Hypocitraturia: Pathophysiology and Medical Management

Management Review

5. RIU0424_10-22.qxd 10/22/09 4:26 PM Page 134 MANAGEMENT REVIEW Hypocitraturia: Pathophysiology and Medical Management Jack M. Zuckerman, BS, Dean G. Assimos, MD Department of Urology, Wake Forest University School of Medicine, Winston-Salem, NC Low urinary citrate excretion is a known risk factor for the development of kidney stones. Citrate inhibits stone formation by complexing with calcium in the urine, inhibiting spontaneous nucleation, and preventing growth and agglomeration of crystals. Hypocitraturia is a common metabolic abnormality found in 20% to 60% of stone formers. It is most commonly idiopathic in origin but may be caused by distal renal tubular acidosis, hypokalemia, bowel dysfunction, and a high-protein, low-alkali diet. Genetic factors, medications, and other comorbid disorders also play a role. Hypocitraturia should be managed through a combination of dietary modifications, oral alkali, and possibly lemonade or other citrus juice–based therapy. This review concerns the pathophysiology of hypocitraturia and the management of stone formers afflicted with this abnormality. [Rev Urol. 2009;11(3):134-144 doi:10.3909/riu0424] © 2009 MedReviews®, LLC Key words: Hypocitraturia • Citrate metabolism • Citrate pathophysiology • Hypocitraturia etiologies • Medical management of stone disease • Alkali citrate • Potassium citrate • Citrus juice • Lemonade ow urinary citrate excretion is a known risk factor for the development of kidney stones.1 Hypocitraturia, generally defined as urinary citrate excretion less than 320 mg (1.67 mmol) per day for adults,2 is a common metabolic abnormality in stone formers, occurring in 20% to 60%.1,3-6 Citrate is a known inhibitor of stone formation, working through a variety of mechanisms. In the renal tubule citrate complexes with calcium, increasing its solubility and reducing the concentration of free calcium in the urine. This calcium-citrate complex L 134 VOL. 11 NO. 3 2009 REVIEWS IN UROLOGY 5. RIU0424_10-22.qxd 10/22/09 4:26 PM Page 135 Hypocitraturia limits calcium supersaturation and prevents nucleation of both calcium oxalate and calcium phosphate, at least partly through interactions with Tamm-Horsfall protein.7,8 Additionally, citrate prevents crystal agglomeration and growth through its ability to bind to the crystal’s surface and may also prevent adhesion of calcium oxalate to renal epithelial cells.9-11 Hypocitraturia may be corrected with dietary modifications and the administration of citrate preparations or other forms of alkali therapy. Citrate excretion is linked to urinary pH and thus may influence the generation of a number of types of stones. Herein we review the pathophysiology of hypocitraturia and the management of stone formers with this abnormality. reabsorption takes place predominantly in the proximal tubule.16 Because there is currently no evidence that significant citrate secretion occurs in the nephron, the extent of reabsorption largely regulates citrate excretion.16 In humans, 65% to 90% of the filtered load of citrate is reabsorbed.17,18 Transport of citrate across the apical membrane in the proximal tubule has been extensively studied. First cloned by Pajor,19 the dominant membrane protein is a sodium-dependent dicarboxylate transporter (NaDC-1) found not only in renal tubules, but also in the small intestine, colon, liver, and brain.18 The NaDC-1 transporter has broad specificity; it is also used by other TCA intermediates, including succinate and -ketoglutarate (Figure 1).20,21 Apical membrane reabsorption of citrate is an electrogenic process requiring secondary active transport that is highly pH dependent.18 The binding of 3 sodium ions induces a conformational change in the NaDC protein, which allows their cotransport with 1 uncomplexed, divalent citrate molecule (citrate2).22 This movement of ions creates the net transfer of a positive charge into the cell, relying on a basolateral Na/K adenosine triphosphatase to maintain electrical neutrality. Whereas the Km for this reaction is approximately 15 M/L, the Km for the transport of trivalent citrate (citrate3) is far greater. Thus, more of the former is transported, whereas the latter acts as a competitive inhibitor.23 The pKa of citrate is 5.6; thus the