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.     

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.     

Effects of potassium-magnesium citrate supplementation on cytosolic ATP citrate lyase and mitochondrial aconitase activity in leukocytes: A window on renal citrate metabolism

BACKGROUND: An increase in urinary citrate excretion is associated with a decrease in activity of renal cortical cytosolic ATP citrate lyase (ACL) and mitochondrial aconitase (m-aconitase). Because potassium-magnesium citrate causes an increase in urinary citrate excretion, we decided to assess its effects on ACL and m-aconitase in the leukocytes of renal stone patients. METHODS: Twenty male renal stone patients were supplemented with potassium-magnesium citrate twice daily (i.e. 42 mEq potassium, 21 mEq magnesium, and 63 mEq citrate per day) for a period of 1 month. Two 24-h urine and one 15-mL heparinized blood samples were collected from each patient before and after supplementation. Urine samples were analyzed for relevant biochemical compositions. Leukocytes were separated from blood samples by centrifugation and assayed for ACL and m-aconitase activity. RESULTS: Supplementation with potassium-magnesium citrate significantly increased urinary pH (P < 0.005) and excretions of potassium (P < 0.001), magnesium (P < 0.001) and citrate (P < 0.0001). The activity of both ACL and m-aconitase were significantly decreased (P < 0.004 and P < 0.02 respectively). The decrease in ACL activity was inversely correlated with an increase in urinary excretion of both potassium (r = -0.620, P < 0.0001) and citrate (r = -0.451, P < 0.004). A similar inverse correlation was observed between m-aconitase activity and urinary excretion of citrate (r = -0.322, P < 0.043). CONCLUSION: Changes in enzyme activity, related to citrate metabolism in leukocytes, might reflect the status of renal tubular cells.     

Renal handling of citrate in chronic renal insufficiency

Citrate is a relevant component of the inhibitory potential of the urine environment. Its excretion and renal handling have been widely studied in subjects with normal renal function, but little is known about changes induced by chronic renal insufficiency. We have investigated renal handling of citrate in 50 patients with different degrees of renal insufficiency as compared to 30 healthy subjects with normal renal function. Among patients 34 were defined as having mild renal insufficiency based on a GFR of 80 through 40 ml/min/1.73 m2 BSA, while 16 had moderate-to-severe renal failure, defined by a GFR ranging from 40 to 20 ml/min/1.73 m2 BSA. Serum citrate increased in mild renal insufficiency, while it tended to be restored to normal values at more advanced renal failure. There was a stepwise decrease in the filtered load of citrate as GFR decreased, while its renal clearance was significantly reduced only at higher degrees of renal failure. This behavior was due to an increase in the fractional excretion of citrate which was inversely related to the decrease in GFR (p = 0.015). These data suggest that serum citrate levels and excretion are governed by renal mechanisms at mild degrees of renal insufficiency; in these conditions citrate is shown to behave conformly to other poorly reabsorbable anions such as sulfate. At more advanced renal failure the ensuing metabolic acidosis plays a crucial role as a regulatory factor of both serum concentration and renal handling of citrate, by increasing cellular uptake and metabolism as well as tubular reabsorption of this anion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Associations between renal sodium-citrate cotransporter (hNaDC-1) gene polymorphism and urinary citrate excretion in recurrent renal calcium stone formers and normal controls

PURPOSE: Urinary citrate is a potent inhibitor of renal stone formation. Its excretion is regulated by Na(+)/dicarboxylate cotransporter-1 (NaDC-1), which is expressed on the apical membrane of renal proximal tubules. Many patients with calcium urolithiasis exhibit hypocitraturia, however, the mechanisms are not perfectly understood. We examined whether or not the I550V polymorphism in human NaDC-1 gene (hNaDC-1) influenced urinary citrate excretion. MATERIALS AND METHODS: I550V polymorphism was investigated in 105 patients with recurrent renal calcium stone formation (RSF) and 107 age-matched healthy volunteers with non-renal stone formation (NSF), using polymerase chain reaction (PCR) restriction fragment length polymorphism analysis and two 24-h urine samples. RESULTS: Overall and in the RSF groups, subjects with a BB (homozygous for the digested Bcl-I allele) genotype exhibited a significantly lower urinary citrate excretion level than subjects with a bb (homozygous for the undigested allele) genotype. Genotype distributions between subjects with hypocitraturia and normocitraturia were significantly different, with the BB genotype being more frequently observed in subjects with hypocitraturia - both overall and in each of the RSF and NSF groups. Although the BB genotype was observed more frequently in the RSF group than in the NSF group, no statistical differences among the distributions of the three genotypes (BB, Bb [heterozygous] and bb) were observed between the RSF and NSF groups. CONCLUSION: These results suggest that the B allele of I550V polymorphism of hNaDC-1 may be associated with a reduction in urinary citrate excretion and contribute to hypocitraturia in recurrent renal stone formers.     

