Contrasting Effects of Potassium Citrate and Sodium Citrate Therapies on Urinary Chemistries and Crystallization of Stone-Forming Salts

Kidney International, Vol. 24 (1983), PP. 348—352

CLINICAL INVESTIGATION

Contrasting effects of potassium citrate and sodium citrate therapies on urinary chemistries and crystallization of stone-forming salts

KHASHAYAR SAKHAEE, MICHAEL NICAR, KATHY HILL, and CHARLES Y.C. PAK

Section on Mineral Metabolism, Department of Internal Medicine, The University of Texas Health Science Center at Dallas, Southwestern Medical School, Dallas, Texas

Contrasting effects of potassium citrate and sodium citrate therapies on produit d'activité) de l'oxalate de calcium a diminué d'une saturation de urinary chemistries and crystallization of stone-forming salts. Effects of 3.21 fois a une saturation de 1.69 fois (P <0.01), et I'activité inhibitrice potassium citrate therapy (60 mEq/day) on urinary chemistries and de Ia precipitation d'oxalate de calcium (rapport de produit de forma- crystallization were compared to those of sodium citrate treatment in tion) a augmenté significativement. Toutefois, le traitement par Ic five patients with uric acid lithiasis. Both alkali treatments significantly citrate de potassium n'a pas diminué significativement Ia calciurie (a 139 increased urinary pH (P < 0.001), from 5.35 0.18 so to 6.68 0.14 for 24 mg/jour), bien qu'elle ait augmenté Ic citrate urinaire de facon potassium citrate and 6.73 0.20 for sodium citrate. During substantielle (a 799 89 mg/jour, p < 0.01). L'environnement urinaire potassium citrate therapy, urinary calcium significantly declined from est devenu sursaturC en brushite (phosphate de calcium) et en urate 154 47 mg/day to 99 23 mg/day (P < 0.01) and urinary citrate rose monosodique. L'activité inhibitrice de Ia precipitation d'oxalate de from 398 119 mg/day to 856 103 mg/day (P < 0.001). The urinary calcium n'Ctait pas modifiée de facon significative pour le groupe entier; saturation (activity product ratio) of calcium oxalate decreased from chez deux malades dIe a diminuC de plus de 30%. Ces résultats 3.21-fold to 1.69-fold saturation (P < 0.01), and the inhibitor activity indiquent que (1) les deux traitements alcalinisants sont aussi efficaces against calcium oxalate precipitation (formation product ratio) signifi- l'un que l'autre pour prCvenir La formation de calculs d'acide urique en cantly increased. However, sodium citrate therapy did not significantly raison de leur capacité a augmenter Ic pH urinaire, et (2) le citrate de decrease urinary calcium (to 139 24 mg/day), although it increased potassium pourrait prévenir Ia complication a type de lithiase rénale urinary citrate substantially (to 799 89 mg/day, P < 0.01). Urinary calcique chez les malades ayant des calculs d'acide urique, cc que ne environment became supersaturated with respect to brushite (calcium pourrait faire Ic citrate de sodium. phosphate) and monosodium urate. The inhibitor activity against calcium oxalate precipitation was not significantly altered for the whole group; in two patients, it decreased by more than 30%. The results indicate that (1) both alkali therapies are equally effective in preventing An important determinant for the formation of uric acid uric acid stone formation because of their ability to increase urinary pH, and (2) potassium citrate may prevent the complication of calcium stones is the passage of uncommonly acid urine. The urinary nephrolithiasis in patients with uric acid stones, whereas sodium citrate pH in patients with uric acid lithiasis is typically less than the may not. dissociation constant (pKa) of uric acid of 5.47 [1]; thus, their urinary environment is supersaturated with respect to uric acid. Because uric acid is more soluble at a higher pH, it has been Effets opposes de traitements par le citrate de potassium et le citrate de sodium sur les paramètres biochimiques et Ia cristallisation urinaires des customary to recommend alkalinization of urine for manage- sels Iithogenes. Les effets d'un traitement par Ic citrate de potassium (60 ment of uric acid nephrolithiasis [2]. Sodium salts of bicarbon- mEq/jour) sur les paramètres biochimiques et Ia cristallisation urinaires ate and citrate have sometimes been used as alkalinizing agents. été compares a ceux d'un traitement par le citrate de sodium chez cinq Although it may cause dissolution or inhibit formation of uric malades atteints de lithiase urique. Ces deux traitements alcalinisants ont augmenté significativement Ic pH urinaire (P < 0.001), de 5.35 acid stones, sodium alkali therapy may be complicated by the 0.18 SD a 6.68 0.14 pour Ic citrate de potassium, et 6.73 0.20 pour Ic development of calcium-containing renal stones (calcium phos- citrate de sodium. Pendant Ic traitement par le citrate de potassium, Ia phate and/or calcium oxalate) [3—6]. However, our preliminary calciurie a diminué significativement de 154 47 mg/jour a 99 23 study indicated that potassium alkali therapy may avert such a mg/jour (P < 0.01) et Ic citrate urinaire s'est élevé de 398 119mg/jour complication in uric acid lithiasis [4]. Moreover, the treatment a 856 103 mg/jour (P < 0.001). La saturation urinaire (rapport de with potassium citrate was shown to correct hypocitraturia (low urinary citrate), a defect frequently encountered in calcium nephrolithiasis [7—17]. This finding suggested that potassium Received for publication October 22, 1982 alkali may also be useful in the management of calcium urolith- and in revised form February 8, 1983 iasis associated with hypocitraturia. © 1983 by the International Society of Nephrology These circumstances led us to compare in detail the biochem-