majority of citrate exists as citrate3 in the renal Citrate Physiology Overview Citrate, a tricarboxylic acid, is synthesized in mitochondria from oxaloacetate and acetyl-CoA (coenzyme A) by the enzyme citrate synthase; it is a central component of the tricarboxylic acid (TCA) cycle. After first describing TCA cycle reactions, Krebs and colleagues12,13 demonstrated that citrate is excreted in urine. Through its metabolism in the TCA cycle, citrate generates a significant amount of energy through reduced nicotinamide-adenine dinucleotide, guanosine triphosphate, and reduced flavin– adenine dinucleotide, creating CO2 and H2O in this process. If all the citrate in the kidney were metabolized, it would provide 10% of the renal energy requirement.14 Figure 1. Representation of proximal tubule citrate absorption and metabolism. CoA, coenzyme A; ATP, adenosine triphosphate. Proximal Tubule Cell Tubule Lumen Oxaloacetate  Acetyle-CoA 2K ATPase ATP Citrate Lyase CoA 3 Na Citrate3 H Citrate2 Citrate NaDC-1 Citrate3 3 Na 3 Na CO2 Mitochondria Citrate Citrate m-aconitase Isocitrate Renal Transport In serum, the concentration of citrate is relatively constant, ranging from 0.05 mM to 0.3 mM.15 The majority of citrate exists complexed to divalent ions, such as calcium and magnesium, and is filtered freely at the glomerulus; VOL. 11 NO. 3 2009 REVIEWS IN UROLOGY 135 5. RIU0424_10-22.qxd 10/22/09 4:26 PM Page 136 Hypocitraturia continued tubule.17 These properties reflect the important role that pH has in the regulation of citrate absorption in the nephron. Once absorbed through the apical membrane of the proximal tubule, citrate does not pass through a basolateral transporter into the interstitium. In fact, there is some evidence that citrate moves in the opposite direction, though transport across this membrane is not well understood.24 Unlike the movement of citrate across the apical membrane, transport on the basolateral side into proximal tubular cells is electroneutral and not affected by changes in pH.25 This transport is also sodium dependent. Citrate is thought to be absorbed across the basolateral membrane and into proximal tubular cells in its trivalent form, reflecting its pH independence.25 Renal Citrate Metabolism A portion of the citrate absorbed in the kidney will pass into the mitochondria for utilization in the TCA cycle.18 Adenosine triphosphate citrate lyase, however, reacts with some of the citrate while it remains in the cytoplasm.26 This enzyme catalyzes the conversion of citrate and CoA to oxaloacetate and acetyl-CoA. AcetylCoA produced through this pathway may be used in the synthesis of fatty acids and cholesterol and is also involved in other types of metabolism. Oxaloacetate is a substrate for gluconeogenesis, which is catalyzed by the enzyme phosphoenolpyruvate carboxykinase.26 Gastrointestinal Citrate Absorption Information about the intestinal absorption of citrate is limited. It is thought that citrate absorption in the small intestine uses the same NaDC transporter as the proximal tubule.19,27,28 Such transporters have also been found in membranes within the intestines of several animal 136 VOL. 11 NO. 3 2009 species.29-34 Clinically, there is strong evidence for intestinal absorption of citrate. Fegan and associates,35 using an intestinal washout technique, reported 96% to 98% absorption of an oral citrate load within 3 hours in both stone-forming and normal subjects. Others have demonstrated a significant increase in serum citrate after an oral citrate load.36 Patients with intestinal malabsorption syndromes tend to have low urinary citrate excretion,37 but this association is thought to be due to gastrointestinal bicarbonate wasting.38,39 In contrast to renal citrate transport, there is evidence for citrate efflux from intestinal enterocytes.32 pH Regulation of Citrate Excretion Modulation of citrate excretion in the kidney is influenced by multiple factors; however, pH (systemic, tubular, and intracellular) has the strongest impact. It has long been known that acidosis decreases renal citrate excretion, whereas alkalosis increases it.40,41 There are several mechanisms through which pH exerts these effects. As noted previously, citrate is reabsorbed through the sodium citrate cotransporter as citrate2 but exists predominately as citrate3 