Citrate and Renal Calculi: New Insights and Future Directions Charles Y.C. Pak, MD • Citrate is pathogenetically important in stone formation, because it retards the crystallization of stone-forming calcium salts and because its level in urine is low in many patients with nephrolithiasis. Potassium citrate is useful therapeutically, because it can often restore normal urinary citrate. Hypocitraturia often results from dietary aberrations, including sodium excess, and exaggerated intake of animal proteins. Hypocitraturia is frequently accompanied by a low net gastrointestinal absorption of alkali. New drugs are under development as improvements or refinements of currently available potassium citrate. They are potassium citrate 10-mEq-tablet preparation, effervescent calcium citrate, and potassium-magnesium citrate. © 1991 by the National Kidney Foundation, Inc. INDEX WORDS: Citrate; potassium citrate; hypocitraturia.
D
URING THE PAST decade, citrate has received increasing and renewed interest as an important pathogenetic factor in stone formation and as an exciting modality in the prevention of new stone formation.! The physicochemical background responsible for the inhibitor activity of citrate has been largely elucidated. It is now generally recognized that hypocitraturia is a frequent biochemical disturbance among patients with nephrolithiasis. The approval of potassium citrate by the Food and Drug Administration (FDA) in 1985 has introduced a new dimension for the management of a wide variety of stone-forming disorders. However, it is clear that the potential therapeutic role of alkali had been appreciated for many years before. In 1826, Sir Astley Cooper prescribed "liquor potasse, potassium carbonate, and sodium carbonate" for nephrolithiasis, presumably for stones of uric acid composition. 2 In 1954, Howard used a mixture of sodium citrate, potassium citrate, and citric acid as an alkalinizing agent to treat patients with stones composed of uric acid or cystine. 3 In 1981, Gregory et al administered to patients with enteric hyperoxaluria, sodium bicarbonate at a dosage sufficient to alkalinize the From the Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center at Dallas, Dallas, TX. Supported by Public Health Service Grants No. P01DK20543 and M01-RR00633. Address reprint requests to Charles yc. Pak, MD, Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75235. © 1991 by the National Kidney Foundation, 1nc. 0272-6386/9111704-0014$3.00/0
420
urine. 4 They observed a reduction in urinary calcium, urinary saturation of calcium oxalate, and crystalluria. The principal reasons for the recent rejuvenation in citrate research are the facility with which urinary citrate can now be measured and the availability of drugs to ameliorate hypocitraturia. I have been fortunate in being a part of this exciting development. This involvement would not have been as successful without the background research and personal encouragement of our colleague and friend, whom we are honoring at this symposium. While much progress has been made, newexciting research opportunities await us. It is the object of this presentation to briefly review the pathogenetic and therapeutic role of citrate in nephrolithiasis, and to consider new insights and future directions in citrate research. REVIEW OF PAST CITRATE RESEARCH
Evidence That Citrate is an Inhibitor of Stone Formation Citrate retards the crystallization of stone-forming calcium salts by two broad means. First, it complexes calcium and reduces ionic calcium concentration in urine. 5 .6 Second, citrate directly inhibits crystallization of calcium oxalate and calcium phosphate. Citrate has been shown to inhibit spontaneous precipitation of calcium oxalate7 and to retard agglomeration of preformed calcium oxalate crystals. 8 Citrate has a modest inhibitory effect against crystal growth of calcium oxalate when corrected for the reduction in activity product occurring from ion pair formation. 5 Citrate is believed to be a more potent inhibitor of the crystal
American Journal of Kidney Diseases, Vol XVII, No 4 (April), 1991: pp 420-425
CITRATE AND RENAL CALCULI
growth of calcium phosphate. Finally, citrate has been found to prevent heterogeneous nucleation of calcium oxalate by monosodium urate. 9 Frequent Occurrence of Hypocitraturia in Nephrolithiasis
Hypocitraturia has been reported in 19% to 63% of patients with nephrolithiasis in various reports. I In the laboratory at Dallas, the lower normal limit for citrate has been established at 1.69 mmol/d (320 mg/d) for both men and women, and irrespective of age (> 18 years). In distal renal tubular acidosis (complete, as well as incomplete), urinary citrate is invariably less than 1.69 mmol/d (320 mg/d). \0 This limit provides a good empirical definition of hypocitraturia, since patients with urinary citrate below this level often show a superior clinical response to potassium citrate therapy than those whose citrate exceeds 1.69 mmol/d (320 mg/d).11 Physiological Action of Potassium Citrate