Effect of dietary calcium and magnesium on experimental renal tubular deposition of calcium oxalate crystal induced by ethylene glycol administration and its prevention with phytin and citrate

Oral administration of ethylene glycol to rats, and the resultant intratubular depositions of microcrystals of calcium oxalate were studied investigating the influences of dietary calcium or magnesium and assessing the protective efficacies against the crystallizations by treatment with phytin and sodium citrate. With increase of calcium intake and consequent increase of urinary calcium excretion there was a marked increase in the amount of tubular deposit of calcium oxalate crystal and in the calcium content of renal tissue. Although magnesium deficiency accelerated renal tubular calcium oxalate deposition, the protection against the crystal formation was not observed with excessive dietary magnesium. When rats were fed a high-calcium diet supplemented with phytin, a significant inhibition of the intratubular crystallization was observed. It appeared obvious that a hypocalciuric action of phytin was attributed to the effect of the prevention. There was vigorous protection of crystal formation by treatment with sodium citrate, which correlated with the level of citrate concentration in the drinking water.     

The effects of methenamine-hippurate upon urinary risk factors for renal stone formation

Among the various treatments for renal calcium stone disease, none has been documented to reduce urinary oxalate. Methenamine-hippurate (Hiprex) has been used extensively in the treatment of urinary tract infections and from micropuncture studies in the rat, using para-aminohippurate, it could be expected to reduce the renal secretion of oxalate. A daily dose of 3 g was given orally to 15 healthy subjects for 2 weeks. However, there was no net decrease in the urinary excretion of oxalate, but a risk index based on the urinary content of calcium, magnesium, oxalate, citrate and urine became reduced during treatment. The urinary inhibition of calcium oxalate crystal growth was unaffected. It is concluded that there may be a potential in methenamine-hippurate for the treatment of calcium stone disease, which can only be evaluated, however, by a clinical trial in stone patients.     

The effect of different diets on urine composition and the risk of calcium oxalate crystallisation in healthy subjects

OBJECTIVE: The aim of the study was to determine the impact of defined diet modifications on urine composition and the risk of calcium oxalate crystallisation. METHODS: Ten healthy male volunteers consumed a self-selected diet (SD) for 14 days, and three different standard diets for a period of 5 days each. Whereas the western-type diet (WD) is representative of the usual dietary habits, the normal mixed diet (ND) and the ovo-lacto-vegetarian diet (VD) were calculated according to the requirements. RESULTS: The risk of calcium oxalate crystallisation, calculated as relative supersaturation (EQUIL2) from urine composition, was highest during ingestion of diets SD and WD. The intake of diet ND resulted in a significant decrease in relative supersaturation with calcium oxalate by 58% (p<0.05) compared with diet WD, due to a significant decline in urinary calcium and uric acid excretion and a significant increase in urinary volume, pH-value and citrate excretion. In spite of an increase in urinary pH, citrate and magnesium excretion and a decline in calcium excretion, no further significant decrease in the risk of calcium oxalate crystallisation was observed on diet VD, due to a significant increase in urinary oxalate by 30% (p<0.05) on average. CONCLUSIONS: The change of usual dietary habits for a normal mixed diet significantly reduces the risk of calcium oxalate crystallisation. With a vegetarian diet a similar decline in urinary supersaturation with calcium oxalate can be achieved compared to a normal mixed diet. Since urinary oxalate excretion increased significantly, a vegetarian diet without adequate intake of calcium may not be recommended to patients with mild hyperoxaluria.     

