Chronobiology of urinary citrate excretion amongst stone-formers and healthy males from North Western India

Summary Urinary citrate excretion was estimated colorimetrically from urine samples collected every 3 h for 24 h from 25 healthy adult males (non-stone formers; mean age 39±7 years) and 25 male patients suffering from calcium nephrolithiasis (stone formers; mean age 41±6 years). The 24 h citrate excretion was 2.47±0.65 mmol in non-stone formers and 2.02±0.71 mmol in stone formers. This difference was not significant. However, cosinor rhythmometry revealed a significant circadian rhythmicity in urinary citrate excretion in the healthy males which was absent in the stone formers; the amplitude was 0.06 mmol in non-stone formers and 0.017 mmol in stone formers. The acrophase was located at 14:25 h in non-stone formers and at 23:30 h in stone formers.This work was supported by a financial grant from the Indian council of Medical Research, New Delhi     

Value of routine citrate analysis and calcium/citrate ratio in calcium urolithiasis

24-hour urinary citrate excretion was measured in 176 calcium oxalate stone formers and 100 normal controls. A statistically significant difference (p less than 0.03) could be found between the two groups. When stone formers were divided into a group of 69 patients with recurrent calcium urolithiasis (RCU) and a group of 106 patients with a single stone episode, the latter did not differ from the control group, while in RCU a significantly lower citrate excretion compared with controls (p less than 0.005) could be found. Thus, patients with RCU could benefit from alkali citrate prophylaxis. A female-male difference in citrate excretion could not be found in either the control group or stone formers. Recurrent stone formers presented a significantly higher calcium/citrate ratio compared with controls, which would indicate an increased risk for stone formation. The value of routine citrate analysis is limited, however, by the great, variability of citrate levels in stone formers and controls.     

Pathophysiology of incomplete renal tubular acidosis in recurrent renal stone formers: evidence of disturbed calcium,bone and citrate metabolism

Summary Urinary acidification, bone metabolism and urinary excretion of calcium and citrate were evaluated in 10 recurrent stone formers with incomplete renal tubular acidosis (RTA), 10 recurrent stone formers with normal urinary acidification (NUA) and 10 normal controls (NC). Patients with iRTA had lower plasma standard bicarbonate after fasting (P<0.01) and lower urinary excretion of titratable acid (P<0.05) and citrate (P<0.01) compared with NUA patients and NC, and higher urinary excretion of ammonia (P<0.05) compared with NC (P<0.05). Hypercalciuria was found in 6 of 10 patients with iRTA compared with 3 of 10 with NUA, and O of 10 NC. The citrate/calcium ratio in urine was significantly reduced in iRTA compared with the value in NUA (P<0.01), and in NUA compared with NC (P<0.05). Biochemical markers of bone formation (serum osteocalcin) and bone resorption (urinary hydroxyproline) were significantly increased in iRTA compared with NUA and NC (P<0.01), indicating increased bone turnover in stone formers with iRTA. Stone formers with iRTA thus presented with disturbed calcium, bone and citrate metabolism-the same metabolic abnormalities which characterize classic type 1 RTA. Mild non-carbonic acidosis during fasting may be a pathophysilogical factor of both nephrolithiasis and disturbed bone metabolism in stone formers with iRTA     

Acute acid load in recurrent oxalate stone formers

An acute acid load was used to evaluate potential chemical differences of urinary composition in recurrent oxalate stone formers and healthy controls. After intake of ammonium chloride, total calcium, ionized calcium and magnesium increased and citrate decreased significantly in both groups. Differences between stone formers and controls could be demonstrated from the excretion of total calcium, citrate, oxalate and uric acid only after acute acid load, whereas ionized calcium did not improve discrimination. These findings support the stone-promoting role of high acid food as well as the possibility of discriminating recurrent oxalate stone formers from controls by an acute acid-loading test.     

Role of inhibitor deficiency in urolithiasis. I. Rationale of urinary magnesium, citrate, pyrophosphate and glycosaminoglycan determinations.