within In addition to increased capability to transport citrate in acidotic states, acidosis drives citrate metabolism. This is demonstrated by an increase in citrate reabsorption and decreased citrate tissue levels reported with acidosis.18 Intracellular acidosis has been shown to increase mitochondrial citrate transport and oxidation.18 Alkalosis, which produces the opposite effect, is thought to be modulated at least partly through pH regulation of the mitochondrial enzyme aconitase (m-aconitase).45 m-Aconitase is the enzyme responsible for the first step in citrate metabolism within the mitochondria. Alkali feeding decreases the activity and amount of this enzyme, thus inhibiting citrate metabolism; acidosis increases the activity of the enzyme.45 In addition to mitochondrial oxidation, intracellular acidosis increases citrate metabolism in the cytoplasm through increased activity of adenosine triphosphate citrate lyase.26 Products of both cytoplasmic and mitochondrial metabolism are further metabolized by phosphoenolpyruvate carboxykinase, whose activity is also increased with acidosis.46 Although these metabolic changes are also seen with reductions in systemic pH, hypokalemia produces similar effects, Even small decreases in tubular pH (7.4 to 7.2) significantly increase tubular reabsorption. renal tubules. Lowering tubular pH increases the concentration of citrate2 available for transport and reduces the concentration of citrate3, thereby limiting its competitive inhibition. Even small decreases in tubular pH (7.4 to 7.2) significantly increase tubular reabsorption.42 Acute acidosis is associated with increased activity of the NaDC transporter,43 and chronic acidosis leads to increased transporter messenger ribonucleic acid and the transporter itself.44 REVIEWS IN UROLOGY suggesting a strong intracellular component to pH regulation of citrate metabolism.18,26,45 Etiologies Although the majority of patients have idiopathic hypocitraturia, there are a number of causes for this abnormality, which are reviewed here (Table 1). Renal Tubular Acidosis Distal renal tubular acidosis (dRTA) significantly reduces citrate excretion, 5. RIU0424_10-22.qxd 10/22/09 4:26 PM Page 137 Hypocitraturia Table 1 Etiologies of Hypocitraturia Acid-base balance Renal tubular acidosis Other systemic acidosis Diarrhea/malabsorption Exercise Hypokalemia Diet Dietary animal protein High sodium intake Ketosis promoting diets Low fruit/vegetable intake Starvation Medications ACE inhibitors Acetazolamide Amiloride Calcitonin Calcium Ethacrynic acid Lithium Topiramate Vitamin D Genetic influence VDR polymorphisms NaDC-1 gene polymorphisms Other associated disorders Renal insufficiency Hyperaldosteronism Type I glycogen storage disease Hypocalciuria, hypomagnesuria Precursor compounds Metabolic inhibitors ACE, angiotensin-converting enzyme; VDR, vitamin D receptor. producing urinary citrate less than 100 mg/d in the complete form of the disease.47,48 Incomplete dRTA poses less risk for stone development49; however, it is still associated with hypocitraturia in the absence of systemic acidosis.50 Compared with complete dRTA, incomplete dRTA is not as clinically apparent and may be the pathology underlying many “idiopathic” hypocitraturic patients.51 This diagnosis has been made with acid load testing. However, this is not a clinically necessary test because the treatment is similar to that of idiopathic hypocitraturia. The systemic and intracellular acidosis produced in both these disorders leads to decreased citrate excretion. The systemic acidosis occurring in complete dRTA may also cause increased calcium excretion due to the release of calcium from bone and reduced reabsorption in the nephron. These patients have increased urine pH. This and the other aforementioned abnormalities place them at risk for calcium phosphate stone formation. Other forms of renal tubular acidosis are not associated with the same stone risks. Type II RTA is not associated with either increased stone formation or hypocitraturia,48 and type IV RTA may be protective against stone formation through decreased concentration of calcium and uric acid in the urine.52 Potassium Low urinary potassium is associated with hypocitraturia.53 Hypokalemia produces both intracellular acidosis54,55 and a decrease in tubular