Nephrolithiasis and urine ion changes in ulcerative colitis patients undergoing colectomy and endorectal ileal pullthrough

Nephrolithiasis occurs in 5 to 13% of patients with ulcerative colitis (UC) who undergo colectomy and abdominal ileostomy, presumably from chronic dehydration and urinary concentration. Whether endorectal ileal pullthrough with ileal reservoir (PTR) changes the incidence of stones (primarily calcium oxalate) after colectomy is not known. Urinary excretion of Na2+, K+, Ca2+, Mg2+, phosphate, urate, oxalate, and citrate was measured in a prospective study of 12 UC patients undergoing PTR with temporary end ileostomy. Twenty-four-hour urine samples were obtained before colectomy (t1), after colectomy but before ileostomy closure (t2), and 5 months after ileostomy closure (t3). Urine volumes decreased from 831 +/- 101 cc (mean +/- SE) at t1 to 715 +/- 101 cc at t2 and then increased to 1278 +/- 421 cc at t3 (significant, with P less than 0.01 by t test). Urinary excretions of Mg2+, oxalate, and citrate were low in UC patients compared to those in controls (15 healthy adult volunteers). Excretion of Ca2+ increased significantly following temporary ileostomy while excretion of Mg2+ fell. Excretion of Ca2+ fell and excretion of Mg2+ and citrate increased following PTR. We conclude that PTR patients have increased urine volumes and urinary ion changes known to decrease the risk of developing renal stones.     

Effects of magnesium citrate and phytin on reducing urinary calcium excretion in rats

Summary The aim of this study was to determine and compare the effects of both magnesium citrate and phytin on reducing urinary calcium excretion under high-calcium-diet conditions during single and combined treatments. An animal experiment was carried out over a period of 4 weeks in 35 male rats. Urinary calcium excretion was reduced significantly by magnesium citrate and/or phytin in rats fed on high-calcium diets. The hypocalciuric effect of magnesium citrate was more evident than that of phytin. Urinary magnesium excretion was high in all experimental groups. However, the urinary magnesium/calcium ratios showed a consistent increase only in the groups treated with magnesium citrate. Urinary citrate excretion showed a relative increase with the introduction of magnesium citrate plus phytin; however, in both the high-calcium-diet group and the magnesium-citrate group this was found to be reduced. Urinary phosphate excretion was slightly higher in the groups treated with phytin. There was no definite difference in urinary oxalate concentration between the groups. No significant change was noted in the serum concentration of calcium, magnesium, or phosphate.     

24h尿枸橼酸定量分析在尿石症患者诊治中的意义

目的对30例含钙尿石症患者24h尿枸橼酸排泄进行了病例对照研究,旨在从病因学角度对尿石症的影响因素进行探讨,为临床诊治提供依据。方珐测定30例尿石症患者和30例正常人的24h尿枸橼酸和钙的含量,比较两组的差异;并比较低枸橼酸尿症与高钙尿症与尿石症发病的相关性。结果24h尿枸橼酸的排泄量在结石患者为（224．26±147．63）mg,显著低于正常人（434．58土280．89）mg,且性别差异具有显著性意义,男性低于女性（P〈0．05）。结石患者24h尿液中的枸橼酸／钙比值明显高于正常人（P〈0．05）。低枸橼酸尿症与尿石症发病的相关性高于高钙尿症（P〈0．05）。结论女性24h尿枸橼酸排泄量约为男性的1．4～1．6倍,建议对尿石症患者的代谢评估应考虑性别差异。在结石的代谢评估中,按照性别分类的24h尿枸橼酸／钙比值的降低可能比单纯尿枸橼酸降低更有意义。低枸橼酸尿症在尿石症的代谢评估中可能是比高钙尿症更加重要的指标。     

Prevention of recurrent calcium stone formation with potassium citrate therapy in patients with distal renal tubular acidosis

