Alkali action on the urinary crystallization of calcium salts: contrasting responses to sodium citrate and potassium citrate

Alkali therapy is used commonly to prevent recurrent stone formation in patients with distal renal tubular acidosis. We compared the effects of potassium citrate to those of sodium citrate in 6 well defined cases of incomplete distal renal tubular acidosis. The patients were studied during a control phase, during potassium citrate treatment (80 mEq. per day) and during sodium citrate treatment (80 mEq. per day) chosen in random order. Potassium citrate caused a decrease in urinary calcium and a significant increase in urinary citrate that resulted in a significant decrease in the urinary saturation of calcium oxalate. It did not alter the saturation of brushite and sodium urate. However, while sodium citrate also was able to increase the urinary citrate level, there was no decrease in the urinary calcium (owing to the increased sodium load). Thus, the urinary saturation of calcium oxalate did not decrease as much as with potassium citrate and the saturation of brushite increased significantly. Moreover, the urinary saturation of sodium urate increased significantly owing to the enhanced sodium excretion. The results suggest that potassium citrate therapy may retard the crystallization of calcium oxalate and may not cause calcium phosphate crystallization. In contrast, sodium citrate may have no effect or it sometimes may accentuate the crystallization of calcium salts. Thus, our study supports the potential clinical advantage of potassium citrate therapy over sodium alkali treatment in patients with incomplete distal renal tubular acidosis and recurrent calcium nephrolithiasis.     

Long-term treatment of calcium nephrolithiasis with potassium citrate

The long-term effects of potassium citrate therapy (usually 20 mEq. 3 times daily during 1 to 4.33 years) were examined in 89 patients with hypocitraturic calcium nephrolithiasis or uric acid lithiasis, with or without calcium nephrolithiasis. Hypocitraturia caused by renal tubular acidosis or chronic diarrheal syndrome was associated with other metabolic abnormalities, such as hypercalciuria or hyperuricosuria, or occurred alone. Potassium citrate therapy caused a sustained increase in urinary pH and potassium, and restored urinary citrate to normal levels. No substantial or significant changes occurred in urinary uric acid, oxalate, sodium or phosphorus levels, or total volume. Owing to these physiological changes, uric acid solubility increased, urinary saturation of calcium oxalate decreased and the propensity for spontaneous nucleation of calcium oxalate was reduced to normal. Therefore, the physicochemical environment of urine following treatment became less conducive to the crystallization of calcium oxalate or uric acid, since it stimulated that of normal subjects without stones. Commensurate with the aforementioned physiological and physicochemical changes the treatment produced clinical improvement, since individual stone formation decreased in 97.8 per cent of the patients, remission was obtained in 79.8 per cent and the need for surgical treatment of newly formed stones was eliminated. In patients with relapse after other treatment, such as thiazide, the addition of potassium citrate induced clinical improvement. Thus, our study provides physiological, physicochemical and clinical validation for the use of potassium citrate in the treatment of hypocitraturic calcium nephrolithiasis and uric acid lithiasis with or without calcium nephrolithiasis.     

Hypocitraturic and hypercalciuric renal tubular acidosis with nephrocalcinosis in a 4-year-old boy

A 4-year-old boy suffering from hypocitraturic and hypercalciuric renal tubular acidosis with nephrolithiasis and nephrocalcinosis is reported. Renal function tests indicated that the patient had type 1 renal tubular acidosis. Potassium citrate rather than potassium bicarbonate, sodium citrate or bicarbonate is the preferred treatment for stones in RTA-I.     

Calcium nephrolithiasis and distal tubular acidosis in type 1 glycogen storage disease

A 36-year-old man was admitted to hospital due to right flank pain as a result of ureteral stones. He had been followed up for type 1 glycogen storage disease since the age of 11 years. He had four episodes of spontaneous stone birth during the previous 2 years, and each stone was composed mainly of calcium oxalate. Intravenous pyelography showed right hydronephrosis due to ureteral stones and bilateral multiple renal stones. We carried out transurethral ureterolithotripsy (TUL) on the right ureteral stones. The composition was a mixture of calcium oxalate and calcium phosphate. Laboratory evaluation demonstrated the association of distal renal tubular acidosis (RTA). These observations suggest that hypocitraturia and distal RTA are strongly correlated to recurrence of calcium nephrolithiasis. The patient's serum uric acid and urinary citrate excretion levels normalized after allopurinol and potassium citrate administration.     