pH.56 As described above, these changes are associated with increased citrate uptake and metabolism. Additionally, similar to acidosis, hypokalemia has been shown to stimulate the NaDC cotransporter.57 Gastrointestinal Disorders Chronic diarrheal states and gastrointestinal malabsorption due to a variety of anatomic and functional bowel disorders are associated with hypocitraturia.37,49 A primary defect in citrate absorption has been suggested.58 However, the primary mechanism for this is thought to be gastrointestinal bicarbonate wasting resulting in acidosis and reduced citrate excretion.38,39,51,53 Diet Diets high in animal protein provide an acid load. This promotes mild metabolic acidosis, leading to reduced citrate excretion, hypercalciuria, and a reduction in urine pH.38,59,60 Severely carbohydrate-restricted and animal protein–rich diets, such as the Atkins diet, further exacerbate this metabolic acidosis through the creation of ketones. Compared with a normal diet, both the induction and maintenance phases of an Atkinstype diet promote lower urine pH and citrate excretion.60 Other forms of dietary protein may also influence citrate excretion. For example, rats fed a high-casein diet have lower citrate and increased calcium excretion. The reduced citrate excretion in these animals is thought to be due to increased activity of the NaDC transporter induced by casein.61 Fruits, vegetables, and dietary fiber, often under-consumed in stone patients, provide a source of alkali with the potential to reverse the effects of protein consumption.38,51 When these foods are removed from the diets of normal patients, they have decreased urinary citrate excretion and higher saturations of calcium oxalate and calcium phosphate; opposite changes are seen with increased consumption of fruits and vegetables.62 High-sodium diets, possibly through a mild expansion acidosis, decrease urinary citrate.63 Finally, starvation has been shown to increase citrate absorption through an increase in NaDC transporters and systemic acidosis.64 Genetic Associations Vitamin D receptor (VDR) gene polymorphisms are epidemiologically associated with recurrent and familial stone disease.65-67 In the nephron, 1,25(OH)2D3, the active form of vitamin D, utilizes the VDR to modulate citrate metabolism and transport.68 It also plays a role in the protein kinase pathway, altering the function of NaDC transporters.69 Recently, certain VDR gene polymorphisms, specifically VOL. 11 NO. 3 2009 REVIEWS IN UROLOGY 137 5. RIU0424_10-22.qxd 10/22/09 4:26 PM Page 138 Hypocitraturia continued the bb and TT subtypes, have been demonstrated with higher frequency in hypocitraturic stone formers when compared with both normocitraturic stone formers and normal controls.68 Certain VDR haplotypes are also associated with higher familial incidence of stone disease and lower mean age of onset.70 Shah and colleagues71 suggest further genetic influences on citrate handling. They propose a codominant inheritance of alleles at a single locus based on their trimodality frequency distribution for citrate excretion. This theory would account for the apparent “low,” “medium,” and “high” phenotypic expression found in their study, which is similar to what they found when investigating the genetics of calcium oxalate stone disease.72,73 There has also been recent identification of a single nucleotide polymorphism in the gene encoding NaDC-1, which may be associated with reduced urinary citrate excretion in recurrent stone formers.74 Ethnic background does not seem to play a role in citrate excretion.75 Other Factors Many drugs are associated with altered citrate excretion. Acetazolamide, a carbonic anhydrase inhibitor, is known to inhibit citrate excretion, increase urine pH, and place patients at risk for developing calcium phosphate stones.76 These changes have been prevented in rat proximal tubules by controlling luminal pH and in other animals by reversing systemic acidosis.17,42 Topiramate, a commonly prescribed antiepileptic drug, is also a carbonic anhydrase inhibitor and associated with increased risk of developing calcium phosphate stones.77,78 It has recently been shown to have a dosedependent effect on urinary citrate.79 Patients experienced an average 40% reduction in citrate at their starting 138 VOL. 11 NO. 