Between October 1988 and March 1990, 173 urinary stone patients (average age 38.3 years) were evaluated metabolically, especially with regard to urinary magnesium, pyrophosphate (Ppi) citrate and glycosaminoglycans (GAG). 25 healthy subjects served as controls. Inhibitory deficiency was found to be the most frequent causal factor in our series, with an incidence of 48.7% in first-time stone formers and 51.08% in recurrent urolithiasis (p less than 0.1). Deficient citrate levels were present in 46.56%, hypomagnesiuria in 24.4%, hypopyrophosphaturia in 10.7% and deficient GAG in 2.7% of the patients. Deficient urinary Ppi was seen in only 2.7% of the stone formers as the only metabolic defect, while deficient GAG was never the only causal factor. All 4 inhibitors showed no correlation with age, sex, activity of stone disease, stone weight and burden. There were no statistically significant differences with controls. We think that routine metabolic evaluation must be performed both in recurrent patients and first-time stone formers and must include urinary citrate and Mg determinations in every case. Urinary Ppi should be determined in selected cases and GAG determinations are irrational.     

Acute caffeine effects on urine composition and calcium kidney stone risk in calcium stone formers

PURPOSE: Caffeine increases urinary calcium (ca) excretion in nonstone formers. We designed a study to determine the effect of caffeine consumption on urinary composition in stone formers. MATERIALS AND METHODS: A total of 39 normocalcemic patients with calcium stones consumed caffeine (6 mg/kg lean body mass) after 14 hours of fasting. Urinary composition was compared 2 hours before and 2 hours after caffeine consumption. Control subjects included 9 nonstone formers studied contemporaneously with patients plus data from 39 nonstone formers from previous studies matched to each patient by level of fasting calcium/creatinine (Cr), gender and age. RESULTS: Caffeine increased urinary Ca/Cr, magnesium/Cr, citrate/Cr and sodium/Cr but not oxalate/Cr in stone formers and controls. The Tiselius stone risk index for calcium oxalate precipitation increased from 2.4 to 3.1 in stone formers and from 1.7 to 2.5 in nonstone formers. Of the 39 stone formers 32 had an increased Tiselius risk index after caffeine. Post-caffeine increases in Ca/Cr and Na/Cr were highly correlated. CONCLUSIONS: Caffeine consumption may modestly increase risk of calcium oxalate stone formation.     

Hypocitraturia as a pathogenic risk factor in the mixed (calcium oxalate/uric acid) renal stones.

A small group of patients with nephrolithiasis who forms mixed (calcium oxalate and uric acid) calculi presents particular problems in their clinical management. In 3,158 stones analyzed in our laboratory, we found 158 mixed calculi in 86 of the patients. In this work, the clinical and biochemical results obtained from 27 patients with mixed stones were compared with those from 27 control patients with calcium oxalate renal lithiasis. A significant difference was found in oxalate and citrate urinary elimination (mean +/- SD) in mixed stone formers versus pure calcium oxalate stone formers: oxaluria (mg/24 h: 38 +/- 15 vs. 28 +/- 12; p less than 0.01) and citraturia (mg/24 h: 214 +/- 139 vs. 437 +/- 303; p less than 0.01). Citraturia was decreased in a high proportion (77%) in mixed stone formers, and only a reduced percentage of them (23%) presented normal values, although in the low limit of normality. As treatment and prophylactic measure, we proposed oral administration of citrates in mixed stone patients because citrate inhibits spontaneous nucleation of calcium salts and crystal growth, and it also increases the urinary pH with a consequent increase in uric acid solubility.     