远端肾小管酸中毒的诊断和治疗

报告远端肾小管酸中毒１６例，其中完全型２例，不完全型１４例。完全型有高氯低钾性酸中毒，不完全型无酸中毒，但氯化铵负荷试验阳性。在口服枸橼酸钾期间，两型均观察到尿钙明显降低，尿ｐＨ和枸橼酸显著升高，完全型代谢性酸中毒得到纠正。对远端肾小管酸中毒的诊断和治疗进行了讨论。     

Low urinary citrate excretion in nephrolithiasis

The urinary citrate excretion was examined in patients with nephrolithiasis who were categorized on the basis of different physiologic or metabolic abnormalities. A wide prevalence of low citrate excretion (hypocitraturia) was observed, with over one half of our patients with stones exhibiting it. Hypocitraturia was found in all patient categories except primary hyperparathyroidism and hyperuricosuric calcium oxalate nephrolithiasis. As expected, hypocitraturia was present in renal tubular acidosis and in enteric hyperoxaluria. However, urinary citrate was also low in absorptive and renal hypercalciurias, and in patients in whom an acid-base disturbance was clearly excluded.     

Alkalizitrate in der Urologie

Alkaline citrates have been used as an efficient therapy in hypocitraturic calcium nephrolithiasis, uric acid lithiasis, cystinuria, and renal tubular acidosis. Furthermore, alkaline citrates are very effective in treating and preventing hyperchloremic metabolic acidosis in patients with urinary diversion. The main physiological effects during urolithiasis therapy have been significant increases in urinary pH, in citrate and potassium, and a decrease in calcium excretion. This paper reviews current indications, therapy modalities, and metaphylactic use reported in the literature and/or recommended by the Deutsche Gesellschaft für Urologie (DGU) and the European Association of Urology (EAU). It is intended to give useful advice for the urologist's daily practice.     

Calculi complicating a renal transplant

Four months after a cadaver kidney transplant, kidney stones were found in the renal allograft. Three major predisposing causes of nephrolithiasis were found in the patient, including hyperparathyroidism, renal tubular acidosis, and urinary tract infection. Hypercalcemia was corrected by parathyroidectomy. During the subsequent three years there was no enlargement of the renal stones and adequate kidney function was maintained. Renal tubular acidosis was not severe and seemed to be related to chronic rejection. Urinary tract infection was readily corrected with antibiotics and did not recur after the immediate post-transplant period. Surgical therapy for nephrolithiasis involving a kidney allograft was deferred since urinary flow was not obstructed. This course of management is recommended for use in patients with calculi complicating renal transplantation.     

Multiple urinary lithiasis and nephrocalcinosis secondary to primary Sjögren syndrome

A 39 year old women with a primary Sj?gren syndrome (pSS) had bilateral and multiple nephrolithiasis and nephrocalcinosis due to distal renal tubular acidosis (dRTA), hypercalciuria and hypocitraturia. She had in serum positive antinuclear antibodies with mottled pattern 1/320, totals ENA, Anti-SSA/Ro 52, Anti-SSA/Ro 60 and Anti-SSB-La antibodies. Stones were removed with extracorporeal shock wave lithotripsy satisfactory and were composed of calcium phosphate and calcium oxalate. Metabolic abnormalities were resolved with potassium citrate and hydrochlorothiazide. At two years of follow-up, the patient hadn't stone recurrence and had normal 24-hour urinary levels of citrate and calcium.     