Under normal circumstances, most of the potassium citrate that is taken orally is probably absorbed. The absorbed citrate is largely oxidized in vivo, whereas the potassium ion remains, thus leaving an alkali load. The alkali load raises urinary citrate by affecting renal citrate handling, as well as by increasing urinary pH. In the presence of hypokalemia, the potassium ion itself may augment citrate excretion by correcting intracellular acidosis. Physicochemical Action of Potassium Citrate
The physicochemical effects of potassium citrate therapy may be ascribed to its citraturic and alkalinizing action. I There is an inhibition of the crystallization of calcium oxalate in urine due to the increase in urinary citrate1.12 by mechanisms previously described. Moreover, the rise in urinary pH contributes to the retardation of the crystallization of calcium oxalate, and inhibits uric acid crystallization. At a higher pH, more phosphate and citrate ions become dissociated, augmenting the complexation of calcium. The resulting reduction in ionized calcium concentration lowers urinary saturation of stone-forming calcium salts. The further dissociation of citrate, pyrophosphate, and certain macromolecules may accentuate their inhibitor activity against crystallization of calcium
421
salts. Finally, the rise in urinary pH increases the dissociation of uric acid, reducing the concentration of undissociated uric acid and the propensity for uric acid lithiasis. \3 NEW INSIGHTS IN CITRATE RESEARCH
Origin of Citraturic Response to Potassium Citrate Treatment
The increase in urinary citrate following potassium citrate therapy has been traditionally ascribed to the provision of alkali, which then alters the renal citrate handling of citrate. Our recent study suggests another pathway. Five normal subjects stabilized on a constant dietary regimen were challenged with 50 mEq citric acid orally. During the succeeding 4 hours, urinary citrate significantly increased (above the corresponding placebo values), commensurate with an increase in serum citrate. Since there was no change in acid-base status, the results suggested that some of the absorbed citrate escapes in vivo oxidation and appears in urine. This route probably accounts for about 20% of citraturic response to potassium citrate therapy. Gastrointestinal Etiology for Hypocitraturia
The importance of acidosis as a cause of hypocitraturia was previously recognized. Thus, hypocitraturia was encountered in distal renal tubular acidosis,14 chronic diarrheal states (acquired metabolic acidosis),15 and thiazide-induced hypokalemia (intracellular acidosis).16 However, in many patients with hypocitraturic calcium nephrolithiasis, the exact cause for low citrate excretion was not disclosed. Recently, some clarification of "idiopathic" hypocitraturia has been made. Sodium-induced hypocitraturia. Using an uncontrolled diet, a high sodium intake was shown to reduce citrate excretion in a preliminary study. 17 We sought confirmation in 14 normal subjects maintained on a constant dietary regimen (50 mEq sodium/d). When sodium intake was increased to 300 mEq/d (by addition of sodium chloride), urinary citrate decreased significantly from 3.14 to 2.50 mmol/d (593 to 473 mg/d) (P
D
URING THE PAST decade, citrate has received increasing and renewed interest as an important pathogenetic factor in stone formation and as an exciting modality in the prevention of new stone formation.! The physicochemical background responsible for the inhibitor activity of citrate has been largely elucidated. It is now generally recognized that hypocitraturia is a frequent biochemical disturbance among patients with nephrolithiasis. The approval of potassium citrate by the Food and Drug Administration (FDA) in 1985 has introduced a new dimension for the management of a wide variety of stone-forming disorders. However, it is clear that the potential therapeutic role of alkali had been appreciated for many years before. In 1826, Sir Astley Cooper prescribed "liquor potasse, potassium carbonate, and sodium carbonate" for nephrolithiasis, presumably for stones of uric acid composition. 2 In 1954, Howard used a mixture of sodium citrate, potassium citrate, and citric acid as an alkalinizing agent to treat patients with stones composed of uric acid or cystine. 3 In 1981, Gregory et al administered to patients with enteric hyperoxaluria, sodium bicarbonate at a dosage sufficient to alkalinize the From the Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center at Dallas, Dallas, TX. Supported by Public Health Service Grants No. P01DK20543 and M01-RR00633. Address reprint requests to Charles yc. Pak, MD, Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75235. © 1991 by the National Kidney Foundation, 1nc. 0272-6386/9111704-0014$3.00/0
420
urine. 4 They observed a reduction in urinary calcium, urinary saturation of calcium oxalate, and crystalluria. The principal reasons for the recent rejuvenation in citrate research are the facility with which urinary citrate can now be measured and the availability of drugs to ameliorate hypocitraturia. I have been fortunate in being a part of this exciting development. This involvement would not have been as successful without the background research and personal encouragement of our colleague and friend, whom we are honoring at this symposium. While much progress has been made, newexciting research opportunities await us. It is the object of this presentation to briefly review the pathogenetic and therapeutic role of citrate in nephrolithiasis, and to consider new insights and future directions in citrate research. REVIEW OF PAST CITRATE RESEARCH