A study on the cause of urolithiasis of the upper urinary tract--clinical study of risk factors in the formation of stones in the upper urinary tract

Various risk factors and inhibitors of the stone formation of the upper urinary tract have been pointed out in urine. We examined the amount of daily excretion of several important risk factors (calcium, phosphorus, urate and oxalate) and inhibitors (magnesium and citrate) in the urine of 21 healthy males, 13 male single stone formeks and recurrent and/or multiple stone formers before and after taking the regular diet which contains 500 mg of calcium and 1,000 mg of phosphorus a day. The daily excretion of calcium, phosphorus and magnesium indicated no significant differences among the 3 groups. The excretion of oxalate in urine for 24 hours was significantly decreased in the stone formers after taking the regular diet. The urinary excretion of the urate per body surface area in the stone formers was significantly higher than that in the healthy control. The amount of the excretion of the citrate in urine in the recurrent and/or multiple stone formers was significantly lower than that in the other 2 groups. Many patients of the recurrent and/or multiple urinary stones had more than two abnormal values of above-mentioned risk factors and inhibitors. These results suggest that the causes of the formation of the upper urinary stone were not single but multiple and that the dietary advice to these patients was important against the recurrence of the urolithiasis.     

Calcium and citrate excretion by patients with calculi and healthy probands during induced acidosis

Acidosis induced increase in renal calcium excretion and decrease in renal citrate excretion was produced by means of ammonium chloride load in 15 patients with recurrent oxalate lithiasis and in 15 control subjects. The expected increase in the calcium citrate relationship in urine is more marked and more lasting in stone patients. Stone formers obviously respond to an acidotic metabolic situation by a more clear relative decrease in citrate excretion, in addition to more intensive calcium excretion, which is known. A certain individual sensitivity of renal tubular mechanisms is discussed with regard to acid base changes.     

A study of the etiology of idiopathic calcium urolithiasis in children: hypocitruria is the most important risk factor

PURPOSE: To determine the association of metabolic risk factors with pediatric calcium urolithiasis we compared metabolic evaluation data on children with idiopathic calcium stones and those on healthy children. MATERIALS AND METHODS: Metabolic evaluation was done in 78 calcium stone formers 1 to 15 years old (mean age 7.2) who were free of urinary tract infection, anatomical abnormalities, and metabolic, endocrinological and intestinal disorders, and in 24 healthy children. Evaluation included serum biochemistry, and measurement of daily excretion of urinary calcium, oxalate, urate, phosphorus, citrate and magnesium. RESULTS: Demographic characteristics, serum parameters, and daily excretion of calcium, urate, phosphorus and magnesium did not differ statistically in the 2 groups. However, urinary oxalate was significantly higher and urinary citrate was significantly lower in stone formers than in controls (p = 0.002 and 0.028, respectively). Hypocitruria and hyperoxaluria were 4.3 and 3-fold more common in stone formers than in controls, respectively. Multivariate analysis using logistic regression showed that hypocitruria was the only significant risk factor for idiopathic calcium stones (p = 0.008). CONCLUSIONS: Hypocitruria was the most important risk factor in our patients. Hyperoxaluria was also common and accompanied hypocitruria in many stone formers. In contrast to many previous reports, we failed to show that hypercalciuria is an important metabolic defect for idiopathic calcium stones, possibly because our study evaluated a different population.     

Estimation of the concentration of urinary ionic calcium and its clinical role in urolithiasis

The concentration of urinary ionic calcium was estimated using an ion-selective electrode and ion analyzer for healthy controls and patients with calcium urolithiasis. The following results were obtained: 1) After calculating the ionic strength and calibrating the standard solutions of ionic calcium in each urine, the urinary ionic calcium was estimated using an ion-selective electrode and ion analyzer. The reproducibility and accuracy of the value of urinary ionic calcium were satisfactory. 2) There was a significant correlation between the concentration of urinary ionic calcium and the total calcium excretion. Although the percentage of ionic calcium did not show any correlations among the total calcium, oxalate and urinary pH, it had an inverse relation to urinary citrate and phosphate. 3) In calcium stone formers, the excretion of ionic calcium was higher than in healthy controls significantly. 4) In hypercalciuric calcium stone formers, the concentrations and excretions of total and ionic calcium were significantly higher than in normocalciuric calcium stone formers. However, the percentage of ionic calcium was not different. 5) When the patients were treated with citrate orally, the excretion of urinary citrate was increased, and the excretion of ionic calcium and the percentage for total calcium were decreased significantly. There were significant reductions of ionic calcium in the urine after oral administration of rice-bran. 6) The estimation of urinary ionic calcium might be important to evaluate the urinary risk in recurrent calcium stone, and to estimate the effects of the preventive treatments for its recurrence.     