Long-term lemonade based dietary manipulation in patients with hypocitraturic nephrolithiasis

PURPOSE: Citrus fruits and juices are a known natural source of dietary citrate. Of all the citrus juices, lemon juice appears to have the highest concentration of citrate. Therefore, lemonade therapy has been proposed as a potential treatment for patients with hypocitraturia. We retrospectively evaluated the impact of long-term lemonade therapy on urinary metabolic parameters and stone formation in patients with hypocitraturic nephrolithiasis. MATERIALS AND METHODS: A total of 32 patients were identified as being on long-term lemonade therapy for hypocitraturic nephrolithiasis. The 11 patients on lemonade therapy who met the entrance criteria for evaluation were compared to an age and sex matched control group of patients treated with oral slow release potassium citrate. Pre-therapy and post-therapy urinary parameters were recorded for both groups. The effect of lemonade therapy on stone burden and stone formation rate was calculated. New stone formation was defined as passage, surgical removal or appearance of new stones, or an increase in the size of existing stones on radiographic imaging. RESULTS: Four males and 7 females (mean age 52.7 years) were treated with lemonade therapy for a mean of 44.4 months. The control group consisted of 4 males and 7 females (mean age 54.5 years) treated with potassium citrate for a mean of 42.5 months. Of the 11 patients on lemonade 10 demonstrated increased urinary citrate levels (mean increase +383 mg per day, p <0.05). All potassium citrate therapy subjects demonstrated an increase in urinary citrate (mean increase +482 mg per day, p <0.0001). Mean pretreatment and posttreatment stone burden in the lemonade group was 37.2 and 30.4 mm(2), respectively (p >0.05). During lemonade therapy the stone formation rate decreased from 1.00 to 0.13 stones per patient per year (p >0.05). CONCLUSIONS: Due to its significant citraturic effect, lemonade therapy appears to be a reasonable alternative for patients with hypocitraturia who cannot tolerate first line therapy. Future study in the form of a prospective, randomized trial is needed to validate these findings.     

Effect of potassium citrate therapy on stone recurrence and residual fragments after shockwave lithotripsy in lower caliceal calcium oxalate urolithiasis: a randomized controlled trial

BACKGROUND AND PURPOSE: To evaluate the efficacy of potassium citrate treatment in preventing stone recurrences and residual fragments after shockwave lithotripsy (SWL) for lower pole calcium oxalate urolithiasis. PATIENTS AND METHODS: One hundred ten patients who underwent SWL because of lower caliceal stones and who were stone free or who had residual stone 4 weeks later were enrolled in the study. The average patient age was 41.7 years. All patients had documented simple calcium oxalate lithiasis without urinary tract infection and with normal renal morphology and function. Four weeks after SWL, patients who were stone free (N = 56) and patients who had residual stones (N = 34) were independently randomized into two subgroups that were matched for sex, age, and urinary values of citrate, calcium, and uric acid. One group was given oral potassium citrate 60 mEq per day, and the other group served as controls. RESULTS: In patients who were stone free after SWL and receiving medical treatment, the stone recurrence rate at 12 months was 0 whereas untreated patients showed a 28.5% stone recurrence rate (P < 0.05). Similarly, in the residual fragment group, the medically treated patients had a significantly greater remission rate than the untreated patients (44.5 v 12.5%; P < 0.05). CONCLUSION: Potassium citrate therapy significantly alleviated calcium oxalate stone activity after SWL for lower pole stones in patients who were stone free. An important observation was the beneficial effect of medical treatment on stone activity after SWL among patients with residual calculi.     

Citraturic, alkalinizing and antioxidative effects of limeade-based regimen in nephrolithiasis patients

