Citrate and recurrent idiopathic calcium urolithiasis

Summary In male patients with idiopathic recurrent calcium urolithiasis (RCU) the effects of oral potassium sodium citrate (PSC) on acid-base, citrate and mineral metabolism were investigated. There were 17 normocitraturic and 15 hypocitraturic patients. The examination time points in our clinical laboratory were prior to medication and after 3, 6 and over 12 months of medication. Urine collection periods were over 24 h, 2 h — after an overnight fast — 3 h postprandially. Acceptance by the patients was poor, a large number refusing to take PSC for 12 months. Compliance of the patients continuing with the study was adequate as assessed by the urinary excretion of potassium and sodium. No unwanted side effects were observed. After 3 months of PSC medication a compensated metabolic alkalosis developed; in the urine calcium was decreased, while citrate, pH and oxalate were increased, as were hydroxyapatite supersaturation and calcium phosphate particles. After more than 12 months of PSC medication, citrate and pH tended toward the pretreatment baseline values, while hydroxyapatite supersaturation and calcium had already returned to pretreatment values. Despite ongoing PSC intake, patients with pre-existing hypocitraturia had lower urinary citrate than patients with previous normocitraturia, while the concomitant pH and hydroxyapatite supersaturation in the urine of the former remained at levels close to those of the latter. Under the influence of PSC, parathyroid gland function remained unchanged, but serum levels of bone alkaline phosphatase and osteocalcin were low, and urinary hydroxyproline was high. We conclude that (1) PSC shifts the acid-base status toward metabolic alkalosis, and also modulates bone metabolism; (2) over the long term, PSC may be unable to achieve a constantly high urinary citrate, in particular in RCU with pre-existent hypocitraturia — in contrast to its short- and medium-term effects. Long-term interrupted medication with PSC is proposed for the metaphylaxis of RCU. A regimen of this type may also be expected to yield more insight into the mechanism(s) underlying hypocitraturia.     

Fasting gastrinemia and elevated supersaturation with hydroxyapatite of fasting urine — Observations in renal calcium stone patients and controls

Summary We evaluated serum gastrin, acid-base status, variables of mineral metabolism in fasting blood, as well as pH, relative supersaturation of stone forming constituents, and crystalluria in the associated fasting urine, of control subjects (n=12), and in age-and weight-matched male normocalciuric (n=12) and hypercalciuric (n=12) patients with idiopathic recurrent calcium urolithiasis (RCU). In RCU, mineral metabolism and acid-base data are unchanged, whereas mean serum gastrin is only insignificantly higher as compared to controls. Subclassification of all participants into categories with either high-normal or low-normal gastrin reveals that in RCU with low-normal gastrin there is a higher-than-normal urinary pH and significantly elevated supersaturation of urine with hydroxyapatite. Crystalluria and stone analysis support the assumption that the physicochemical environment accompanied by low gastrin levels predisposes to urinary precipitation of calcium phosphate with subsequent formation of a stone nidus. pH in fasting urine and integrated fasting serum gastrin correlate significantly, suggesting that low fasting serum gastrin in RCU patients may be considered a rick factor for calcium phosphate stone formation.Abbreviations used in this paper RCU Recurrent calcium urolithiasis - NC Normocalciuria - I-HC Idiopathic hypercalciuria - HAP Hydroxyapatite - cAMP cyclic AMP     

Postprandial hyperinsulinaemia, insulin resistance and inappropriately high phosphaturia are features of younger males with idiopathic calcium urolithiasis: Attenuation by ascorbic acid supplementation of a test meal