348 Potassium citrate and sodium citrate therapeutic effects 349 ical and physicochemical effects of potassium citrate therapy oxalate) to steady state. The ratio of activity products in the from those of sodium citrate therapy. It will be shown thatoriginal sample and the ambient fluid after incubation to steady- potassium citrate is more effective than sodium citrate instate with the solid phase, gave a quantitative measure of inhibiting the crystallization of calcium oxalate in urine. saturation, where a value of I indicated saturation, greater than 1 supersaturation and less than I undersaturation. Methods The urinary saturation with respect to urate salts was estimat- Experimental subjects. Five patients with documented uriced from the relative saturation ratio. The RSR represented the acid lithiasis who developed the complication of calcium stones ratio of the activity product in the original sample and the on sodium alkali treatment participated in the study. Thethermodynamic solubility product [27]. The RSR of monosodi- patients ranged in age from 42 to 69 years. All were men. All um urate was previously shown to correspond closely with APR subjects had adequate endogenous creatinine clearance, rang- [25]. ing from 75 to 130 mI/mm. None of the participating subjects The formation product ratio indicated the limit of metastabil- suffered from hyperkalemia, fluid retention, urinary tract infec-ity or minimum supersaturation required for spontaneous nucle- tion, or urinary tract obstruction during the study. Only oneation [24]. Strictly, it represented heterogenous nucleation by patient suffered gout. None had chronic diarrheal syndrome.naturally occurring nuclei in urine. To samples rendered devoid The study was approved by the human experimentation com- of cellular debris and crystalline material by filtration (Millipore mittee, and informed consent was obtained from each of the 0.22 m, Millipore Corp., Bedford, Massachusetts), a solution participating subjects. of calcium chloride or sodium oxalate was added in increasingly Study protocol. The study comprised three phases, consistinglarge amounts to cause precipitation of calcium phosphate or of control phase (no drug), potassium citrate phase, and sodiumcalcium oxalate, respectively. The minimum activity product citrate phase, conducted randomly. The dosage of the two ratio that permitted precipitation at 3 hr represented the FPR. forms of alkali were the same (60 mEq/day in three dividedThus, an increased FPR reflected increased inhibition of doses orally). All other drugs were withheld during the study.crystallization. Each phase was 4 weeks long. After 3 weeks of stabilization in Statistical analysis. The paired t test was used to test the an outpatient setting, patients underwent an inpatient evalua-significance of changes in measured parameters between con- tion during the last week. trol and treatment phases. During each inpatient evaluation, subjects were maintained on a constant metabolic diet with a daily composition of 400 mg Results calcium, 800 mg phosphorus, 100 mEq sodium, 60 mEq potassi- Effect of alkali therapy on urinary chemistries. In five pa- um, and sufficient fluid to ensure approximately 2 liters of urinetients with uric acid lithiasis, urinary pH rose significantly daily for the entire study period of 6 days. After 3 days ofduring both alkali treatments (Table I). The rise in urinary pH stabilization, urine samples were collected daily in 24-hr poolsoccurring from potassium citrate therapy was equivalent to that during the last 3 days for total volume, pH, calcium, oxalate, resulting from sodium citrate therapy. Urinary calcium declined phosphorus, sodium, potassium, magnesium, ammonium, ci-significantly during potassium citrate therapy but not during trate, sulfate, and uric acid; relative saturation ratio (RSR) ofsodium citrate treatment (Table 1 and Fig. I). Urinary calcium monosodium urate and monopotassium urate; activity productduring potassium citrate therapy was significantly lower than ratio (APR) of brushite (CaHPO4 •2H20)and calcium oxalate; during sodium citrate therapy. Urinary sodium increased signif- and formation product ratio (FPR) of brushite and calciumicantly during sodium citrate treatment and urinary potassium oxalate. rose significantly during potassium citrate treatment (Table I). Analytical procedures. Urinary calcium and magnesium were Urinary ammonium decreased significantly during both alkali determined by atomic absorption spectrophotometry and sodi-phases (Table 1); the decline was more prominent during um and potassium by flame photometry. Phosphorus was potassium citrate therapy. Urinary citrate increased significant- measured by the colorimetric technique of Chen et al [18],ly during both alkali phases; the rise was greater during oxalate by the method of Hodgkinson and Williams [19], sulfate potassium citrate treatment than during sodium citrate therapy by turbidimetric procedure of Ma and Chan [20], and uric acid although the difference was not significant (Table I and Fig. I). by the enzymatic method of Liddle, Seegmiller, and Laster [21]. There were small or no significant changes in urinary total Citrate was determined enzymatically with kits from Boeh-volume, oxalate, phosphorus, magnesium, sulfate, or uric acid ringer-Mannheim Biochemicals (Indianapolis, Indiana), which between the three phases (Table 1). Moreover, no significant gave a 3 and 6%, intra- and interassay variation, respectively.change in endogenous creatinine clearance occurred during This enzymatic method was found to be comparable in yield to alkali treatment. the pentabromacetone colorimetric method of Beutler and Yeh Effect of alkali therapy on urinary crystallization. Both alkali [22]. Citrate values were within 10% agreement between thesetherapies caused a significant decline in urinary APR of calcium two methods. Ammonium was measured colorimetrically by aoxalate; however, the decline was more prominent during method adapted from Chaney and Marbach [23]. potassium citrate therapy than during sodium alkali therapy Crystallization studies. Methods for the assessment of uri-(Table 1, Fig. 2). Thus, urinary saturation of calcium oxalate nary crystallization were previously reported [24—27] and willdeclined during alkali therapies, more so when potassium be briefly described here. citrate was given. Urinary APR of brushite increased during The activity product ratio represented the state of saturation both alkali therapies; the rise was more prominent during with respect to the solid phase [24]. The urine sample was sodium citrate therapy (Table 1). Urinary environment became incubated with an excess of solid phase (brushite or calciumsupersaturated (APR >1)with respect to brushite during 350 Sakhace'ta!