Evidence That Citrate is an Inhibitor of Stone Formation Citrate retards the crystallization of stone-forming calcium salts by two broad means. First, it complexes calcium and reduces ionic calcium concentration in urine. 5 .6 Second, citrate directly inhibits crystallization of calcium oxalate and calcium phosphate. Citrate has been shown to inhibit spontaneous precipitation of calcium oxalate7 and to retard agglomeration of preformed calcium oxalate crystals. 8 Citrate has a modest inhibitory effect against crystal growth of calcium oxalate when corrected for the reduction in activity product occurring from ion pair formation. 5 Citrate is believed to be a more potent inhibitor of the crystal
American Journal of Kidney Diseases, Vol XVII, No 4 (April), 1991: pp 420-425
CITRATE AND RENAL CALCULI
growth of calcium phosphate. Finally, citrate has been found to prevent heterogeneous nucleation of calcium oxalate by monosodium urate. 9 Frequent Occurrence of Hypocitraturia in Nephrolithiasis
Hypocitraturia has been reported in 19% to 63% of patients with nephrolithiasis in various reports. I In the laboratory at Dallas, the lower normal limit for citrate has been established at 1.69 mmol/d (320 mg/d) for both men and women, and irrespective of age (> 18 years). In distal renal tubular acidosis (complete, as well as incomplete), urinary citrate is invariably less than 1.69 mmol/d (320 mg/d). \0 This limit provides a good empirical definition of hypocitraturia, since patients with urinary citrate below this level often show a superior clinical response to potassium citrate therapy than those whose citrate exceeds 1.69 mmol/d (320 mg/d).11 Physiological Action of Potassium Citrate
Under normal circumstances, most of the potassium citrate that is taken orally is probably absorbed. The absorbed citrate is largely oxidized in vivo, whereas the potassium ion remains, thus leaving an alkali load. The alkali load raises urinary citrate by affecting renal citrate handling, as well as by increasing urinary pH. In the presence of hypokalemia, the potassium ion itself may augment citrate excretion by correcting intracellular acidosis. Physicochemical Action of Potassium Citrate
The physicochemical effects of potassium citrate therapy may be ascribed to its citraturic and alkalinizing action. I There is an inhibition of the crystallization of calcium oxalate in urine due to the increase in urinary citrate1.12 by mechanisms previously described. Moreover, the rise in urinary pH contributes to the retardation of the crystallization of calcium oxalate, and inhibits uric acid crystallization. At a higher pH, more phosphate and citrate ions become dissociated, augmenting the complexation of calcium. The resulting reduction in ionized calcium concentration lowers urinary saturation of stone-forming calcium salts. The further dissociation of citrate, pyrophosphate, and certain macromolecules may accentuate their inhibitor activity against crystallization of calcium
421
salts. Finally, the rise in urinary pH increases the dissociation of uric acid, reducing the concentration of undissociated uric acid and the propensity for uric acid lithiasis. \3 NEW INSIGHTS IN CITRATE RESEARCH
Origin of Citraturic Response to Potassium Citrate Treatment
The increase in urinary citrate following potassium citrate therapy has been traditionally ascribed to the provision of alkali, which then alters the renal citrate handling of citrate. Our recent study suggests another pathway. Five normal subjects stabilized on a constant dietary regimen were challenged with 50 mEq citric acid orally. During the succeeding 4 hours, urinary citrate significantly increased (above the corresponding placebo values), commensurate with an increase in serum citrate. Since there was no change in acid-base status, the results suggested that some of the absorbed citrate escapes in vivo oxidation and appears in urine. This route probably accounts for about 20% of citraturic response to potassium citrate therapy. Gastrointestinal Etiology for Hypocitraturia
The importance of acidosis as a cause of hypocitraturia was previously recognized. Thus, hypocitraturia was encountered in distal renal tubular acidosis,14 chronic diarrheal states (acquired metabolic acidosis),15 and thiazide-induced hypokalemia (intracellular acidosis).16 However, in many patients with hypocitraturic calcium nephrolithiasis, the exact cause for low citrate excretion was not disclosed. Recently, some clarification of "idiopathic" hypocitraturia has been made. Sodium-induced hypocitraturia. Using an uncontrolled diet, a high sodium intake was shown to reduce citrate excretion in a preliminary study. 17 We sought confirmation in 14 normal subjects maintained on a constant dietary regimen (50 mEq sodium/d). When sodium intake was increased to 300 mEq/d (by addition of sodium chloride), urinary citrate decreased significantly from 3.14 to 2.50 mmol/d (593 to 473 mg/d) (P