3 2009 dose and a 65% reduction at higher doses. Angiotensin-converting enzyme inhibitors are associated with decreased urinary citrate, thought to be promoted by increased adenosine triphosphate citrate lyase activity.80 Thiazide-induced hypokalemia leads to decreased citrate excretion, whereas lithium, through its inhibition of citrate transport, has been shown to increase urinary citrate.81,82 Other medications noted to alter renal citrate excretion include amiloride, calcitonin, and ethacrynic acid.83 Several other disorders are known to affect citrate handling. Chronic renal insufficiency produces a stepwise reduction in filtered citrate, with decreases in glomerular filtration rate; however, increased fractional excretion keeps urinary citrate stable until the development of severe renal dysfunction.84 Primary hyperaldostero- urinary citrate levels.89 Both of these ions complex with citrate in the urine and prevent its interaction with the NaDC transporter. Additionally, a deficiency in magnesium places patients at risk for hypokalemia and makes potassium replacement less effective. Finally, metabolic inhibitors (malonate and maleate), as well as precursor compounds (malate, succinate, and fumarate), increase excretion of citrate.18 Medical Management Dietary modifications benefit the majority of patients with nephrolithiasis. These include high fluid and citrus fruit intake, normal calcium consumption, and restriction of sodium, oxalate, animal protein, and fructose intake.87,90 Increased consumption of fruits and vegetables has been demonstrated to significantly increase Increased consumption of fruits and vegetables has been demonstrated to significantly increase citrate excretion in hypocitraturic stone formers. nism, through a sodium-dependent volume expansion and chronic hypokalemia, is associated with both hypercalciuria and hypocitraturia.85 An association between type I glycogen storage disease and hypocitraturia has been reported.86 Paradoxically, there is a positive correlation between body mass index and urinary excretion of citrate, despite obesity being a risk factor for stone formation.87 Exercise has been shown to cause a mild reduction in urinary citrate, but dehydration increases free water reabsorption in the kidney, maintaining citrate concentration.88 Certain electrolytes and other organic acids alter citrate excretion. Increased urinary calcium and magnesium are both associated with increased excretion of citrate,17 and replacing magnesium in hypocitraturic patients has been shown to raise REVIEWS IN UROLOGY citrate excretion in hypocitraturic stone formers.62 The administration of citrate preparations or other alkali has been demonstrated to benefit hypocitraturic stone formers.91,92 Although many forms of citrate have been used for these patients (potassium citrate, sodium citrate, potassium-magnesium-citrate), potassium citrate has emerged as the most tolerable and beneficial.93,94 These citrate preparations raise urinary citrate by providing an alkali load. An advantage of the potassium preparations is that they may prevent or correct hypokalemia. They also increase urine pH, which benefits uric acid and cystine stone formers.48 Potassium citrate has also been demonstrated to prevent stone formation in patients with infection-related stones.95 It can be administered in conjunction with 5. RIU0424_10-22.qxd 10/22/09 4:26 PM Page 139 Hypocitraturia thiazide agents being used to reduce calcium excretion. Pak and associates81 demonstrated a reduction in stone formation from 4.69 to 0.57 stones per patient per year when potassium citrate was added to the medical regimen of thiazide-unresponsive patients. They also showed a significant increase in urinary citrate excretion and pH in these patients. Others have shown that the addition of either potassium citrate or potassium-magnesium-citrate was more beneficial than potassium chloride for stone prevention in thiazide-resistant patients.96,97 Potassium-magnesiumcitrate has not yet been approved for use in the United States. There have been 4 prospective randomized controlled trials aimed at preventing stone recurrence through the administration of citrate preparations. Treatment was for 3 years in 3 of these trials and for only 1 year for the other (Table 2).93,98-100 Two of these