The value of urine citrate/calcium ratio in the estimation of risk of urolithiasis

The urine saturation is considered as the better parameter for the estimation of risk of urolithiasis than any single urinary constituent. However, the determination of urine saturation is unsuitable for routine clinical practice. To evaluate a simpler and cheaper test than urine saturation for distinguishing stone formers from healthy individuals, urinary citrate/calcium ratio was determined in 30 children with urolithiasis, 36 children with isolated hematuria, and 15 healthy control children. The ratio was significantly lower in urolithiasis group comparing to controls, and significantly higher in hematuria than in urolithiasis group. The cut-off points between normal children and children with urolithiasis, accuracy, specificity and sensitivity were determined and compared with those of the urine saturation calculated with the computer program EQUIL 2. The data mining Weka software was used for the determination of the cut-off points. Children with urolithiasis had citrate/calcium ratio below 1.38 and urine saturation above 5.285. The citrate/calcium ratio showed in comparison to urine saturation similar high accuracy (91.11 vs. 88.89%), somewhat lesser specificity (73.33% vs. 93.33%) and much better sensitivity (100% vs. 86.89%) in discrimination of stone formers from normal children. The advantage in comparison to urine saturation is that it can be easily performed in clinical practice.     

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     

Effects of sodium citrate, potassium citrate, and citric acid in preventing experimental calcium oxalate urolithiasis in rats

Male Wistar-strain rats which had been fed a glycolic-acid diet developed severe nephrocalcinosis with urinary calculi within 4 weeks. Rats fed the same diet with citrate salts added had, however, either slight or no nephrocalcinosis without any stones in the urinary system. Nephrocalcinosis intermediate between those in the citrate groups and the glycolic-acid group, with some urinary calculi, was observed in the citric-acid group. During the experiment, the urinary oxalate concentration increased markedly and was higher in the citrate and citric-acid than in the glycolic-acid group. The urinary citrate concentration was significantly higher in the citrate groups and lower in the citric acid and glycolic-acid groups. Therefore, citrate salts can be concluded to inhibit nephrocalcinosis and calculi formation as a result of decreased urinary saturation by means of increase in urinary citrate, in spite of a slight increase in the urinary oxalate.     

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.     

Prevention of spinal bone loss by potassium citrate in cases of calcium urolithiasis

PURPOSE: We assessed the effectiveness and safety of holmium:YAG laser lithotripsy for managing upper urinary tract calculi in a prospective cohort of 598 patients. MATERIALS AND METHODS: Ureteroscopic holmium:YAG laser lithotripsy was performed in 598 patients between 1993 and 1999. Calculi were located in the distal ureter in 39.6% of cases, mid ureter in 18.6%, proximal ureter in 32.4% and kidney in 9.4%. Patients were treated on an outpatient basis with various flexible and semirigid endoscopes. Of the cases 59% were referred as previous treatment failures. Patients were assessed 6 to 12 weeks postoperatively with repeat plain x-ray and ultrasound or excretory urography for late obstructive complications. RESULTS: The overall stone-free rate was 97%. As stratified by location, the stone-free rate was 98% in the distal ureter, 100% in the mid ureter, 97% in the proximal ureter and 84% in the kidney. Fragmentation was incomplete in 6% of cases and secondary intervention was required in 6%. The overall complication rate was 4%. New onset ureteral stricture developed postoperatively in 0.35% of patients. CONCLUSIONS: Holmium:YAG laser lithotripsy is a highly effective and safe treatment modality for managing ureteral and a proportion of intrarenal calculi on an outpatient basis. The effectiveness and versatility of the holmium laser combined with small rigid or flexible endoscopes make it our modality of choice for ureteroscopic lithotripsy.     

Inhibitory effect of pyrophosphate, citrate, magnesium and chondroitin sulphate in calcium oxalate urolithiasis

The inhibitory capacity of pyrophosphate, citrate, magnesium and chondroitin sulphate was investigated, using the urine of 21 calcium oxalate stone-forming patients without metabolic alterations. The inhibitory effect of these substances was assessed by a combination of nephelometry (light scattering) and optical microscopy. The results showed that citrate and magnesium had an inhibitory effect in a significant number of cases. Pyrophosphate and chondroitin sulphate had a less marked effect. The main urinary lithogenic biochemical parameters of the patients were also studied to see if there was a relationship between them and the inhibitory capacity of the compounds.     

