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Correction of hypocitraturia and prevention of stone formation by combined thiazide and potassium citrate therapy in thiazide-unresponsive hypercalciuric nephrolithiasis
CLINICAL STUDIES
Correction of Hypocitraturia and Prevention of Stone Formation by Combined Thiazide and Potassium Citrate Therapy in Thiazide-Unresponsive Hypercalciuric Nephrolithiasis
CHARLES Y. C. PAK, M.D. ROY PETERSON, R.N. KHASHAYAR SAKHAEE,M.D. CINDY FULLER, B.S. GLENN PREMINGER,M.D. JOAN REISCH, Ph.D. Dallas.
Thirteen patients with hypercalciuric calcium nephrolithiasis continued to form calcium stones when treated with thiazide (4.69 f 6.62 [mean f SD] stones per patient-year to 5.12 f 10.67 stones per patient-year), despite adequate hypocalciuric response (a reduction in,urinary calcium levels from 303 f 119 mg per day to 193 f 66 mg per day, p
Texas
From the Section on Mineral Metabolism, Southwestern Medical School, University of Texas Health Science Center at Dallas, Dallas, Texas. This work was supported by United States Public Health Service Grants POI-AM20543, MOlRR00633, and 5T32-AM07307. Requests for reprints should be addressed to Dr. Charles Y. C. Pak, Section on Mineral Metabolism, Southwestern Medical School, University of Texas Health Science Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75235. Manuscript accepted December 13, 1964.
294
September
1995
The American
Journal
Thiazide diuretics have been widely used for the medical management of hypercalciuric calcium nephrolithiasis [ 1, 21. The main rationale for this treatment is the ability of thiazide to reduce calcium excretion [3] and thereby lower the urinary saturation of stone-forming calcium salts (calcium oxalate and calcium phosphate) [4, 51. Other biochemical effects of thiazide engendered to justify its use in calcium nephrolithiasis include reduced oxalate excretion and increased excretion of certain inhibitors of the crystallization of calcium salts (such as pyrophosphate, magnesium, and zinc) [5, 61. In several clinical trials, thiazides have been shown to be effective in preventing new stone formation [ 1, 21. Even in these favorable reports, some patients continue to form stones. Moreover, in other studies, thiazides have been found to be of limited usefulness in controlling calcium nephrolithiasis [7,8]. This poor clinical response may be ascribed to the failure of thiazide to induce the aforementioned appropriate biochemical changes in urine under certain circumstances. Another potential cause for the inadequate clinical response is thiazide-induced hypocitraturia [ 1, 91. Thiazides have been shown to reduce citrate excretion, probably by causing hypokalemia and intracellular acidosis. Citrate normally inhibits crystallization of calcium
of Medicine
Volume
79
COMBINED
THIAZIDE
AND
POTASSIUM
oxalate in urine by reducing urinary saturation (via complexation of calcium) [IO], and by directly inhibiting crystal growth [ 111 and spontaneous nucleation [ 121. The reduced citrate excretion produced by thiazides may therefore present a risk for calcium stone formation, and may attenuate the beneficial effects of treatment just enumerated, such as the decline in urinary calcium excretion. Recently, it was shown that potassium supplementation in patients taking thiazide with potassium citrate not only prevents the development of hypokalemia but also increases urinary citrate levels [9]. In this report, we present favorable responses to the addition of potassium citrate therapy in patients who had relapses (continued to form stones) during thiazide treatment.