In idiopathic recurrent calcium urolithiasis (RCU) the state of insulin and carbohydrate metabolism, and relationships to minerals such as phosphate, are insufficiently understood. Therefore, in two groups of males with RCU (n = 30) and healthy controls (n = 8) the response to an oral carbohydrate- and calcium-rich test meal was studied with respect to glucose, insulin, and C-peptide in peripheral venous blood (taken before and up to 180 min post-load), and phosphate and glucose in fasting and post-load urine. In one RCU group (n = 16) the meal was supplemented with ascorbic acid (ASC; 5 mg/kg body weight). The mean age (RCU 29, RCU + ASC 30, controls 27 years) and mean body mass index [RCU 24.4, RCU + ASC 25.0, controls 24.0 kg/m²] were similar. Insulin resistance (synonymous sensitivity of peripheral organs to insulin) was calculated from insulin serum concentration, as was also integrated insulin, C-peptide, and glucose. Untreated stone patients (RCU) developed hyperinsulinaemia between 60 and 120 min post-load, increased integrated insulin, and insulin resistance (P 0.05 vs controls)., whereas the rise of C-peptide and glycaemia (absolute and integrated values) was only of borderline significance. Fasting phosphaturia was low in both RCU subgroups vs controls; however, phosphaturia in untreated RCU rose in response to the meal, contrasting sharply with a decrease in controls. ASC supplementation of the meal (in the RCU + ASC subgroup) normalized insulin, failed to normalize postload phosphaturia, but reduced post-load glucosuria and urinary pH significantly (mean pH values 5.55 vs 5.93 in untreated RCU, controls 5.50). Postprandial urinary oxalate, calcium, protein, and supersaturation products were not changed. The postprandial changes in phosphaturia and insulin sensitivity were inversely correlated (n = 38,r = -0.44,P = 0.007). It was concluded that in younger RCU males: (1) postprandial hyperinsulinaemia, the failure to reduce phosphaturia and —within limits — glucosuria, appropriately, as well as poor urine acidification are important features of the metabolism; (2) these phenomena are probably caused by insulin resistance of organs, the kidney included; and (3) the addition of a supraphysiological dose of ASC to a meal, the subsequent abolition of hyperinsulinaemia, and the restoration of normal urine acidification suggest that this antioxidant is capable of counteracting some preexisting basic abnormality of cell metabolism in RCU.     

Acute oral alkali citrate load in healthy humans — Response of blood and urinary citrate,mineral metabolism,and factors related to stone formation

Summary In ten healthy volunteers (/=5/5) the effects of two doses (2.5 and 5.0 g) of orally ingested alkali citrate (AC) on serum citrate, variables of mineral metabolism in serum, the urinary excretion of citrate, sodium and minerals were studied and compared with the effects of an oral vehicle load. Also, phosphate crystalluria and the supersaturation of several stone forming phases in urine were evaluated under all loads. The data allow to conclude that 1) the rise in serum citrate may result from citrate absorbed intestinally under AC;2) systemic metabolic alkalosis is not detectable with the chosen AC doses but may be reflected by the more alkaline urinary pH and a higher citrate excretion; 3) mineral metabolism, serum ionized calcium, parathormone, calcitonin and urinary cyclic AMP included, are more or less stable under acute loads of AC;4) postprandial phosphate crystalluria is more pronounced with increasing AC, but despite this the direct correlation with the supersaturation of hydroxyapatite is progressively weakened with both doses AC suggesting that the inhibitory effects of this drug may dominate over its effects upon initiation of precipitation.Parts of this work were presented at the European Urolithiasis Symposium, held in Vienna, from March 21 to 23, 1985     

Urinary phosphate excretion in the pathophysiology of idiopathic recurrent calcium urolithiasis: Hormonal interactions and lipid metabolism

Previous work in younger males with recurrent idiopathic calcium urolithiasis (RCU) demonstrated inappropriately high postprandial phosphaturia, hyperinsulinemia and insulin resistance, but normal glycemia. To investigate further whether these abnormalities occur also in RCU patients with a mean age corresponding to the life period with peak formation of calcium-containing stones, two trials were carried out in 155 males of comparable age and body mass index. All participants underwent a standardized laboratory examination, including collection of urine and blood before and following a test meal rich in carbohydrate and calcium but low in phosphorus. In trial 1, comprising control subjects (n = 12, mean age 42 years) and RCU patients (n = 24, mean age 41 years), phosphate (Pi) excretion and fractional Pi excretion in postprandial urine of controls did not change compared with the values in fasting urine, but were significantly increased in RCU, despite the fact that there was almost equal suppression of serum parathyroid hormone (PTH) and increase in serum calcitonin. Postprandially, RCU patients were hyperinsulinemic but still normoglycemic versus controls. In trial 2, carried out in unclassified (in terms of calciuria) RCU patients (n = 119, mean age 40 years) only, the post-load Pi-uria was similar in magnitude to Pi-uria of RCU patients in trial l; increased postprandial Pi-uria was a phenomenon also of normocalciuria but was slightly more pronounced in hypercalciuria, while changes in calcium phosphate (brushite) and calcium oxalate supersaturation of urine were unrelated to calciuria. In RCU patients, but not controls, there was a tendency toward higher urinary glucose in post-load as compared with fasting urine. When urinary Pi and fractional Pi excretion in trial 2 were considered as dependent variables in multivariate regression analysis, they appeared unrelated to age, but positively associated with postprandial glycemia as the best predictor, followed by insulinemia, insulin resistance, to a lesser degree fasting serum PTH and the metabolic activity of stone disease, negatively associated with blood total lipids and very low density lipoprotein (VLDL) cholesterol. It was concluded that RCU males (1) show low Piuria during fasting but impaired renal Pi conservation in response to a mixed meal, a situation carrying the risk of Pi deficiency over the long term; (2) represent a population developing hyperei-uria despite suppressed PTH; (3) exhibit insulin resistance but are still able to maintain normoglycemia at the expense of hyperinsulinemia. It is suggested that calcium-containing renal stones are related to impaired Pi and glucose translocation across cell membranes, and that the role of lipids in this setting deserves further investigation.     