Table1. Effectof alkalitherapies on urinarychemistriesand crystallization in patients with uric acid lithiasis" Control Potassium citrate Sodiumcitrate

Total volume, mi/day 2456 290 2525 359 2669 296 pH 5.35 0.18 6.68 0.l4 6.73 0.20e Calcium, mg/day 154 47 99 23d 139 24d Oxalate, mg/day 28.6 2.3 28.6 2.7 31.8 44c( Phosphorus, mg/day 680 143 657 109 663 78 Sodium, mEq/day 104 33 88 26 166 30° Potassium, mEq/day 42 II 114 l6 48 9c Magnesium, mg/day 85 22 88 14 96 16 Ammonium, mEq/day 30.1 7.8 9.7 3.6 12.2 3.8 Citrate, mg/day 398 119 856 103c 799 89 Sulfate, msi/day 18.9 7.3 17.5 5.6 20.3 4.1 Uric acid, mg/day 417 121 522 171 512 132

Activity product ratio Calcium oxalate 3.21 0.96 1.69 0.76d 2.21 0.63cd Brushite 0.04 0.03 0.74 0.22w 1.17 0.44'

Formation product ratio Calcium oxalate 16.1 5.6 22.2 6.6 14.1 5.3 Brushite 2.62 0.87 2.53 0.52 3.07 0.25