PATIENTS AND METHODS Clinical Data. Thirteen patients (10 men and three women, 25 to 68 years with mean age of 44 years) participated in the study after informed written consent was obtained. They were randomly chosen from those who had relapses (continued to form stones) during thiazide treatment. All patients had a history of active formation of calcium stones (principally calcium oxaiate but sometimes with calcium phosphate). All 13 patients had hypercalciuria, 11 cases due to absorptive hypercaiciuria and two from renal hypercaiciuria. Three patients had hyperuricosuria as well. These diagnoses were made initially from outpatient evaluation described previously [ 131. They had normal serum calcium, potassium, and carbon dioxide levels, and their endogenous creatinine clearance exceeded 80 ml per minute. None had cardiac disease, peptic ulcer, chronic diarrheai syndrome, or acute urinary tract infection. One patient had incomplete renal tubular acidosis since he had inadequate urinary acidification following ammonium chloride loading. In four patients, renal tubular acidosis (distal) was considered unlikely because they had a urinary pH of less than 5.3 in the setting of normal levels of serum electrolytes or had a normal response to ammonium chloride loading. In the remaining eight patients, 24-hour urinary pH was greater than 5.3, but ammonium chloride loading was not performed. Study Protocol. These patients were initially treated with thiazide (trichlormethiazide 4 mg per day in three, hydrochiorothiazide 50 mg per day or 50 mg twice a day in seven, and hydrochiorothiazide [25 to 50 mg] with amiloride [2.5 to 5 mg] twice a day in three) in order to reduce urinary caicium excretion [ 141. Eight patients received sufficient potassium chloride (8 to 16 meq three times per day) in order to prevent hypokalemia. The remaining five patients were normokalemic without potassium supplements. Three patients also took aiiopurinoi (100 mg three times per day) because of concurrent hyperuricosuria. When stone formation continued unabated during the aforementioned treatment (1 .O to 4.5 years, mean duration 1.76 years), potassium chloride supplementation was terminated, and all patients were given potassium citrate at a dosage of 10 to 20 meq three times per day. The same dose and type of thiazide were continued. In the three patients with
September
CITRATE
IN HYPERCALCIIJRIC
NEPHROLITHIASIS-PAK
ET AL
hyperuricosuria, allopurinoi was continued at the identical dose. During both treatment phases (thiazide phase with or without potassium chloride, and thiazide with potassium citrate phase), patients were offered the same general advice [ 151 (high fluid intake, moderate oxaiate intake, sodium restriction of less than 150 meq per day and limited calcium intake of less than 600 mg per day) by the same group of investigators, and were followed at four-month intervals in the same clinic. During each visit, a careful history was taken for “stone episodes” (colic, hematuria, passage), and new stone formation documented by collection of stones and by appropriate roentgenoiogic examination [ 161. The following tests were performed before treatment, at the conclusion of the thiazide phase, and at four-month intervals during treatment with thiazide and potassium citrate: fasting venous blood calcium, potassium, and carbon dioxide; 24-hour urinary pH, citrate, calcium, uric acid, sodium, oxaiate, and total volume; and creatinine clearance. Blood tests were performed as a part of a multi-channel screen (SMA-20). Urinary citrate was analyzed by the enzymatic method using the Boehringer-Mannheim kit, calcium by atomic absorption spectrophotometry, and uric acid by the uricase method. Sodium and potassium were determined by flame photometry and oxalate by the calorimetric technique of Hodgkinson and Williams [ 171. Significant differences in biochemical values between the control and treatment phases and between the two treatment phases were assessed by repeated-measures analysis of variance [ 181. Significant difference from values in control subjects (normal subjects) was assessed by the Student t test. The significance of the change in the stone formation rate (predicted versus actual) was calculated by the chi-square test. Ail values following the f signs are standard deviations.
RESULTS Effect on Stone Formation.
Before treatment, all 13 patients had active stone disease with documented new formation of two or more stones during the preceding three years, for a mean of 4.69 f 6.62 stones per patient-year (Figure 1). When thiazide was given with or without potassium chloride over 2.09 f 0.97 years per patient, all patients continued to form stones at an equivalent rate (5.12 f 10.87 stones per patient-year, p >O.i) (Figure 1). When potassium citrate was added to thiazide treatment, 10 patients (76.9 percent) had remission (stopped forming stones) and 13 (100 percent) experienced a reduced stone formation rate over 1.76 f 0.53 years per patient (Figure 1). The mean stone formation rate declined to 0.57 f 1.65 stones per patient-year (p
1985
The Amerfcan
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of Medlclne
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79
285
COMBINED
THIAZIDE
AND POTASSIUM
Thiazide .-.A-.+
-.-.-.
CITRATE
IN HYPERCALCIURIC
NEPHROLITHIASIS-PAK
Thiazide K Citrate
Treatment
ET AL
+ Treatment
-.-.-.d-.-.-.-.-.-.-.
I
-3
-2
I
-1
0
I
I
I
I
I
I
I
2
3
4
5
6
Figure 7. Effect of thiazide treatment and thiazide and potassium citrate treatment on new stone formation. Each line represents the study in separate patients. Each point indicates new stone formation. Combined thiazide and potassium citrate treatment was begun immediate/y after thiazide treatment.