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.     

Crystalluria determined by polarization microscopy

Summary A retrospective study was done on the nature and degree of crystalluria in spontaneously voided fasting and postprandial urine of patients with recurrent idiopathic calcium urolithiasis (RCU) divided into normocalciuria (20 males, 20 females) and hypercalciuria patients (20 males, 20 females), and controls (20 males, 20 females). The crystals were obtained using a filter technique and identified by microscopy. In addition, individual data, clinical chemistry variables and indices reflecting the risk of calcium phosphate and calcium oxalate crystallization were evaluated. In contrast to findings of other investigators of crystalluria we observed only a few crystals on the filters. The most frequently occurring phases were (in this order) a urate-containing phase (tentatively termed uric), an amorphous calcium phosphate phase (tentatively termed isotropic) and a phase of spheroid-like particles, not yet definitely characterized (tentatively termed spheroid). Calcium oxalate crystals were found only exceptionally. There was no relationship between the degree of calciuria (normo-versus hypercalciuric RCU) and crystalluria. Among RCU, males generally had a predominance of the isotropic, females of the spheroid phase, as compared with controls. Also, RCU females were generally obese, and their spheroid score and lean body mass correlated negatively and significantly. The calcium phosphate and calcium oxalate risk indices were always low in normal individuals, higher in RCU. Patients of both sexes with urinary stones had normal parathyroid gland function, but higher total calcium in fasting serum and higher urinary pH as compared with controls. From these data we concluded that (1) crystalluria is a regular finding in human urine, but is more pronounced in RCU; (2) in males, the isotropic phase, in terms of frequency and its score, may be causally related to the development of urolithiasis; (3) the spheroid phase, more frequently observed in RCU females, may reflect an as yet unknown metobolic disorder; (4) the rareness of calcium oxalate crystals despite a high calcium oxalate risk index suggests that such crystals may be adherent to upstream tissue.Part of this work was published as an abstract in Urol Res (1988) 16:235     

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.     

Calcium stone disease: a multiform reality

In calcium renal stones, calcium oxalate and calcium phosphate in various crystal forms and states of hydration can be identified. Calcium oxalate monohydrate (COM) or whewellite and calcium oxalate dihydrate (COD) or weddellite are the commonest constituents of calcium stones. Calcium oxalate stones may be pure or mixed, usually with calcium phosphate or sometimes with uric acid or ammonium urate. The aim of this study was to compare the clinical and urinary patterns of patients forming calcium stones of different composition according to infrared spectroscopic analysis in order to obtain an insight into their etiology. The stones of 84 consecutive calcium renal stone formers were examined by infrared spectroscopy. In each patient, a blood sample was drawn and analysed for serum biochemistry and a 24-h urine sample was collected and analysed for calcium, phosphate, oxalate, citrate and other electrolytes. We classified 49 patients as calcium oxalate monohydrate (COM) stone formers, 32 as calcium oxalate dihydrate (COD) stone formers and three as apatite stone formers according to the main component of their stones. Patients with COM stones were significantly older than patients with COD stones (P<0.002). Mean daily urinary calcium and urinary saturation with respect to calcium oxalate were significantly lower in patients with COM than in those with COD stones (P<0.000). Patients with calcium oxalate stones containing a urate component (10%) presented with higher saturation (P<0.012) with respect to uric acid in their urine (and lower with respect to calcium oxalate and calcium phosphate, respectively P<0.024 and P<0.003) in comparison with patients without a urate component in the stone. Patients with calcium oxalate stones with a calcium phosphate component (15%) showed higher (P<0.0016) urinary saturation levels with respect to calcium phosphate (and lower with respect to uric acid (P<0.009), compared with patients forming stones without calcium phosphate or with a low calcium phosphate component. Patients with calcium stones mixed with urate had a significantly lower urinary pH (P<0.002) and urinary calcium (P<0.000), and patients with calcium phosphate >15%, higher urinary pH (P<0.004) and urinary calcium (P<0.000). In conclusion, in the evaluation of the individual stone patient, an accurate analysis of the stone showing its exact composition and the eventual presence of minor components of the stone is mandatory in order to plan the correct prophylactic treatment. Patients with calcium stones could require various approaches dependent on the form and hydration of the calcium crystals in their stones, and on the presence of minor crystalline components that could have acted as epitaxial factors.     