Relative saturation ratio Monosodium urate 0.51 0.20 0.95 0.33 1.45 0.44dd Monopotassiumurate 0.05 0.019 0.33 0.07d 0.12 0.04 Values are presented as mean SD. ' There is a significant difference between each alkali and control phase, determined by the paired i' test; it is shown by P<Øo5,'P<0.01and P <0.001. The significant differences between potassium citrate and sodium citrate phases are indicated in parentheses by the same footnotes.

sodium alkali treatment, whereas it remained undersaturated lithiasis. Five patients with uric acid stones were evaluated to when potassium citrate was given. compare the ability of potassium citrate therapy from that of The urinary FPR of calcium oxalate rose significantly during sodium citrate treatment in preventing the complication of oral potassium citrate treatment (Table I, Fig. 2). Thus, sponta- calcium nephrolithiasis. These patients gave a history of pas- neous precipitation of calcium oxalate commenced at a higher sage of a mixture of uric acid and calcium stones (calcium level of supersaturation when potassium was given. However, phosphate and/or calcium oxalate) or predominantly calcium FPR of calcium oxalate did not change significantly duringstones, coinciding with alkali therapy (sodium bicarbonate or sodium citrate therapy. The difference in FPR between the two sodium citrate). alkali phases was significant. In two of five patients. FPR When sodium citrate was given, no significant reduction in decreased by more than 30% (Fig. 2): thus, spontaneousurinary calcium ensued, despite the well-known effect of alkali precipitation was facilitated in some patients. The FPR oftherapy in lowering calcium excretion [29, 30]. The "hypocal- brushite was not significantly altered by either treatment. ciuric" action of alkali therapy was apparently attenuated by The saturation of monosodium urate (RSR) rose significantly the reduction of renal calcium reabsorption occurring from during both alkali phases, more so during sodium citrate sodium load given with alkali [311. Thus, urinary saturation of therapy (Table 1). The urinary environment became supersatu- calcium oxalate decreased modestly during sodium alkali thera- rated with respect to monosodium urate during sodium citrate py. Although urinary calcium did not change substantially. therapy, but remained undersaturated when potassium citrate urinary pH increased markedly during sodium citrate therapy. was given. The saturation of monopotassium urate (RSR)The resulting increased dissociation of phosphate led to an increased significantly during both alkali treatments, but more increased urinary saturation of calcium phosphate (brushite). so during potassium citrate therapy. Moreover, urinary saturation of monosodium urate rose because of increased dissociation of uric acid (from the rise in Discussion urinary pH) and since more sodium was delivered to urine (from The current study discloses that both potassium citrate and ingested sodium with alkali). The urinary environment became sodium citrate should be effective in the prevention of uric acid supersaturated with respect to brushite and monosodium urate lithiasis. The five patients with documented uric acid lithiasis when sodium citrate was given. initially passed uncommonly acid urine (pH < pK, for uric acid) During sodium citrate therapy, urinary citrate increased [28]. Thus, their urinary environment supported the crystalliza- nearly twofold. Although citrate is a recognized inhibitor of tion of uric acid. Treatment with either alkali significantlycalcium oxalate crystallization [32, 33], no significant change raised their urinary pH to a range where uric acid is more was observed in the urinary inhibitor activity as assessed by the soluble. FPR of calcium oxalate for the whole group of five patients. However, the two forms of alkali may exert different actions Two patients had a substantial reduction in the FPR, a finding with respect to complication or prevention of calcium nephro- suggesting that spontaneous precipitation of calcium oxalate Potassium citrate and sodium citrate therapeutic effects 351

250 5 S a) Ca 4 200 a) 0) xa) E 0 3 :$ E E

C.' C-) a) a) 2- C-) >C.) a) 0 C 0L —

1000

'a 0 E a) 'V

C-) >- a) C 200 :3 E0 — — — Control Potassium Sodium Sodium citrate citrate Control Potassium citrate citrate Fig.1. Effect of potassium and sodium citrate therapies on urinary calcium and citrate in patients with uric acid lithiasis. Each line Fig.2. Effect of potassium and sodium citrate therapies on urinary activity product ratio (APR) and formation product ratio (FPR) of represents a study in separate patients. Horizontal bars indicate group calcium oxalate in patients with uric acid lithiasis. Symbols are: * for P means. Significant difference from the control phase is shown by ** for P < 0.01 and t for P < 0.001. <0.05 and ** for P <0.01.