Years
TABLE
I
Serum
and
Urinary
Chemical
Pretreatment Urinary values PH Citrate @-@day) Calcium (mg/day) Uric acid @w/day) Sodium (mWW Oxalate OWday) Total volume (ml/day) Serum values Calcium OWN Potassium (meq/liter) Carbon dioxide (meq/liter) Creatinine clearance (ml/day)
206
September
Thiaride
Thiazide plus Potassium Citrate (months) 0 12
4
6.62 f 473 f
0.44 86
6.21 f 284 f
0.39’ 105
6.61 f 547 f
303 f
119
193 f
88T
191 f
81t
187 f
95t
249 f
87$
199 f
59z
172 f
57g
721 f 436
565 f
130
503 f
187
563 f 206
591 f
260
553 f
185
456 f
127
154 f
49
200 f
82
166 f 44
168 f 72
166 f
57
192 f
77
737 f 34
29.3 f
6.1
30.5
f
5.7
32.6
14.8
6.69 f 557 f
35.1
f
12.0
35.1
2,544
f
496
2,634
f
0.41*+ 152*+
6.78 f 0.39*+ 543 f 143*+
f
10.0
32.45
f
5.0
f 803
2,580
f
522
2,204
f
601
0.27
9.81
f
0.27
f 0.71
4.10
f
0.77
28.0
f
2.3
93 f
13
2,656
f
536
2,483
9.55
f
0.32
9.74
f
0.43
9.78
f
0.41
9.88
f
0.26
9.80
f
0.26
9.80 f
4.10
f
0.57
3.80
f
0.56
4.00
f
0.42
4.14
f
0.54
3.81
f
0.57
4.15
27.2
f
1.5
29.3
f
2.4
28.9
f
2.3
29.0
f
2.3
28.7
f
1.5
29.5 f
1.8
105 f
24
105 f
27
102 f
20
112 f
23
102 f
21
mean
f
SD. Analysis
was not performed
(p
1965
The American
Journal
beyond
20 months
of treatment
because
of low number
phase and combined thiazide and potassium citrate phase. value, determined by repeated-measures analysis of variance. value, determined by repeated-measures analysis of variance.
of Medicine
Volume
79
0.48*+ 243*+
33.9
519
24
6.56 f 503 f
5.1
f
105 f
f 689
0.34’+ 146’+
20
5.93 f 250 f
f
0.34*+ 213*+
16
2,214
Values are presented as to receive treatment. Significantly different + Significantly different t Significantly different l
Values
of patients
continuing
COMBINED
THIAZIDE
AND
POTASSIUM
citrate levels were significantly reduced (250 f 86 mg per day versus 643 f 236 mg per day, p
The 13 patients for the current study were chosen from among approximately 40 percent of patients who continued to form stones during long-term treatment with thiazide. They generally represented those with severe cases of relapse. Retrospective examination revealed that they initially had hypocitraturia. When thiazide treatment was instituted with sufficient potassium chloride supplementation to prevent hypokalemia, urinary citrate excretion rose slightly but remained low relative to normal levels. The recognition that potassium citrate could stimulate renal citrate excretion [ 191 led us to substitute this drug for potassium chloride or to add it to ongoing thiazide therapy. Biochemically, the addition of potassium citrate to thiazide therapy prevented the development of hypokalemia, and caused a sustained increase in urinary pH and citrate levels. No change in urinary calcium, oxalate, or sodium levels or in total volume was encountered. Although no direct measurements were made, it is expected that those urinary changes should have been accompanied by a reduced propensity for the crystallization of calcium oxalate. Thus, urinary satu-
September
CITRATE
7.5
E f .-e 5
z
IN HYPERCALCIURIC
NEPHROLITHIASIS-PAK
ET AL
r
6.5 6.0
‘, E
600 -
& ! G E e 3c
500 400 300 -
100 L
pre
Thialide
4I
6I
12I
16 1
20 1
Thiazlde + K Citrate (months)
Figure 2. Effect of thiazide treatment and combined thiazkle and potassium citrate therapy on urinary pH, calcium, and citrate values. Bars indicate mean f SD. t Significant difference (p < 0.00 1) from pretreatment values. ( l *) Significant difference (p