Potassium citrate has long been used as a prophylactic remedy for nephrolithiasis recurrence. Lemonade consumption is also suggested as an option. We compared the efficacy of consumption of solution containing manufactured lime powder with that of potassium citrate, on the improvement of metabolic risk factors, oxidative stress and renal tubular damage in nephrolithiasis patients. Patients with kidney stone were enrolled and randomly assigned to three treatment programs for 3 month period consisting of consumption of solution containing lime powder (Group 1, n = 13), potassium citrate (Group 2, n = 11) and lactose as placebo regimen (Group 3, n = 7). Lime powder and potassium citrate contained equal amounts of potassium (21 mEq) and citrate (63 mEq). After treatment, there was an increase in urinary pH, potassium and citrate in Group 1 and 2. Increased plasma potassium and red blood cell glutathione (R-GSH) and decreased urinary malondialdehyde were found in Group 1, but not observed in Group 2. R-GSH was decreased in Group 2. Urinary N-acetyl-beta-glucosaminidase activity and fractional excretion of magnesium, as renal tubular damage indicators, were decreased only in Group 1. In Group 3, all measured parameters were unaltered except for an increased urinary chloride. In conclusion, consumption of our in-house lime powder exerted citraturic and alkalinizing actions as efficient as consumption of potassium citrate. In addition, it provided an antioxidative effect and was able to attenuate renal tubular damage. These pharmacological properties may be clinically useful to diminish the stone-forming potential in kidney stone patients and hence for preventing recurrent calculi.     

A case of incomplete distal renal tubular acidosis undergoing repeated treatment by extracorporeal shock-wave lithotripay and transureteral lithotripsy for recurrent urolithiasis

A 65-year-old woman was referred to our hospital for further examination of recurrent urinary stone formation. She had undergone 49 sessions of extracorporeal shock-wave lithotripay (ESWL) and 3 sessions of transureteral lithotripsy (TUL) under the diagnosis of idiopathic recurrent urolithiasis at another hospital. An excretory urography showed bilateral hydronephrosis and a retrograde urography revealed bilateral lower ureteral stricture. Ammonium chloride loading test demonstrated incomplete distal renal tubular acidosis. Potassium citrate therapy had begun and bilateral nephrostomies were required in order to prevent recurrent urinary tract infection and new stone formation. Literature was reviewed and discussion was made on the ureteral stricture after ESWL and TUL, and on incomplete distal renal tubular acidosis.     

Hyperkalemic distal renal tubular acidosis caused by immunosuppressant treatment with tacrolimus in a liver transplant patient: case report

Nephrotoxicity is one of the most common side effects of long-term immunosuppressive therapy with calcineurin inhibitors. We describe a case of distal renal tubular acidosis secondary to tacrolimus administration. A 43-year-old man with end-stage liver disease due to hepatitis C and B virus infections and alcoholic cirrhosis received a liver transplantation under immunosuppressive treatment with tacrolimus and mycophenolate mofetil. In the postoperative period, the patient developed hyperkalemic hyperchloremic metabolic acidosis, with a normal serum anion gap and a positive urinary anion gap, suggesting distal renal tubular acidosis. We excluded other causes of hyperkalemia. Administration of intravenous bicarbonate, loop diuretics, and oral resin exchanger corrected the acidosis and potassium levels. Distal renal tubular acidosis is one of several types of nephrotoxicity induced by tacrolimus treatment, resulting from inhibition of potassium secretion in the collecting duct. Treatment to correct the acidosis and hyperkalemia should be promptly initiated, and the tacrolimus dose adjusted when possible.     

Oral potassium citrate treatment for idiopathic hypocitruria in children with calcium urolithiasis

PURPOSE :We evaluated the clinical and laboratory outcome of oral potassium citrate treatment in children with idiopathic hypocitruria and calcium stones. MATERIALS AND METHODS: The charts of 64 children 1 to 15 years old with hypocitruria and calcium stones (median age 7.2) treated with oral potassium citrate were reviewed. Evaluation parameters were tolerability, adverse reactions, metabolic profile and stone recurrence. RESULTS: No serious adverse reaction due to potassium citrate administration was recorded. Normal citrate excretion was restored in all patients. After treatment median urinary citrate daily plus or minus SD increased from 197 +/- 72 to 632 +/- 218 mg./1.73 m.2 (p <0.001) and mean urinary pH increased from 5.3 +/- 0.3 to 6.2 +/- 0.7 (p <0.01). Mean calcium excretion decreased from 3.5 +/- 2.7 to 2.5 +/- 2.7 mg./kg. (p <0.05). At an average followup of 22 months (range 3 to 67) the recurrence rate in the group overall was 0.07 per patient-year. The previous recurrence rate of 0.32 per patient-year in the 20 children with a history of recurrent stone disease decreased to 0.17 per patient-year after treatment. None of the 44 initial stone formers had recurrent stones. CONCLUSIONS: Our results show the safety and efficacy of oral potassium citrate treatment for restoring normal urinary citrate and suggest a preventive effect for recurrent calcium stone disease in children with hypocitruria and calcium stones.     