Distal renal tubular acidosis is a common cause of intractable calcium nephrolithiasis. We examined the effect of oral potassium citrate therapy in 9 patients with incomplete distal renal tubular acidosis diagnosed on the basis of an abnormal response to an oral ammonium chloride load. Patients were studied during a control phase and after 3 months of potassium citrate treatment (60 to 80 mEq. daily). Potassium citrate caused a significant increase in urinary pH and urinary citrate, and a decrease in urinary calcium. The urinary relative saturation ratio of calcium oxalate significantly decreased during treatment, while that of brushite did not change. Potassium citrate also was shown to inhibit new stone formation. During a mean treatment period of 34 months none of the 9 patients had new stones, although 39.3 plus or minus 79.7 (standard deviation) stones per patient formed during the 3 years preceding treatment. The results support the potential clinical advantage of potassium citrate therapy in patients with distal renal tubular acidosis and recurrent calcium nephrolithiasis.     

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.     

Calcium excretion in patients with calcium oxalate calculi in acid administration

Acidosis induced increase in renal calcium excretion was produced by means of ammonium chloride load in 12 control persons and in 76 patients with recurrent oxalate lithiasis. This increase is more marked in stone patients - even in those with normocalciuria - than in control persons. The calcium excretion is especially increased in patients with renal hypercalciuria. This might result from the primary nature of the renal defect. The acid load did not prove useful in the diagnosis of hyperparathyroidism.     

Influence of dietary animal protein on renal stone disease

The effect of dietary protein load on the incidence of nephrolithiasis was studied in rats and men. Three groups of adult male Wister rats were fed with a standard protein diet, a high protein diet, or a low protein diet for 4 weeks. In the high protein group, calcium excretion was significantly increased and citrate excretion was remarkably decreased. This group also exhibited low grade metabolic acidosis due to catabolism of excess amino acids, and increases in urinary cyclic AMP excretion and bone resorption. These findings indicate that protein-induced hypercalciuria is due to low grade metabolic acidosis, which directly affects renal handling of calcium. Long-term calcium loss in the urine may lead to negative calcium balance and hyperfunction of the parathyroid gland may induce bone resorption. The influence of 40 g animal protein load on urinary risk factors of calcium stone formation was investigated in 23 healthy males and 26 patients with nephrolithiasis. All subjects were given control diets each day containing 60 g protein for a week and during the next week each received an additional 40 g animal protein. In the controls, added dietary protein resulted in decreased urinary citrate and increased urinary uric acid, with no change in urinary calcium or cyclic AMP excretion. In contrast, the patients showed increased urinary calcium and cyclic AMP as well as decreased urinary citrate. Further examination of the patients revealed that the significant increases of calcium and cyclic AMP excretion occurred only in hypercalciuric patients, who seemed to be classified into renal hypercalciuria.(ABSTRACT TRUNCATED AT 250 WORDS)     

Juvenile renal stone disease: a study of urinary promoting and inhibiting factors

Urinary excretion of the most widely studied renal stone promoting (calcium, oxalate, uric acid and phosphate) and inhibiting (citrate, magnesium, pyrophosphate and glycosaminoglycans) factors, as well as the Tamm-Horsfall mucoprotein, was evaluated in 14 children with idiopathic calcium nephrolithiasis, 6 children with renal stone disease secondary to excretory malformations and 19 normal controls. No statistically significant differences in urinary excretion of promoting and inhibiting factors were found in children with idiopathic calcium nephrolithiasis but the relationship between promoting and inhibiting factors was changed as shown by an abnormal ratio of oxalate/citrate X glycosaminoglycans. This finding suggests that there is an imbalance between promoting and inhibiting factors in children with idiopathic calcium nephrolithiasis, and it is not detected by assay of each single substance.     

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.     