Effect of transdermal l7β-estradiol and oral conjugated equine estrogens on biochemical parameters of bone resorption in natural menopause

Summary Objective: To evaluate and compare the effects or oral and transdermal estrogen replacement therapy on biochemical markers of bone resorption in early postmenopausal women Design: Controlled, randomized group comparison. Setting: Outpatient clinic for menopausal women and research into osteoporosis. Subjects: Sixty healthy women menopausal for less than 5 years and who had never received any medications interfering with bone metabolism. Interventions: The 60 women were randomly allocated to 3 months therapy with either oral conjugated estrogens (0.625 mg/day) (n = 28) or transdermal estradiol (50 jig/day) (n = 32) in cyclical combination with medroxyprogesterone acetate (5 mg/day). Main outcome measures: Traditional (urinary calcium/creatinine and hydroxyproline/creatinine) and the new specific (urinary pyridinoline/creatinine and deoxypyridinoline/creatinine) markers of bone resorption were determined before and after 3 months of treatment. Results: In both groups, circulating levels of estrone and estradiol were significantly (P < 0.001) increased during treatment. In women treated with oral conjugated equine estrogens, urinary calcium/creatinine and hydroxyproline/creatinine ratios were significantly (P < 0.05) reduced. Pyridinoline/creatinine ratio fell from 69.1 (4) [mean (SEM)] to 50 (4) mol/mol (P < 0.01) and deoxypyridinoline/creatinine ratio fell from 10.8 (1) [mean (SEM)] to 8.3 (0.8) mol/mol (P < 0.01). In the group treated with transdermal estradiol, urinary hydroxyproline/creatinine ratio was significantly (P < 0.05) reduced. Pyridinoline/creatinine ratio fell from 66.3 (4) [mean (SEM)] to 46.2 (3) mol/mol (P < 0.01) and deoxypyridinoline/creatinine ratio fell from 11.5 (1.5) [mean (SEM)] to 7.7 (0.6) mol/mol (P < 0.01). There were no differences between the evolution of the biochemical variables in the two groups. Conclusion: These results suggest that oral conjugated equine estrogens and transdermal estradiol, in the given doses, are equally effective in reducing postmenopausal bone resorption.     

Correspondence between Ca2+ and calciuria, citrate level and pH of urine in pediatric urolithiasis

Background

Hypercalciuria and hypocitraturia are considered the most important risk factors for urolithiasis. Citrate binds to urinary calcium to form a soluble complex which decreases the availability of ionized calcium (Ca²⁺) necessary for calcium oxalate formation and phosphate crystallization. The aims of this study were to assess the Ca²⁺ fraction in relation to total calciuria, citraturia and urinary pH and to determine whether urinary Ca²⁺ concentration is a helpful biomarker in metabolic evaluation of children with urolithiasis.

Methods

We collected 24-h urine samples from 123 stone-forming children and adolescents with hypocitraturia and from 424 healthy controls. Total calciuria (total calcium, Ca_total), Ca²⁺, pH, citrate, oxalate and Bonn Risk Index (BRI) were assessed and compared between the two groups.

Results

Total calciuria and Ca²⁺ content were higher in stone-formers than in the healthy children. In both stone-formers and controls, Ca²⁺ content was inversely related to citraturia and urinary pH, whereas the Ca²⁺/Ca_total ratio differed slightly between the groups. A large variability in Ca²⁺ level was found across individuals in both groups. The BRI increased with increasing calciuria and urine acidity.