The influence of diet on urinary risk factors for stones in healthy subjects and idiopathic renal calcium stone formers

The daily intake of 103 recurrent idiopathic calcium stone formers and 146 controls was assessed by means of a computer-assisted 24-h dietary record. Timed 24-h urine samples were collected over the same period to assess the relationship between dietary intake of nutrients and urinary risk factors for calcium stones. After standardisation for sex, age and social status a total of 128 subjects underwent final statistical analysis; 64 renal stone formers and 64 controls. Significant increases in the consumption of animal and vegetable protein and purine were identified as the nutritional factors that distinguished renal stone formers from controls. As expected, the daily urinary excretion of calcium and oxalate was higher and the daily urinary excretion of citrate was lower in stone formers than in controls. No difference with respect to daily urinary uric acid excretion was recorded. Daily urinary excretion of calcium was correlated to dietary protein intake while daily urinary oxalate was correlated to dietary vitamin C intake. It was concluded that renal stone formers could be predisposed to stones because of their dietary patterns. A link between the protein content of the diet and urinary calcium was confirmed, but dietary animal protein had a minimal effect on oxalate excretion.     

The relationship of 3' vitamin D receptor haplotypes to urinary supersaturation of calcium oxalate salts and to age at onset and familial prevalence of nephrolithiasis.

BACKGROUND: Idiopathic hypercalciuria (IHc) and idiopathic hypocitraturia are frequently associated with calcium nephrolithiasis. We investigated the relationship of vitamin D receptor (VDR) polymorphisms (BsmI, TaqI and FokI) to urinary supersaturation of calcium oxalate salts in recurrent calcium oxalate stone formers with IHc and the clinical relevance of this relationship. METHODS: The study included 110 Caucasian stone formers with IHc and 127 unrelated healthy controls without history of nephrolithiasis. Age at onset of nephrolithiasis, familial history score (FHS) and the ion activity product of calcium oxalate salts in urine (AP(CaOx)) were tabulated. BsmI, TaqI and FokI VDR polymorphisms were evaluated in all participants. RESULTS: Patients and controls were classified as homozygous (bbTT and BBtt) or heterozygous in relation to BsmI and TaqI polymorphisms. Compared with BBtt patients, bbTT homozygous stone formers showed lower citrate excretion (1.91+/-0.89 vs 3.46+/-1.39 mmol/24 h, P = 0.004) and higher AP(CaOx) (2.02+/-0.51 vs 1.53+/-0.53, P = 0.006). Among controls, there were similar differences in citrate excretion and AP(CaOx) between the two groups, but they were not statistically significant. Compared with BBtt, bbTT patients showed lower mean age at onset of nephrolithiasis (29.7+/-12.1 vs 38.1+/-12.7 years, P = 0.008) and higher values of FHS (2.45+/-1.9 vs 0.83+/-0.7, P = 0.006). Similar results were obtained for individual BsmI and TaqI alleles. The analysis of FokI alleles was not informative. CONCLUSIONS: Recurrent calcium oxalate stone formers with IHc and the bT VDR haplotype have more aggressive kidney stone diseases as indicated by a higher familial incidence and lower mean age at onset. This clinical severity is associated with the higher urinary supersaturation of calcium oxalate salts and abnormalities of renal citrate handling.     

Chronopharmacological studies on potassium citrate treatment of oxalocalcic urolithiasis

The effect of minimum doses of extradietary potassium citrate ingestion on urolithogenic parameters has been studied. Separate urine fractions were collected in 24-hour periods. Five calcium oxalate stone formers have participated in the study. pH, calcium, citric acid, and the crystallization inhibitory capacity levels in fractional urine samples were determined before and during treatment. The most beneficial effect (increase in citraturia and crystallization inhibitory capacity) was produced by potassium citrate tablets ingested after dinner.     