ration of calcium oxalate should have decreased upon addition of potassium citrate therapy, since the ionic calcium concentration in urine should have fallen from the enhanced citrate complexation of calcium [lo]. Moreover, the inhibitor activity against calcium oxalate crystallization should have increased from the direct action of citrate [ 11,121, and from the enhanced inhibitor activity of other inhibitors at higher pH. Clinically, the addition of potassium citrate to the ongoing thiazide therapy caused remission of stone disease in 77 percent and reduced stone formation in 100 percent of the patients. The favorable response to combined thiazide and potassium citrate therapy, compared with that to thiazide alone or with potassium chloride, suggests that potassium citrate had been largely responsible for the clinical improvement. The “stone clinic effect” cannot be readily implicated [20], since the same conventional care of diet and fluid recommendations was given to patients by the identical group of investigators at the same clinic, during the
1995
The American
Journal
of Medicine
Volume
79
207
COMBINED
THIAZIDE
AND POTASSIUM
period of relapse (receiving thiazide without potassium citrate) as well as during the period of clinical improvement (following the addition of potassium citrate). In conclusion, it is suggested that certain patients with hypercalciuric nephrolithiasis may continue to form stones during thiazide therapy, because of reduced urinary inhibitor activity due to concurrent hypocitraturia. Potassium chloride supplementation does not correct this problem [ 91, even though it may prevent the further exaggeration of hypocitraturia by thiazide therapy [9]. However, the addition of potassium citrate therapy may not only prevent thiazide-induced hypokalemia but may
CITRATE
IN HYPERCALCIURIC
NEPHROLITHIASIS-PAK
ET AL
also restore normal urinary citrate excretion and prevent new calcium stone formation. In patients with initial normocitraturia, thiazide therapy theoretically may sometimes be ineffective in the control of hypercalciuric nephrolithiasis because it may cause hypocitraturia [ 1,9,14]. Although potassium chloride supplementation may prevent the development of hypocitraturia [9], potassium citrate may be more advantageous because of its capacity to further stimulate citrate excretion [9]. Thus, a consideration should be given to potassium citrate supplementation in patients with hypercalciuric nephrolithiasis treated with thiazide.
REFERENCES
2.
3.
4.
5.
6.
7.
a. 9. 10.
200
Yendt El?, Cohanim M: Prevention of calcium stones with thiazides. Kidney Int 1976; 13: 397-409. Coe FL, Kavalach AG: Hypercalciuria and hyperuricosuria in patients with calcium nephrolithiasis. N Engl J Med 1974; 291: 1344-1350. Brickman AS, Massry SG, Coburn JW: Changes in serum and urinary calcium during treatment with hydrochlorothiazide. J Clin Invest 1972; 51: 945-950. Woelfel A, Kaplan RA, Pak CYC: Effect of hydrochlorothiazide therapy on the crystallization of calcium oxalate in urine. Metabolism 1977; 26: 201-205. Pak CYC: Hydrochlorothiazide therapy in nephrolithiasis: effect on urinary activity product and formation product in brushiie. Clin Pharmacol Ther 1973; 14: 209-217. Pak CYC, Ruskin B, Diller E: Enhancement of renal excretion of zinc by hydrochlorothiazide. Clin Chim Acta 1972; 39: 511-517. Wolf HH, Brocks P, Transbol I: Do thiazides prevent recurrent idiopathic renal calcium oxalate stones? Results of a randomized, controlled clinical trial. Kidney Int 1963; 24: 426-428. Scholz D, Schwille PO, Sigel A: Double-blind study with thiazide in recurrent calcium lithiasis. J Urol 1962; 126: 903-907. Nicar MJ, Peterson R, Pak CYC: Use of potassium citrate as potassium supplement during thiazide therapy of calcium nephrolithiasis. J Urol 1964; 131: 430-433. Pak CYC, Nicar MJ, Northcutt C: The definition of the mechanism of hypercalciuria is necessary for the treatment of recurrent stone formers. Contrib Nephrol 1962; 33:
September
1995
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of Medlclne
11.
12. 13.
14.
15. 16.
17.
ia. 19.
20.