Calcium metabolism in acidotic patients induced by carbonic anhydrase inhibitors: responses to citrate

Calcium metabolism and its response to citrate were examined in 51 patients with glaucoma receiving carbonic anhydrase inhibitors (acetazolamide or methazolamide). Metabolic acidosis, hypocitraturia and increased incidence of nephrolithiasis were induced by both drugs. However, the acidosis was milder with methazolamide administration. Normocalciuria was observed in 29 patients and was shown to be a result of low filtered calcium. Renal hypercalciuria in 16 patients was associated with elevated parathyroid hormone but nephrogenic cyclic adenosine monophosphate remained within normal limits. Citrate in the form of potassium citrate (4.3 mmol.) and sodium citrate (4.0 mmol.) did not correct the metabolic acidosis or hypocitraturia but consistently decreased fasting and 24-hour urinary calcium excretion in patients with renal hypercalciuria. This event did not occur in patients with normocalciuria or absorptive hypercalciuria. These results suggest that a small amount of citrate could reverse renal hypercalciuria without correcting the metabolic acidosis.     

Effect of potassium depletion on urinary stone risk factors in Wistar rats

Various studies have suggested that potassium depletion leads to acidosis and hypocitraturia. In Northeastern Thailand, for example, mild hypokalemia and mild hyperoxaluria are observed in most stone formers. However, there are limited reports about the direct link between potassium depletion and the formation of urinary stones, most of which are calcium oxalate stones. Therefore, we studied the direct effect of potassium depletion on the risk factors for calcium oxalate stone formation. Seventy-two rats were fed a control diet or a potassium-deficient diet for 1, 2, or 3 weeks (n = 12 per group). Twenty-four-hour urine collection was done for the measurement of potassium, calcium, oxalate, glycolate, citrate, phosphorus, and magnesium. Lactate dehydrogenase activity was also measured in order to assess renal tubular damage, and kidneys were harvested for histological examination. Furthermore, urinary supersaturation of calcium oxalate was calculated. With potassium depletion, the urinary concentrations of potassium, citrate, magnesium, and phosphorus decreased rapidly. There was no detectable renal damage, renal calcium deposition, and no significant increase of urinary oxalate or calcium. However, the urinary supersaturation index of calcium oxalate increased significantly in rats with potassium depletion. These findings indicate that potassium deficiency may increase the risk of stone formation through enhanced supersaturation.     

Effect of Potassium Citrate on Calcium Phosphate Stones in a Model of Hypercalciuria

Potassium citrate is prescribed to decrease stone recurrence in patients with calcium nephrolithiasis. Citrate binds intestinal and urine calcium and increases urine pH. Citrate, metabolized to bicarbonate, should decrease calcium excretion by reducing bone resorption and increasing renal calcium reabsorption. However, citrate binding to intestinal calcium may increase absorption and renal excretion of both phosphate and oxalate. Thus, the effect of potassium citrate on urine calcium oxalate and calcium phosphate supersaturation and stone formation is complex and difficult to predict. To study the effects of potassium citrate on urine supersaturation and stone formation, we utilized 95th-generation inbred genetic hypercalciuric stone-forming rats. Rats were fed a fixed amount of a normal calcium (1.2%) diet supplemented with potassium citrate or potassium chloride (each 4 mmol/d) for 18 weeks. Urine was collected at 6, 12, and 18 weeks. At 18 weeks, stone formation was visualized by radiography. Urine citrate, phosphate, oxalate, and pH levels were higher and urine calcium level was lower in rats fed potassium citrate. Furthermore, calcium oxalate and calcium phosphate supersaturation were higher with potassium citrate; however, uric acid supersaturation was lower. Both groups had similar numbers of exclusively calcium phosphate stones. Thus, potassium citrate effectively raises urine citrate levels and lowers urine calcium levels; however, the increases in urine pH, oxalate, and phosphate levels lead to increased calcium oxalate and calcium phosphate supersaturation. Potassium citrate induces complex changes in urine chemistries and resultant supersaturation, which may not be beneficial in preventing calcium phosphate stone formation.     