Urinary inhibitors of crystallization in hypercalciuric children with hematuria and nephrolithiasis

Urinary inhibitors are suggested to play a significant role in reducing crystallization in calcium (Ca) stone former and idiopathic hypercalciuria (IH). Urinary inhibitors such as magnesium (Mg), citrate, and glycosaminoglycans (GAGs) were evaluated, as well as urinary Ca and creatinine (Cr), in IH children with nephrolithiasis (LIT) or with hematuria plus IH (HEM) and were compared with a control group. The mean 24-h urinary excretion of Mg was similar in all groups. However, the urine Ca/Mg ratio was significantly increased (P <0.005) in LIT and HEM groups. A higher mean value for GAGs and citrate was found in the HEM group, but a very low level of GAGs (less than 60% of the normal value) and citrate (less than 30% of the normal value) was found in the LIT group. These data suggest that, despite a high urinary Ca excretion (3.6±0.1 mg/kg per day) in the HEM group, elevated urinary GAGs (32.0±1.0 mg/g Cr) and a normal urinary citrate (428.7±62.3 mg/24 h) excretion may prevent Ca crystallization and thus renal stones. In contrast, in the LIT group low urinary GAG (10.3±0.9 mg/g Cr) and citrate (235.2±52.3 mg/24 h) excretion may precipitate stone formation in the presence of a high urinary Ca excretion. Thus, it is reasonable to suggest that patients with hematuria and IH may not develop overt renal stone due to the presence of normal levels of renal stone inhibitors. Received October 30, 1995; accepted December 15, 1995     

Urinary excretion of citrate, glycosaminoglycans, magnesium and zinc in relation to age and sex in normal subjects and in patients who form calcium stones.

One hundred and ninety-seven healthy subjects and 104 patients with idiopathic calcium stone disease had their urinary excretion of citrate, glycosaminoglycans, magnesium, and zinc measured and the results correlated with sex and age. In normal subjects the daily excretion of citrate, magnesium, and zinc increased with age to a maximum during the fifth decade and remained relatively constant until the eighth decade when they decreased. The daily excretion of magnesium and zinc were higher in men than in women, which was attributed to the higher body weights of the men. The urinary excretion of citrate, magnesium, and zinc related to creatinine remained relatively constant with age in adult life; analyses of magnesium and zinc excretion rates divided by urine creatinine did not distinguish men from women. There was no significant difference between men and women for citrate excretion in 24 hour urine, but the citrate:creatinine ratio was significantly higher in women than men. The higher citrate excretion in women may explain the lower incidence of calcium stones in women. The highest glycosaminoglycan excretion rates were seen during the first two decades which is why children and teenagers are less prone to develop calcium stones in spite of high urinary calcium concentrations. Urinary citrate and magnesium excretion were lower, and glycosaminoglycan and zinc excretion were higher, in stone formers than in controls. It seems that a decreased excretion of citrate and magnesium together with an increased excretion of calcium, may contribute to the formation of calcium stones. The role of urinary glycosaminoglycans and zinc in the formation of calcium stones remains uncertain.     

Prospective study on the efficacy of a selective treatment and risk factors for relapse in recurrent calcium oxalate stone patients

OBJECTIVE: The present study was performed to examine the efficacy of a selective treatment according to the guidelines for the prevention of recurrence in calcium oxalate stone patients and to assess risk factors for stone recurrence. METHODS: To investigate the effect of specific diagnostic and therapeutic measures, 134 recurrent calcium oxalate stone formers participated in a prospective study for two years with regular follow-ups of at least every six months. Depending on the results of analysis of 24-hour urine, nutrition record and metabolic situation, selective recommendations were given concerning diet and medication. RESULTS: Throughout the follow-up period, 57 (43%) of the patients experienced relapses. In recurrence-free patients, the significant increase in urinary volume, as well as urinary pH, potassium and citrate excretion, three indexes of compliance with alkalization, resulted in a significant decrease in the calculated risk of calcium oxalate stone formation. In patients with recurrences during follow-up, the relative supersaturation with calcium oxalate increased significantly, mainly due to the significant rise in urinary oxalate excretion exceeding the significant increases in urinary volume, pH, potassium and citrate excretion. Multiple logistic regression analysis revealed previous ESWL treatment and a history of multiple stones as independent predictors of the risk for recurrence. CONCLUSIONS: The results indicate that compliance with drinking advice and alkalization therapy was highest among both, patients with and without recurrences, compared with all other therapeutic measures. The increase in oxalate excretion is identified as the major urinary risk factor for relapse during follow-up in recurrent calcium oxalate stone disease.