Conclusions

Compared to controls, stone-formers with hypocitraturia demonstrated a higher urinary Ca²⁺ concentration, but this was proportional to calciuria. The large individual variability in urinary Ca²⁺ content limits its practical use in metabolic evaluation of children with urolithiasis. However, the Ca/Citrate ratio may be a useful clinical tool in evaluating children with urolithiasis.     

Factors modulating the pH at which calcium and magnesium phosphates precipitate from human urine

The factors controlling the rate at which crystalline bacterial biofilms develop on indwelling bladder catheters are poorly understood. It is known that normally the pH of voided urine (pH_v) is lower than the pH at which calcium and magnesium phosphates come out of urine solution (pH_n). In patients who develop infections with urease producing bacteria, however, the pH_v rises above the pH_n and precipitation of the phosphates occurs in the urine and the biofilm. The aim of this study was to examine ways of manipulating the pH_n of urine so that more of its calcium and magnesium remain in solution under alkaline conditions. The experimental data show that pH_n can be elevated by decreasing the calcium, magnesium and phosphate concentrations. Increasing the fluid intake of a human subject so that the urinary calcium fell from 120 mg/l to 25 mg/l, for example, resulted in the pH_n increasing from 6.48 to 8.22. The addition of citrate to urine also produced a rise in the pH_n. The daily consumption of 500 ml of fresh orange juice increased urinary citrate concentrations from 0.35 to around 1.21 mg/ml and the pH_n rose from 7.24 to 8.2. The pH_n of urine is thus a highly variable parameter. It can be manipulated by controlling the urinary concentrations of magnesium, calcium, phosphate and citrate ions. We suggest that increasing fluid intake with citrate containing drinks would reduce the extent of encrustation on catheters in patients infected with urease producing bacteria.     

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.     

Phyllanthus niruri normalizes elevated urinary calcium levels in calcium stone forming (CSF) patients

Phyllanthus niruri is a plant used for years in Brazil to treat urinary calculi. We prospectively evaluated the effect of P. niruri intake on 24 h urinary biochemical parameters in an attempt to assess its in vivo effect in calcium stone forming (CSF) patients. A total of 69 CSF patients (39 males and 30 females, 38±8 years old) were randomized to take either P. niruri (n=33) (450 mg capsules, td) or placebo (n=36) for 3 months. Blood calcium, uric acid, citrate, magnesium, oxalate, sodium and potassium were determined at baseline and at the end of the study. A subset analysis was made in patients classified according to the presence of metabolic abnormalities (hypercalciuria, hyperuricosuria, hyperoxaluria, hypocitraturia and hypomagnesiuria). Overall, there were no significant differences in the mean values of urinary parameters between the urine samples before and after P. niruri intake, except for a slight reduction in mean urinary magnesium after P. niruri, which was within the normal range. However, in the subset analysis, we observed that P. niruri induced a significant reduction in the mean urinary calcium in hypercalciuric patients (4.8±1.0 vs 3.4±1.1 mg/kg/24 h, P<0.05). In this short-term follow-up, no significant differences in calculi voiding and/or pain relief between the groups taking P. niruri or the placebo were detected. Our data suggest that P. niruri intake reduces urinary calcium based on the analysis of a subset of patients presenting with hypercalciuria. Larger trials including primary hypercalciuric stone formers should be performed in order to confirm these findings and to determine the possible clinical consequences of urinary calcium reduction during P. niruri administration.     

Prophylactic and therapeutic properties of a sodium citrate preparation in the management of calcium oxalate urolithiasis: randomized, placebo-controlled trial

The purpose of this study was to investigate the prophylactic and therapeutic effects of a hitherto untested preparation containing sodium citrate in the management of calcium oxalate urolithiasis. In this study, a host of calcium oxalate kidney stone risk factors was investigated using a randomised, placebo controlled, within-patient clinical trial. The trial involved four groups of subjects: healthy male controls, healthy female controls , calcium oxalate stone-forming males and calcium oxalate stone-forming females. There were 30 subjects in each group. Twenty subjects in each group ingested the preparation containing sodium citrate and ten subjects in each group ingested a placebo for 7 days. Collection of 24 h urines were carried out at baseline, at day 7 and day 10 (i.e. 3 days after suspension of drug/placebo ingestion). These were analysed for biochemical and physicochemical risk factors. They were also tested for their inhibitory properties in crystallization experiments. Data were statistically analyzed using analysis of variance (ANOVA). Key risk factors were significantly and beneficially altered across all groups after ingestion of the preparation. The pH and urinary citrate excretion increased while urinary oxalate and calcium excretions decreased, as did relative supersaturations of calcium oxalate and uric acid. In addition, inhibition of calcium oxalate crystallization increased. Beneficial carryover effects were observed for some risk factors. The results of this study have demonstrated, for the first time, that a sodium citrate-containing preparation favourably alters the risk factors for calcium oxalate urolithiasis.     