肾结石大鼠钠/二羧基转运蛋白1的表达及枸橼酸钾防治机制的研究

目的 研究肾组织钠／二羧基转运蛋白1（SDCT1）与低枸橼酸尿的关系以及枸橼酸钾的干预作用，探讨肾结石发病的分子机制和防治措施。方法 雄性Wistar大鼠分为对照组、肾结石组及枸橼酸钾干预组。血、尿枸橼酸和草酸采用酶法测定，Northern blot检测大鼠肾组织SDCT1mRNA水平的改变，免疫组织化学观察SDCT1在肾组织的分布及表达变化。结果 与对照组比较，肾结石组第3天尿草酸水平显著升高，枸橼酸水平显著降低，同时肾组织SDCT1mRNA及其蛋白水平上调。第7天SDCT1mRNA及其表达产物增加更为显著，同时尿枸橼酸水平进一步降低，尿钙排泄显著增加，87.5%大鼠有中－大量的草酸钙结石形成。第14天上述改变更为明显，结石形成率达100％。枸橼酸钾干预组各时间点尿草酸水平与肾结石组差异无显著性意义，但尿枸橼酸水平显著高于肾结石组及对照组，肾组织SDCT1mRNA及蛋白表达显著低于肾结石组，与对照组差异无显著性意义；结石形成率显著低于肾结石组；肾小管扩张、炎细胞浸润等病变也明显减轻。结论 肾组织SDCT1表达上调可能是低枸橼酸尿的重要原因，与肾结石的形成有密切关系。枸橼酸钾可下调肾结石大鼠肾组织SDCT1的表达，对肾结石的形成具有明显的干预作用。     

Potassium citrate decreases urine calcium excretion in patients with hypocitraturic calcium oxalate nephrolithiasis

Two previous studies (<10 patients each) have demonstrated that alkali therapy may reduce urine calcium excretion in patients with calcium oxalate nephrolithiasis. The hypothesized mechanisms are (1) a decrease in bone turnover due to systemic alkalinization by the medications; (2) binding of calcium by citrate in the gastrointestinal tract; (3) direct effects on TRPV5 activity in the distal tubule. We performed a retrospective review of patients on potassium citrate therapy to evaluate the effects of this medication on urinary calcium excretion. A retrospective review was performed of a metabolic stone database at a tertiary care academic hospital. Patients were identified with a history of calcium oxalate nephrolithiasis and hypocitraturia who were on potassium citrate therapy for a minimum of 3 months. 24-h urine composition was assessed prior to the initiation of potassium citrate therapy and after 3 months of therapy. Patients received 30–60 mEq potassium citrate by mouth daily. Inclusion criterion was a change in urine potassium of 20 mEq/day or greater, which suggests compliance with potassium citrate therapy. Paired t test was used to compare therapeutic effect. Twenty-two patients were evaluated. Mean age was 58.8 years (SD 14.0), mean BMI was 29.6 kg/m² (SD 5.9), and gender prevalence was 36.4 % female:63.6 % male. Mean pre-treatment 24-h urine values were as follows: citrate 280.0 mg/day, potassium 58.7 mEq/day, calcium 216.0 mg/day, pH 5.87. Potassium citrate therapy was associated with statistically significant changes in each of these parameters—citrate increased to 548.4 mg/day (p < 0.0001), potassium increased to 94.1 mEq/day (p < 0.0001), calcium decreased to 156.5 mg/day (p = 0.04), pH increased to 6.47 (p = 0.001). Urine sodium excretion was not different pre- and post-therapy (175 mEq/day pre-therapy versus 201 mEq/day post-therapy, p = NS). Urinary calcium excretion decreased by a mean of 60 mg/day on potassium citrate therapy—a nearly 30 % decrease in urine calcium excretion. These data lend support to the hypothesis that alkali therapy reduces urine calcium excretion.