Genetic and dietary factors in urinary citrate excretion

BACKGROUND AND PURPOSE: Hypocitraturia, an important risk factor for calcium oxalate nephrolithiasis, is the result of numerous factors. We studied citrate excretion by patients with and without stones consuming normal and controlled formula diets. SUBJECTS AND METHODS: Subjects with and without a history of calcium oxalate stones (N = 101 per group) provided two or three 24-hour urine specimens during consumption of self-selected diets. Data also were collected on subsets of subjects consuming formula (Ensure) diets. Citrate was determined using the citrate lyase method of Petrarulo and associates, and values for multiple specimens were averaged. The data were adjusted for creatinine excretion and examined on a per-day basis. RESULTS: The mean citrate excretion of the non-stone formers was slightly but not significantly higher than that of the stone formers (442 +/- 217 versus 378 +/- 153 mg/g of creatinine). All statistical analyses revealed highly significant differences between, but not within, individuals, a result compatible with a genetic influence. In the normal population, 5% of subjects had a citrate excretion <200 mg/g of creatinine, whereas this result was seen in 34% of the stone-forming subjects. When the subjects consumed a formula diet, women in both groups had much higher citrate excretion than when on a self-selected diet, but little difference was seen in the men. The patterns of citrate recovery suggest low, intermediate, and high excretors. In the normal population, 15% of subjects excreted <340 mg/g of creatinine, whereas this was true of 43% of the stone-forming subjects. Analysis of six families suggested three excretor phenotypes, with a codominant pattern of inheritance. CONCLUSION: These findings imply a genetic influence on citrate excretion, as has already been demonstrated for calcium excretion. Further studies of genetic influences on calcium oxalate stone formation are warranted.     

The effect of fruits and vegetables on urinary stone risk factors

BACKGROUND: The overall effect of fruit and vegetable intake on urinary stone risk profile is not yet known. METHODS: We studied the effect of a two-week period of fruit and vegetable elimination on urinary stone risk profile in 12 normal adults, and of supplementing the diet with a fair quantity of low-oxalate fruits and vegetables in 26 idiopathic calcium stone formers characterized by hypocitraturia and a very low fruit and vegetable intake in their usual diet. RESULTS: In the normal subjects, the elimination of fruits and vegetables from the diet decreased the urinary excretion of potassium (-62%), magnesium (-26%), citrate (-44%) and oxalate (-31%), and increased that of calcium (+49%) and ammonium (+12%) (P < 0.05 for all). The relative saturation for calcium oxalate and calcium phosphate increased from 6.33 to 8.24 (P = 0.028), and from 0.68 to 1.58 (P = 0.050), respectively. In the hypocitraturic stone formers, the introduction of these foods in the diet increased urinary volume (+64%), pH (from 5.84 to 6.19), excretion of potassium (+68%), magnesium (+23%), and citrate (+68%), while it decreased the excretion of ammonium (-18%) (P < 0.05 for all). The relative saturation for calcium oxalate and uric acid fell from 10.17 to 4.96 (P < 0.001), and from 2.78 to 1.12 (P = 0.003), respectively. CONCLUSION: The total elimination of fruits and vegetables in normal subjects brings about adverse changes in the urinary stone risk profile that are only partially counterbalanced by a reduction in oxalate. In contrast, the addition of these foods to the diet of hypocitraturic stone formers not used to eating them not only significantly increases citrate excretion without affecting oxalate excretion, but also decreases calcium oxalate and uric acid relative saturation.     