Biochemical control of bone loss and stone-forming propensity by potassium-calcium citrate after bariatric surgery

BackgroundPatients undergoing Roux-en-Y gastric bypass (RYGB) surgery are prone to developing bone loss and kidney stones. The goal of the present study was to test the hypothesis that an effervescent formulation of potassium calcium citrate (PCC) would avert metabolic complications by providing bioavailable calcium and alkali.MethodsA total of 24 patients with RYGB underwent a 2-phase crossover randomized trial comparing PCC and placebo. During the last 2 days of each 2-week phase, the serum and 24-hour urine samples were analyzed for calcium and bone turnover markers, acid base status, and urinary stone risk factors.ResultsCompared with placebo, PCC marginally reduced the serum parathyroid hormone level and significantly decreased urinary deoxypyridinoline by 12% (P <.001) and serum type 1 collagen C-telopeptide by 22% (P <.01). PCC significantly increased the net gastrointestinal alkali absorption, citrate, and pH and significantly lowered the urinary net acid excretion (P <.001). The urinary saturation of uric acid decreased significantly (P <.001). The supersaturation of calcium oxalate and brushite did not change despite an increase in calcium and pH. In untreated urine samples with citrate concentrations altered to mimic those of placebo and PCC, calcium oxalate agglomeration was significantly inhibited by PCC.ConclusionIn RYGB patients, PCC supplementation inhibited bone resorption by providing bioavailable calcium, reduced the urinary saturation of uric acid, and increased the inhibitor activity against calcium oxalate agglomeration by providing alkali that increased urinary pH and citrate.     

Insulin resistance increases the risk of urinary stone formation in a rat model of metabolic syndrome

OBJECTIVE

To investigate the association between metabolic syndrome and urinary stone disease, and whether insulin resistance associated with adiposity affects the risk of urinary stone formation, using a rat model of metabolic syndrome.

MATERIALS AND METHODS

Four‐week‐old male Otsuka Long‐Evans Tokushima ‘Fatty’ (OLETF, a model of human type 2 diabetes and metabolic syndrome) rats, and Long‐Evans Tokushima (LETO, a non‐diabetic control) rats (10 each) were given a standardized diet and free access to water. Body weight and serum and urinary biochemistry were determined every 4 weeks. Ten‐week‐old male OLETF and LETO rats were divided into three groups of nine each and treated with vehicle or oral administration of 3 or 10 mg/kg/day pioglitazone, an agent that improves insulin resistance. After 4 weeks, body weight and serum and urinary biochemistry were determined.

RESULTS

The OLETF rats had significantly lower urinary pH and citrate excretion, and higher urinary uric acid and calcium excretion, than the LETO rats, with increases in body weight, serum triglyceride, glucose and insulin. The administration of pioglitazone to the OLETF rats for 4 weeks significantly increased urinary pH dose‐dependently. There was no change in the urinary excretion of citrate, uric acid, calcium, oxalate or magnesium.

CONCLUSION

These results indicate that metabolic syndrome causes the changes in urinary constituents, leading to increased risk of both uric acid and calcium stone formation. Improvement in insulin resistance, a central cause of metabolic syndrome, might prevent uric acid stone formation by raising urinary pH.     