studies used potassium citrate, 1 used sodium-potassium-citrate, and 1 used magnesium-potassium-citrate. Citrate doses ranged from 60 to 90 mEq/d. Urinary citrate excretion on average increased 31% to 115% in the treatment groups, compared with no change in the control groups. In 3 of the 4 studies, significantly higher rates of stone remission were seen in the treatment groups (72%-100% treatment, 20%-71.4% control). However, Hofbauer and associates,99 using sodium-potassium-citrate, did not see a statistical difference in stone recurrence between the treatment and control groups. Barcelo and colleagues98 analyzed pre- and posttreatment procedure rates and found a significant 92% reduction in the treatment group, compared with a 20% reduction in the control group. In an intention-to-treat analysis of these 4 trials, Mattle and Hess101 reported that 53.5% of alkali citrate–treated patients remained stone free through at least 1 year of follow-up, compared with only 35% of control group patients. Two prospective randomized trials lasting at least 1 year looked at rates of stone clearance after shock wave lithotripsy (Table 3). Soygur and colleagues100 used potassium citrate therapy in patients with lower-pole renal stones. Cicerello and associates95 administered sodium-potassium-citrate to subjects with stones in various locations in the kidney. Both groups found that significantly more patients in the treatment groups were stone free at 1 year of follow-up (44%-86% treatment, 12.5%-40% control). Additionally, they both found that a significantly higher percentage of control group patients had stone growth at 1 year. Less than 5% of the alkali citrate–treated patients, compared with up to 62.5% of the control patients, had an increase in the size of their residual stones on follow-up radiographic and ultrasound examinations. Interestingly, Cicerello and colleagues95 reported that neither the treatment nor control patients with infection-related stones showed any progression in stone burden. On intention-to-treat analysis, 66% of alkali citrate–treated patients became stone free at 1 year, compared with only 27.5% of control patients, a statistically significant difference.95 Side effects of alkali citrate therapy are usually minimal and often gastrointestinally related. Among randomized controlled trial patients, approximately 33% of treated patients, compared with 17% of Table 2 Prospective, Randomized, Controlled Trials for the Treatment of Stone Recurrence With Alkali Citrate Therapy Lasting at Least 1 Year Duration (mo) Rx n Dropout Rate (%) Remission Rate (%) Average Increase in Citrate Excretion (%) Barcelo et al.98 36 K-Citrate Control 18 20 36 31 72.2 20 77 0 Hofbauer et al.99 36 Na-K-Citrate Control 22 16 36 12 31* 27 75 0 Ettinger et al.93 37 K-Mg-Citrate Control 31 33 48 24 87.1 36.5 31 0 Soygur et al.100 12 K-Citrate Control 28 28 NS NS 100 71.4 115 NS Study *No statistically significant difference. NS, not stated. VOL. 11 NO. 3 2009 REVIEWS IN UROLOGY 139 5. RIU0424_10-22.qxd 10/22/09 4:26 PM Page 140 Hypocitraturia continued Table 3 Prospective, Randomized, Controlled Trials for Elimination of Residual Calculi After Shock Wave Lithotripsy With Alkali Citrate Therapy Lasting at Least 1 Year Study Rx Duration (Months) n Drop Out Rate (%) Stone Free (%) Stone Size Increased (%) Cicerello et al.95 Na-K-Citrate Control 12 35 35 3 3 75 (Ca-Ox)/86 (Inf) 32 (Ca-Ox)/40 (Inf) 5 (Ca-Ox)/0 (Inf) 47 (Ca-Ox)/0 (Inf) Soygur et al.100 K-Citrate Control 12 18 16 NS NS 44.4 12.5 0 62.5 Ca-Ox, calcium oxalate stone formers; Inf, infection-related stone formers; NS, not stated. placebo-treated patients, reported side effects from the medication.101 Complaints included abdominal bloating, diarrhea, nausea, and abdominal pain. Potassium citrate is available in 3 formulations: tablets, crystals for dilution, and oral solution. Liquid preparations have been shown to produce need to be higher because these individuals have profound hypocitraturia and acidosis and are frequently hypokalemic. Patients being administered alkali therapy warrant follow-up with blood and urine testing. Serum electrolytes should be checked, urine pH mea- Side effects of alkali citrate therapy are usually minimal and often gastrointestinally related. more gastrointestinal side effects than tablets (33% vs 9.3%).91 Tablet potassium citrate, however, is not absorbed as completely as liquid preparations,35 and patients with chronic diarrheal syndromes typically have short gastrointestinal transit, which limits the effectiveness of potassium citrate tablets.102 Sodium-based alkali (sodium citrate, sodium bicarbonate) may need to be used in hypocitraturic patients who have diminished renal function or those who use potassiumsparing medications. This is mandated in those who are hyperkalemic. The dose of alkali is based on the degree of hypocitraturia and acidosis, as well as on patient size (pediatric patients). Typical doses of potassium citrate for adults with idiopathic hypocitraturia and normal renal function range from 40 to 60 mEq per day. The dose for those with dRTA may 140 VOL. 11 NO. 3 2009 sured, and 24-hour urine metabolic testing obtained. Urine pH may increase to a level that places the patient at risk for developing calcium phosphate stones. The latter stone type is becoming more prevalent, and some have questioned whether this could be due to the widespread use of potassium citrate.103,104 Therefore, if the pH is 7 or greater, the dose of alkali may need to be decreased. An exception is those with dRTA who have high baseline urine pH. Adjustments of alkali dose in these patients are mainly based on serum electrolytes and 24-hour urine testing. Patients who either cannot tolerate or cannot afford potassium citrate may benefit from consuming citrus juices, which contain significant amounts of citrate. Wabner and Pak105 compared orange juice consumption (1.2 L/d) with potassium citrate REVIEWS IN UROLOGY (60 mEq/d). Increases in urinary pH and citrate excretion were similar for both. Orange juice, however, did not decrease urinary saturation of calcium oxalate, whereas potassium citrate did. Grapefruit juice, although shown to have significantly higher levels of citrate than orange juice,106,107 does not seem to reduce urinary risk factors for stone formation.108 Additionally, grapefruit inhibits cytochrome p-450, thereby altering the metabolism of many commonly used medications. Lemonade has been reported to increase citrate consumption. This was initially reported by Seltzer and associates,109 who had hypocitraturic patients consume 2 L of a lemonade preparation per day (120 mL of concentrated lemon diluted up to 2 L with water). Citrate excretion increased 144%. Kang and associates110 retrospectively compared the outcomes of patients receiving lemonade therapy (120 mL concentrated lemon juice diluted to 2 L with water) with those of patients receiving potassium citrate (40 mEq/d). They reported significant increases in renal excretion of citrate in both the lemonade and the potassium citrate groups; however, compared with lemonade consumption, patients taking potassium citrate had significantly greater increases in urinary citrate excretion, as well as 5. RIU0424_10-22.qxd 10/22/09 4:26 PM Page 141 Hypocitraturia increases in urine pH. Urine pH was not altered by lemonade.110 However, not all studies on lemonade therapy have demonstrated positive results. Penniston and associates111 compared lemonade therapy (either 120 mL of concentrated lemon juice diluted in water or 1 L of sugar-free lemonade) with lemonade therapy (same preparation) combined with potassium citrate (20-90 mEq per day). Although both regimens initially promoted a significant increase in citrate excretion, only the potassium citrate cohort had a durable response. Koff and colleagues112 performed a cross-over comparison of potassium citrate (60 mEq/d) and lemonade (90 mL of concentrated lemon juice diluted in 532 mL of water). Potassium citrate consumption significantly increased pH and citrate excretion, whereas this did not occur with lemonade. Odvina and colleagues97 performed a study in which other nutrients were controlled. Lemonade (1200 mL/d), distilled water (1200 mL/d), and orange juice (1200 mL/d) were administered in a cross-over design. Only orange juice resulted in an increase in urine pH and citrate excretion. This investigator thought that this difference was due to orange juice having high potassium citrate content as compared with lemonade, which has a high level of citric acid. The former would theoretically result in an increased alkali load, whereas