Volume
79
136-151. Meyer JL, Smith LH: Growth of calcium oxalate crystals II. Inhibition by natural urinary crystal growth inhibitors. Invest Urol 1975; 13: 36-39. Nicar MJ, Pak CYC: In preparation. Pak CYC, Britton F, Peterson R, et al: Ambulatory evaluation of nephrolithiasis: classification, clinical presentation and diagnostic criteria. Am J Med 1960; 69: 19-30. Leppla D, Browne R, Hill K, Pak CYC: Effect of amiloride with or without hydrochlorothiazide or urinary calcium and saturation of calcium salts. J Clin Endocrinol Metab 1963; 57: 920-924. Pak CYC: Medical management of nephrolithiasis. J Urol 1962; 126: 1157-1164. Pak CYC, Peters P, Hurt G, et al: Is selective therapy of recurrent nephrolithiasis possible? Am J Med 1961; 71: 615-622. Hodgkinson A. Williams A: An improved calorimetric procedure for urine oxalate. Clin Chim Acta 1972; 36: 127132. Weiner BJ: Statistical principles in experimental design, 2nd ed. New York: McGraw-Hill, 1971; 261-306. Pak CYC, Skurla C, Brinkley L, Sakhaee K: Augmentation of renal citrate excretion by oral potassium citrate administration: time course, dose frequency schedule and dose response relationship. J Clin Pharmacol 1964; 24: 1926. Hosking DH, Erickson SB, Van den Berg C, Wilson DM, Smith LH: The stone clinic effect in patients with idiopathic calcium urolithiasis. J Urol 1963; 130: 1115-l 116.
Correction of Hypocitraturia and Prevention of Stone Formation by Combined Thiazide and Potassium Citrate Therapy in Thiazide-Unresponsive Hypercalciuric Nephrolithiasis
CHARLES Y. C. PAK, M.D. ROY PETERSON, R.N. KHASHAYAR SAKHAEE,M.D. CINDY FULLER, B.S. GLENN PREMINGER,M.D. JOAN REISCH, Ph.D. Dallas.
Thirteen patients with hypercalciuric calcium nephrolithiasis continued to form calcium stones when treated with thiazide (4.69 f 6.62 [mean f SD] stones per patient-year to 5.12 f 10.67 stones per patient-year), despite adequate hypocalciuric response (a reduction in,urinary calcium levels from 303 f 119 mg per day to 193 f 66 mg per day, p
Texas
From the Section on Mineral Metabolism, Southwestern Medical School, University of Texas Health Science Center at Dallas, Dallas, Texas. This work was supported by United States Public Health Service Grants POI-AM20543, MOlRR00633, and 5T32-AM07307. Requests for reprints should be addressed to Dr. Charles Y. C. Pak, Section on Mineral Metabolism, Southwestern Medical School, University of Texas Health Science Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75235. Manuscript accepted December 13, 1964.
294
September
1995
The American
Journal
Thiazide diuretics have been widely used for the medical management of hypercalciuric calcium nephrolithiasis [ 1, 21. The main rationale for this treatment is the ability of thiazide to reduce calcium excretion [3] and thereby lower the urinary saturation of stone-forming calcium salts (calcium oxalate and calcium phosphate) [4, 51. Other biochemical effects of thiazide engendered to justify its use in calcium nephrolithiasis include reduced oxalate excretion and increased excretion of certain inhibitors of the crystallization of calcium salts (such as pyrophosphate, magnesium, and zinc) [5, 61. In several clinical trials, thiazides have been shown to be effective in preventing new stone formation [ 1, 21. Even in these favorable reports, some patients continue to form stones. Moreover, in other studies, thiazides have been found to be of limited usefulness in controlling calcium nephrolithiasis [7,8]. This poor clinical response may be ascribed to the failure of thiazide to induce the aforementioned appropriate biochemical changes in urine under certain circumstances. Another potential cause for the inadequate clinical response is thiazide-induced hypocitraturia [ 1, 91. Thiazides have been shown to reduce citrate excretion, probably by causing hypokalemia and intracellular acidosis. Citrate normally inhibits crystallization of calcium
of Medicine
Volume
79
COMBINED
THIAZIDE
AND
POTASSIUM
oxalate in urine by reducing urinary saturation (via complexation of calcium) [IO], and by directly inhibiting crystal growth [ 111 and spontaneous nucleation [ 121. The reduced citrate excretion produced by thiazides may therefore present a risk for calcium stone formation, and may attenuate the beneficial effects of treatment just enumerated, such as the decline in urinary calcium excretion. Recently, it was shown that potassium supplementation in patients taking thiazide with potassium citrate not only prevents the development of hypokalemia but also increases urinary citrate levels [9]. In this report, we present favorable responses to the addition of potassium citrate therapy in patients who had relapses (continued to form stones) during thiazide treatment.