Magnesium, citrate, magnesium citrate and magnesium-alkali citrate as modulators of calcium oxalate crystallization in urine: observations in patients with recurrent idiopathic calcium urolithiasis

The effects of magnesium (Mg) and citrate on the metastable limit of calcium oxalate (CaOx) solubility (synonym: tolerable oxalate TO) were examined in artificial urine and in postprandial urine of male patients with idiopathic calcium urolithiasis (ICU). In artificial urine increasing pH, Mg and citrate elevate TO, decrease CaOx supersaturation only marginally, but elevate considerably free citrate; the effect of Mg alone was small in comparison with citrate alone, and the effects of both substances appeared additive. In ICU patients, matched for sex, age and CaOx supersaturation to non-stone-forming controls, TO was decreased (mean values 0.33 vs. 0.52 mM/l in controls, P < 0.05). Additional significant (P < 0.05) differences were found between ICU and controls: the former exhibited increased CaOx crystal growth, decreased crystal agglomeration time, a more acidic urinary pH, increased concentrations of free calcium and free Mg, and decreased free oxalate and free citrate. After ingestion of a urine-acidifying test meal, or this meal supplemented with either neutral Mg citrate or Mg-alkali citrate, by three groups of male ICU patients, matched for age and CaOx supersaturation, only the last-named preparation evoked an increase in TO and a decrease in crystal diameter, while the normally occurring pH decline from fasting urine was virtually abolished, and the ratios urinary Mg/citrate and calcium/citrate tended towards low values. In contrast, Mg citrate increased crystal agglomeration time, while changes in the other parameters were only insignificant. The crystals formed in urine were CaOx di- and monohydrate (by electron microscopy), and energy dispersive X-ray analysis showed calcium peaks exclusively. However, chemical analysis of crystals verified the presence not only of oxalate and calcium, but also of Mg, phosphate, citrate, and urate; moreover, these crystal constituents seemed to be influenced by Mg citrate and Mg-alkali citrate in different ways. It was concluded that (1) Mg and citrate are effectors of TO in artificial and natural urine; (2) in ICU, low TO and other disturbed CaOx crystallization parameters appear related to the prevailing low urinary pH and low free citrate; (3) Mg-alkali citrate inhibits CaOx crystallization, probably via actions of the citrate, but not the Mg. Because of the eminent role of Mg in human health and ICU, further studies on crystallization after oral intake of Mg in the form of citrate are warranted. Received: 15 May 1998 / Accepted: 9 October 1998     

Measurement of BBN-induced alterations in rat urothelium by electron microscopic X-ray microanalysis

The aim of this study was to analyseN-butyl-n-butanol-4-nitrosamine (BBN)-induced alterations of the urothelium in rats concerning its content of phsphorus, sulphur, chlorine, potassium and calcium using electron microscopic X-ray microanalysis (REM analysis). The following histopathological findings of the bladder mucosa were discovered after exposure to BBN: normal urothelimm (n=36); focal epithelial proliferations (n=12) following 6–12 weeks' exposure; epithelial hyperplasia (n=8) after urothelial carcinoma (n=4) following 12 weeks' exposure. The observed phosphorus/sulphur and phosphorus/calcium ratios based on REM analysis did not show any statistical correlation with the morphological changes classified by light microscopy. Our data do not support the hypothesis raised by other investigators that an increase in phosphorus content or phosphorus/sulphur or phosphorus/calcium ratio could indicate early neoplastic transformations of urothelial cells as tumor markers.     

RENAL STONE RISK ASSESSMENT DURING SPACE SHUTTLE FLIGHTS

Purpose

The metabolic and environmental factors influencing renal stone formation before, during, and after Space Shuttle flights were assessed. We established the contributing roles of dietary factors in relationship to the urinary risk factors associated with renal stone formation.

Materials and Methods

24-hr. urine samples were collected prior to, during space flight, and following landing. Urinary and dietary factors associated with renal stone formation were analyzed and the relative urinary supersaturation of calcium oxalate, calcium phosphate (brushite), sodium urate, struvite and uric acid were calculated.

Results

Urinary composition changed during flight to favor the crystallization of calcium-forming salts. Factors that contributed to increased potential for stone formation during space flight were significant reductions in urinary pH and increases in urinary calcium. Urinary output and citrate, a potent inhibitor of calcium-containing stones, were slightly reduced during space flight. Dietary intakes were significantly reduced for a number of variables, including fluid, energy, protein, potassium, phosphorus and magnesium.

Conclusions

This is the first in-flight characterization of the renal stone forming potential in astronauts. With the examination of urinary components and nutritional factors, it was possible to determine the factors that contributed to increased risk or protected from risk. In spite of the protective components, the negative contributions to renal stone risk predominated and resulted in a urinary environment that favored the supersaturation of stone-forming salts. Dietary and pharmacologic therapies need to be assessed to minimize the potential for renal stone formation in astronauts during/after space flight.