was facilitated by sodium citrate therapy. Though not conclu- environmentwas undersaturated with respect to monopotas- sively proven, there is some evidence for the scheme indicatingsium urate, probably because of the high solubility of this urate participation of monosodium urate in initiating calcium oxalatephase [25]. crystallization [26, 34—37]. Since sodium citrate therapy is Potassium citrate significantly increased urinary citrate ex- accompanied by urinary supersaturation with monosodium cretion, as has been reported with alkali therapy [38—421. The urate, the urate-induced facilitation of calcium oxalate nucle-increase in urinary citrate was more prominent than that ation could have opposed the inhibitory effect of citrate. encountered with sodium citrate therapy. Though not signifi- The results suggest that sodium citrate does not prevent thecant, this difference could be due to the effect of the potassium complication of calcium nephrolithiasis when given to patientsion on citrate metabolism [43—45]. Unlike the situation with with uric acid stones. It might cause this complication because sodium citrate therapy, the rise in urinary citrate occurring from of increased urinary saturation of calcium phosphate, and inpotassium citrate therapy was accompanied by an inhibition of some patients when the effect of monosodium urate-inducedthe spontaneous precipitation of calcium oxalate (indicated by a calcium oxalate crystallization overrides the inhibitory action ofrise in FPR). Thus, the inhibitory effect of citrate was apparent- citrate. ly unopposed by the urate-induced crystallization of calcium In contrast to the action of sodium citrate, potassium citrateoxalate. This conclusion is supported by the maintenance of at the same equimolar dosage significantly reduced urinary urinary undersaturation with respect to both monosodium urate calcium excretion. Since additional sodium was not given withand monopotassium urate during potassium citrate therapy. alkali, the hypocalciuric effect of alkali load [29, 30] was Even if urinary supersaturation of monopotassium urate had apparently unopposed. Owing principally to the fall in urinary been achieved, it is unlikely that calcium oxalate crystallization calcium, urinary saturation of calcium oxalate decreased signifi- would have been facilitated. It has been difficult to show the cantly to a greater extent than during sodium citrate therapy. participation of this urate phase in calcium oxalate crystalliza- Moreover, the urinary environment remained undersaturated tion [37]. with respect to brushite, because the effect of increased phos- From these considerations, this study suggests that potassi- phate dissociation was opposed by a decline in urinary calcium. um citrate, unlike sodium citrate, may prevent the complication The urinary environment also remained undersaturated withof calcium oxalate nephrolithiasis when given to patients with respect to monosodium urate during potassium citrate treat-uric acid lithiasis, by reducing urinary saturation and inhibiting ment, since no sodium was delivered with alkali. Potassiumspontaneous precipitation of calcium oxalate. It is acknowl- citrate significantly increased the urinary saturation of monopo-edged that a mixture of sodium citrate and potassium citrate has tassium urate owing to increased delivery of potassium to urineoften been used as an alkalinizing agent in the management of and enhanced dissociation of urate. However, the urinaryuric acid stones. Whether the sodium contained in this mixture 352 Sakhaee et a! would exert the same "undesirable" effect as pure sodium of citric acid. J Lab Clin Med 54:125—131, 1959 citrate used in this study remains to be determined. 23. CHANEY AL, MARBACH EP: Modified reagents for determination of urea and ammonia. C/in Chim 8:130—132, 1962 Acknowledgments 24. PAK CYC, HOLT K: Nucleation and growth of brushite and calcium oxalate in urine of stone formers. Metabolism 25:665—673. 1976 This work was supported by United States Public Health Service 25. PAK CYC, WATERS 0, ARNOLD L, Cox C, BARILLA D: Mechanism grant R0l-AM16061, Program Project P0l-AM20543, and GCRC MO!- for calcium urolithiasis among patients with hyperuricosuria: Su- RR00633. The authors thank J. Becknal and F. Britton for technical persaturation of urine with respect to monosodium orate. J C/in assistance and L. Dieterich for secretarial assistance. Invest 59:426—431, 1977 26. PAK CYC, BARILLA DE, HOLT K, BRINKLEY L, TOLENTINO R, Reprint requests to Dr. K. Sakhaee, Department of Internal Medi- ZERWEKH JE: Effect of oral purine load and allopurinol on the cine, General Clinical Research Center, University of Texas Health crystallization of calcium salts in urine of patients with hyperurico- Science Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235, suric calcium urolithiasis. Am J Med 65:593—599, 1978 USA 27. 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