PATIENTS AND METHODS Clinical Data. Thirteen patients (10 men and three women, 25 to 68 years with mean age of 44 years) participated in the study after informed written consent was obtained. They were randomly chosen from those who had relapses (continued to form stones) during thiazide treatment. All patients had a history of active formation of calcium stones (principally calcium oxaiate but sometimes with calcium phosphate). All 13 patients had hypercalciuria, 11 cases due to absorptive hypercaiciuria and two from renal hypercaiciuria. Three patients had hyperuricosuria as well. These diagnoses were made initially from outpatient evaluation described previously [ 131. They had normal serum calcium, potassium, and carbon dioxide levels, and their endogenous creatinine clearance exceeded 80 ml per minute. None had cardiac disease, peptic ulcer, chronic diarrheai syndrome, or acute urinary tract infection. One patient had incomplete renal tubular acidosis since he had inadequate urinary acidification following ammonium chloride loading. In four patients, renal tubular acidosis (distal) was considered unlikely because they had a urinary pH of less than 5.3 in the setting of normal levels of serum electrolytes or had a normal response to ammonium chloride loading. In the remaining eight patients, 24-hour urinary pH was greater than 5.3, but ammonium chloride loading was not performed. Study Protocol. These patients were initially treated with thiazide (trichlormethiazide 4 mg per day in three, hydrochiorothiazide 50 mg per day or 50 mg twice a day in seven, and hydrochiorothiazide [25 to 50 mg] with amiloride [2.5 to 5 mg] twice a day in three) in order to reduce urinary caicium excretion [ 141. Eight patients received sufficient potassium chloride (8 to 16 meq three times per day) in order to prevent hypokalemia. The remaining five patients were normokalemic without potassium supplements. Three patients also took aiiopurinoi (100 mg three times per day) because of concurrent hyperuricosuria. When stone formation continued unabated during the aforementioned treatment (1 .O to 4.5 years, mean duration 1.76 years), potassium chloride supplementation was terminated, and all patients were given potassium citrate at a dosage of 10 to 20 meq three times per day. The same dose and type of thiazide were continued. In the three patients with
September
CITRATE
IN HYPERCALCIIJRIC
NEPHROLITHIASIS-PAK
ET AL
hyperuricosuria, allopurinoi was continued at the identical dose. During both treatment phases (thiazide phase with or without potassium chloride, and thiazide with potassium citrate phase), patients were offered the same general advice [ 151 (high fluid intake, moderate oxaiate intake, sodium restriction of less than 150 meq per day and limited calcium intake of less than 600 mg per day) by the same group of investigators, and were followed at four-month intervals in the same clinic. During each visit, a careful history was taken for “stone episodes” (colic, hematuria, passage), and new stone formation documented by collection of stones and by appropriate roentgenoiogic examination [ 161. The following tests were performed before treatment, at the conclusion of the thiazide phase, and at four-month intervals during treatment with thiazide and potassium citrate: fasting venous blood calcium, potassium, and carbon dioxide; 24-hour urinary pH, citrate, calcium, uric acid, sodium, oxaiate, and total volume; and creatinine clearance. Blood tests were performed as a part of a multi-channel screen (SMA-20). Urinary citrate was analyzed by the enzymatic method using the Boehringer-Mannheim kit, calcium by atomic absorption spectrophotometry, and uric acid by the uricase method. Sodium and potassium were determined by flame photometry and oxalate by the calorimetric technique of Hodgkinson and Williams [ 171. Significant differences in biochemical values between the control and treatment phases and between the two treatment phases were assessed by repeated-measures analysis of variance [ 181. Significant difference from values in control subjects (normal subjects) was assessed by the Student t test. The significance of the change in the stone formation rate (predicted versus actual) was calculated by the chi-square test. Ail values following the f signs are standard deviations.
RESULTS Effect on Stone Formation.
Before treatment, all 13 patients had active stone disease with documented new formation of two or more stones during the preceding three years, for a mean of 4.69 f 6.62 stones per patient-year (Figure 1). When thiazide was given with or without potassium chloride over 2.09 f 0.97 years per patient, all patients continued to form stones at an equivalent rate (5.12 f 10.87 stones per patient-year, p >O.i) (Figure 1). When potassium citrate was added to thiazide treatment, 10 patients (76.9 percent) had remission (stopped forming stones) and 13 (100 percent) experienced a reduced stone formation rate over 1.76 f 0.53 years per patient (Figure 1). The mean stone formation rate declined to 0.57 f 1.65 stones per patient-year (p
1985
The Amerfcan
Journal
of Medlclne
Volume
79
285
COMBINED
THIAZIDE
AND POTASSIUM
Thiazide .-.A-.+
-.-.-.