with the latter the benefits of citrate would be contained significant amounts of citrate; however, both contained less than lemon and lime juices. In a similar study, Haleblian and associates106 used nuclear magnetic resonance spectroscopy to quantify citrate content. Using this technique, they found grapefruit juice to have the highest citrate content, followed by lemon juice and orange juice. They also Grapefruit juice and orange juice contained significant amounts of citrate; however, both contained less than lemon and lime juices. negated by the accompanying hydrogen proton that neutralizes the effects of citrate. The citric acid contents of various juice preparations have been measured. Penniston and colleagues107 quantified citrate content in natural and commercially available fruit juices, using ion chromatography. They found that natural lemon and lime juice contain the greatest quantity of citric acid, followed closely by lemon and lime juice concentrates. Grapefruit juice and orange juice found that among low-calorie beverages, Crystal Light® lemonade (Kraft Foods, Glenview, IL) had the highest citrate levels. Conclusions Citrate is a urinary inhibitor of the crystallization of several stoneforming salts. Citrate excretion is modulated by systemic factors, including acidosis. It may also be impacted by nephron dysfunction, such as dRTA, and may be influenced by medications and diet. Main Points • Hypocitraturia, generally defined as urinary citrate excretion less than 320 mg (1.67 mmol) per day for adults, is a common metabolic abnormality in stone formers, occurring in 20% to 60%. • Modulation of citrate excretion in the kidney is influenced by multiple factors; however, pH (systemic, tubular, and intracellular) has the strongest impact. • Although the majority of patients have idiopathic hypocitraturia, there are a number of causes for this abnormality, including distal renal tubular acidosis, hypokalemia, bowel dysfunction, and a high-protein, low-alkali diet. • Other factors associated with altered citrate excretion include genetic factors, certain drugs (eg, acetazolamide, topiramate, angiotensin-converting enzyme inhibitors, and thiazide), renal insufficiency, hyperaldosteronism, type I glycogen storage disease, and exercise. • Dietary modifications benefit the majority of patients with nephrolithiasis. These include high fluid and citrus fruit intake, normal calcium consumption, and restriction of sodium, oxalate, animal protein, and fructose intake. • The administration of citrate preparations or other alkali has been demonstrated to benefit hypocitraturic stone formers. Although many forms of citrate have been used for these patients (potassium citrate, sodium citrate, potassium-magnesium-citrate), potassium citrate has emerged as the most beneficial. • Patients who either cannot tolerate or cannot afford potassium citrate may benefit from consuming citrus juices, which contain significant amounts of citrate. VOL. 11 NO. 3 2009 REVIEWS IN UROLOGY 141 5. RIU0424_10-22.qxd 10/22/09 4:26 PM Page 142 Hypocitraturia continued Hypocitraturia is a risk factor for stone formation. There is solid evidence that correction of this abnormality with medical therapy reduces stone risk. Dietary modifications should also be used in conjunction with medical therapy. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 142 Curhan GC, Taylor EN. 24-h uric acid excretion and the risk of kidney stones. Kidney Int. 2008; 73:489-496. Chow K, Dixon J, Gilpin S, et al. Citrate inhibits growth of residual fragments in an in vitro model of calcium oxalate renal stones. Kidney Int. 2004;65:1724-1730. Nicar MJ, Skurla C, Sakhaee K, Pak CY. Low urinary citrate excretion in nephrolithiasis. Urology. 1983;21:8-14. Rudman D, Kutner MH, Redd SC 2nd, et al. Hypocitraturia in calcium nephrolithiasis. J Clin Endocrinol Metab. 1982;55:1052-1057. Pak CY. Etiology and treatment of urolithiasis. Am J Kidney Dis. 1991;18:624-637. Pak CY, Poindexter JR, Adams-Huet B, Pearle MS. Predictive value of kidney stone composition in the detection of metabolic abnormalities. Am J Med. 2003;115:26-32. Nicar MJ, Hill K, Pak CY. Inhibition by citrate of spontaneous precipitation of calcium oxalate in vitro. J Bone Miner Res. 1987;2:215-220. 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