Worcester.
Supervision: Megan Prochaska, Elaine Worcester.
Writing – original draft: Audrey Steely.
Writing – review & editing: Megan Prochaska, Elaine Worcester.
Data Sharing Statement
All data are included in the manuscript and/or supporting information.
Supplemental Material
This article contains the following supplemental material online at http://links.lww.com/KN9/A430.
Supplemental Table 1. Post-treatment baseline values for all patient groups by treatment type and stone type.
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Supplementary Materials
Data Availability Statement
All data are included in the manuscript and/or supporting information.