CITRATE
IN HYPERCALCIURIC
NEPHROLITHIASIS-PAK
Thiazide K Citrate
Treatment
ET AL
+ Treatment
-.-.-.d-.-.-.-.-.-.-.
I
-3
-2
I
-1
0
I
I
I
I
I
I
I
2
3
4
5
6
Figure 7. Effect of thiazide treatment and thiazide and potassium citrate treatment on new stone formation. Each line represents the study in separate patients. Each point indicates new stone formation. Combined thiazide and potassium citrate treatment was begun immediate/y after thiazide treatment.
Years
TABLE
I
Serum
and
Urinary
Chemical
Pretreatment Urinary values PH Citrate @-@day) Calcium (mg/day) Uric acid @w/day) Sodium (mWW Oxalate OWday) Total volume (ml/day) Serum values Calcium OWN Potassium (meq/liter) Carbon dioxide (meq/liter) Creatinine clearance (ml/day)
206
September
Thiaride
Thiazide plus Potassium Citrate (months) 0 12
4
6.62 f 473 f
0.44 86
6.21 f 284 f
0.39’ 105
6.61 f 547 f
303 f
119
193 f
88T
191 f
81t
187 f
95t
249 f
87$
199 f
59z
172 f
57g
721 f 436
565 f
130
503 f
187
563 f 206
591 f
260
553 f
185
456 f
127
154 f
49
200 f
82
166 f 44
168 f 72
166 f
57
192 f
77
737 f 34
29.3 f
6.1
30.5
f
5.7
32.6
14.8
6.69 f 557 f
35.1
f
12.0
35.1
2,544
f
496
2,634
f
0.41*+ 152*+
6.78 f 0.39*+ 543 f 143*+
f
10.0
32.45
f
5.0
f 803
2,580
f
522
2,204
f
601
0.27
9.81
f
0.27
f 0.71
4.10
f
0.77
28.0
f
2.3
93 f
13
2,656
f
536
2,483
9.55
f
0.32
9.74
f
0.43
9.78
f
0.41
9.88
f
0.26
9.80
f
0.26
9.80 f
4.10
f
0.57
3.80
f
0.56
4.00
f
0.42
4.14
f
0.54
3.81
f
0.57
4.15
27.2
f
1.5
29.3
f
2.4
28.9
f
2.3
29.0
f
2.3
28.7
f
1.5
29.5 f
1.8
105 f
24
105 f
27
102 f
20
112 f
23
102 f
21
mean
f
SD. Analysis
was not performed
(p
1965
The American
Journal
beyond
20 months
of treatment
because
of low number
phase and combined thiazide and potassium citrate phase. value, determined by repeated-measures analysis of variance. value, determined by repeated-measures analysis of variance.
of Medicine
Volume
79
0.48*+ 243*+
33.9
519
24
6.56 f 503 f
5.1
f
105 f
f 689
0.34’+ 146’+
20
5.93 f 250 f
f
0.34*+ 213*+
16
2,214
Values are presented as to receive treatment. Significantly different + Significantly different t Significantly different l
Values
of patients
continuing
COMBINED
THIAZIDE
AND
POTASSIUM
citrate levels were significantly reduced (250 f 86 mg per day versus 643 f 236 mg per day, p
The 13 patients for the current study were chosen from among approximately 40 percent of patients who continued to form stones during long-term treatment with thiazide. They generally represented those with severe cases of relapse. Retrospective examination revealed that they initially had hypocitraturia. When thiazide treatment was instituted with sufficient potassium chloride supplementation to prevent hypokalemia, urinary citrate excretion rose slightly but remained low relative to normal levels. The recognition that potassium citrate could stimulate renal citrate excretion [ 191 led us to substitute this drug for potassium chloride or to add it to ongoing thiazide therapy. Biochemically, the addition of potassium citrate to thiazide therapy prevented the development of hypokalemia, and caused a sustained increase in urinary pH and citrate levels. No change in urinary calcium, oxalate, or sodium levels or in total volume was encountered. Although no direct measurements were made, it is expected that those urinary changes should have been accompanied by a reduced propensity for the crystallization of calcium oxalate. Thus, urinary satu-
September
CITRATE
7.5
E f .-e 5
z
IN HYPERCALCIURIC
NEPHROLITHIASIS-PAK
ET AL
r
6.5 6.0
‘, E
600 -
& ! G E e 3c
500 400 300 -
100 L
pre
Thialide
4I
6I
12I
16 1
20 1
Thiazlde + K Citrate (months)
Figure 2. Effect of thiazide treatment and combined thiazkle and potassium citrate therapy on urinary pH, calcium, and citrate values. Bars indicate mean f SD. t Significant difference (p < 0.00 1) from pretreatment values. ( l *) Significant difference (p