Crystal agglomeration is a major element in calcium oxalate urinary stone formation

The effects of urines from 36 healthy subjects and 86 calcium oxalate renal stone formers on calcium oxalate monohydrate crystallization kinetics were studied using a seeded crystal growth method in which the solubility, the growth and the agglomeration of the crystals are measured as three separate and system-independent parameters. The urines of healthy subjects were found to increase the solubility and to strongly inhibit the growth and the agglomeration of calcium oxalate monohydrate crystals. The urines of stone formers had a similar effect on the solubility, but a significantly lower ability to inhibit the crystal growth and the crystal agglomeration. Of these two kinetic processes the inhibition of crystal agglomeration was more clearly affected, with 55% of the stone formers having abnormally low values, while the changes in crystal growth inhibition occurred within the normal range. The defect in crystal agglomeration inhibition was related to stone frequency, and urines from patients with very high stone frequency rates had also the most severely impaired ability to inhibit the agglomeration of the calcium oxalate monohydrate crystals. The inhibitory effect of urines on crystal agglomeration was found to be related to its citrate content (r = 0.68, P less than 0.001). All patients with hypocitraturia, except two, had also abnormally low values for crystal agglomeration inhibition. In a group of 15 hypocitraturic stone formers, alkali treatment for a mean period of 18 months resulted in a parallel increase in urinary citrate excretion and in the ability of urines to inhibit crystal agglomeration (r = 0.77, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Epidemiology and medical management of stone disease

Recurrent stone formation in the urinary tract is a common and important problem that must be considered in daily urological practice. With a prevalence of> 10% and an expected recurrence rate of approximately 50%, stone disease has an important effect on the healthcare system. It is generally agreed that patients with uric acid/urate, cystine or infection stones always should be treated pharmacologically. For calcium stone formers the treatment should be chosen according to the severity of the disease. Recurrence in patients with calcium-stone disease can be prevented with general or specific dietary and drinking advice, and with pharmacological therapy. For idiopathic calcium stone formers the most convincing therapeutic effects have been reported with thiazide and alkaline citrate.     

Evolution of lithogenic urinary parameters with a low dose potassium citrate treatment

The changes in some nocturnal urine urolithogenic parameters in response to the extradietary ingestion of 2.16 g potassium citrate (20 meq) after dinner have been determined. The study included 15 patients (hypocitraturic calcium oxalate stone formers). On the basis of the different pH changes three groups have been differentiated. Different kinetics of citrate metabolism can justify the existence of these three groups. In general, a beneficial effect on urolithogenic parameters was confirmed, and a pH control of patients under treatment was recommended.     

Rethinking the role of urinary magnesium in calcium urolithiasis

BACKGROUND AND PURPOSE: The role of magnesium in urinary stone formation remains undefined. In vivo, magnesium inhibits stone formation in hyperoxaluric rats, and small clinical studies suggest a protective effect of magnesium supplementation in calcium oxalate stone formers. We performed a retrospective review of more than 7,000 stone patients to see if there is a relation between urinary magnesium and other stone risk variable constituents. MATERIALS AND METHODS: A national database of stone formers categorized by residential ZIP code was queried, and, using strict inclusion criteria, 2,147 patients having pure calcium oxalate stones were identified. There were 1,912 (89%) eumagnesuric (43-246 mg/24 hours) and 235 (11%) hypomagnesuric (<43 mg/24 hours) patients. RESULTS: Patients with decreased urinary magnesium excretion had significantly less daily urine excretion of citrate, calcium, oxalate, uric acid, and sodium than the eumagnesuric group (p < 0.0001). Stone recurrence was slightly more common in the hypomagnesuric group, although the difference was not statistically significant. The percentage of patients voiding <1 L of urine per day was significantly higher in the hypomagnesuric group. In the eumagnesuric group, males outnumbered females 2:1, whereas hypomagnesuric patients showed a female predominance of 1.4:1. CONCLUSION: The beneficial effects of urinary magnesium on stone formation may be less than previously reported. The role of oral magnesium supplementation and the subsequent increase in urinary magnesium in calcium urinary stone formation remains unknown. Our data suggest that its effect on or interaction with citrate may be influential on urinary citrate concentrations. If magnesium has a protective effect, it may work through pathways that enhance citrate excretion.