ration of calcium oxalate should have decreased upon addition of potassium citrate therapy, since the ionic calcium concentration in urine should have fallen from the enhanced citrate complexation of calcium [lo]. Moreover, the inhibitor activity against calcium oxalate crystallization should have increased from the direct action of citrate [ 11,121, and from the enhanced inhibitor activity of other inhibitors at higher pH. Clinically, the addition of potassium citrate to the ongoing thiazide therapy caused remission of stone disease in 77 percent and reduced stone formation in 100 percent of the patients. The favorable response to combined thiazide and potassium citrate therapy, compared with that to thiazide alone or with potassium chloride, suggests that potassium citrate had been largely responsible for the clinical improvement. The “stone clinic effect” cannot be readily implicated [20], since the same conventional care of diet and fluid recommendations was given to patients by the identical group of investigators at the same clinic, during the
1995
The American
Journal
of Medicine
Volume
79
207
COMBINED
THIAZIDE
AND POTASSIUM
period of relapse (receiving thiazide without potassium citrate) as well as during the period of clinical improvement (following the addition of potassium citrate). In conclusion, it is suggested that certain patients with hypercalciuric nephrolithiasis may continue to form stones during thiazide therapy, because of reduced urinary inhibitor activity due to concurrent hypocitraturia. Potassium chloride supplementation does not correct this problem [ 91, even though it may prevent the further exaggeration of hypocitraturia by thiazide therapy [9]. However, the addition of potassium citrate therapy may not only prevent thiazide-induced hypokalemia but may
CITRATE
IN HYPERCALCIURIC
NEPHROLITHIASIS-PAK
ET AL
also restore normal urinary citrate excretion and prevent new calcium stone formation. In patients with initial normocitraturia, thiazide therapy theoretically may sometimes be ineffective in the control of hypercalciuric nephrolithiasis because it may cause hypocitraturia [ 1,9,14]. Although potassium chloride supplementation may prevent the development of hypocitraturia [9], potassium citrate may be more advantageous because of its capacity to further stimulate citrate excretion [9]. Thus, a consideration should be given to potassium citrate supplementation in patients with hypercalciuric nephrolithiasis treated with thiazide.
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136-151. Meyer JL, Smith LH: Growth of calcium oxalate crystals II. Inhibition by natural urinary crystal growth inhibitors. Invest Urol 1975; 13: 36-39. Nicar MJ, Pak CYC: In preparation. Pak CYC, Britton F, Peterson R, et al: Ambulatory evaluation of nephrolithiasis: classification, clinical presentation and diagnostic criteria. Am J Med 1960; 69: 19-30. Leppla D, Browne R, Hill K, Pak CYC: Effect of amiloride with or without hydrochlorothiazide or urinary calcium and saturation of calcium salts. J Clin Endocrinol Metab 1963; 57: 920-924. Pak CYC: Medical management of nephrolithiasis. J Urol 1962; 126: 1157-1164. Pak CYC, Peters P, Hurt G, et al: Is selective therapy of recurrent nephrolithiasis possible? Am J Med 1961; 71: 615-622. Hodgkinson A. Williams A: An improved calorimetric procedure for urine oxalate. Clin Chim Acta 1972; 36: 127132. Weiner BJ: Statistical principles in experimental design, 2nd ed. New York: McGraw-Hill, 1971; 261-306. Pak CYC, Skurla C, Brinkley L, Sakhaee K: Augmentation of renal citrate excretion by oral potassium citrate administration: time course, dose frequency schedule and dose response relationship. J Clin Pharmacol 1964; 24: 1926. Hosking DH, Erickson SB, Van den Berg C, Wilson DM, Smith LH: The stone clinic effect in patients with idiopathic calcium urolithiasis. J Urol 1963; 130: 1115-l 116.