Estrogen replacement increased the citrate and calcium excretion rates in postmenopausal women with recurrent urolithiasis.

PURPOSE: Epidemiological data indicate a sharp increase in urinary calcium stone formation after menopause. We investigated the role of menopausal estrogen replacement therapy on the urinary constituents and characteristics that may influence recurrent calcium oxalate stone disease. MATERIALS AND METHODS: Urinary constituents in 28 postmenopausal women on estrogen replacement therapy for more than 6 months were compared with those in 41 women who had never been exposed to estrogen after menopause. These 2 groups had a history of recurrent calcium oxalate urolithiasis. A group of age matched, nonstone forming volunteers who were and were not on estrogen served as controls. RESULTS: The 24-hour urine collection revealed significantly higher mean calcium plus or minus standard deviation (188.8 +/- 101.5 versus 129.2 +/- 80.9 mg./24 hours, p <0.01), citrate (576.6 +/- 237.9 versus 306.2 +/- 209.9 mg./24 hours, p <0.001) and agglomeration inhibition (203 +/- 106 versus 159 +/- 81 minutes, p <0.05) in stone forming women who were versus were not on estrogen. CONCLUSIONS: Higher urinary citrate and higher agglomeration inhibition in women exposed to estrogen may decrease the risk of subsequent calcium stone formation.     

Prophylaxis in idiopathic calcium urolithiasis

Summary The most important measure in the prophylaxis of idiopathic calcium urolithiasis is dietary advice. Patients should be kept to a high-fluid intake, increasing their diuresis by at least 0.51. The mineral content of drinking water seems to be of minor importance, but the liquid should be low in carbohydrates and oxalate. The intake of animal proteins should be reduced to no more than five meals with meat, fish or poultry per week. Excesses of oxalate-rich food must be avoided. The daily intake of calcium in dairy products should be in the range of 800–1200 mg. Sodium and refined carbohydrates should be moderately restricted. Medical treatment is indicated only in cases of recurrence under the appropriate diet. Selective treatment according to urinary chemical composition is favoured; alkali citrate, thiazides, allopurinol, and pyridoxine are of major interest.     

Urinary citrate excretion in patients with urolithiasis and normal subjects

Citrate is a normal constituent of urine which combines with calcium to form a soluble salt. Urinary citrate excretion was examined in patients with urolithiasis and normal subjects by a specific enzymatic technique. There was a considerable overlap in the urinary citrate excretion between normal subjects and stone-formers, but the citrate-creatinine ratio, the citrate-calcium ratio and the citrate-magnesium-calcium ratio, which were all highly significantly lower (p less than 0.001) in stone-formers than in controls, proved most reliable in discriminating between these groups.     

Rational prevention of calcium urolithiasis

Considerable progress has been made regarding pathogenesis, diagnosis and conservative management of urolithiasis. The cause of the disease can now be determined in nearly 80% of the patients. New stone formation may be prevented in the majority of patients by selective medical treatment. The metabolic, physicochemical and clinical effects of diet, thiazides, allopurinol, sodium cellulose phosphate and potassium-sodium citrate (Oxalyt-C) are described in detail. Intrinsic problems involved in clinical trial with recurrent stone formers are discussed.     

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.     

Crystalluria in idiopathic recurrent calcium urolithiasis

Summary A retrospective study was done on the nature and degree of crystalluria in fasting and postprandial urine in patients with recurrent idiopathic calcium urolithiasis (RCU) for whom stone analysis was available. RCU was stratified into subgroups in accordance with stone analysis. The crystals were obtained and identified using a filter technique and polarization microscopy, respectively. Crystalluria score, relative saturation products (RSPs), and low-molecular-weight inhibitors were assessed. Calcium oxalate crystals were never observed in either male or female patients with stones composed exclusively of calcium oxalate, and only sporadically in patients with mixed stones (the additional component was calcium phosphate in most cases). Other crystalluria phases, such as amorphous calcium phosphate, a urate-containing phase, and a phase presenting as spherolytic particles, were slightly more frequent in patients with mixed stones. In contrast to crystalluria, RSPs and inhibitors differed in male and female patients, suggesting that crystalluria may not be under the exclusive control of these factors. The following conclusions were reached. (1) Calcium oxalate crystalluria is absent from RCU with pure calcium oxalate stones; hence, calcium oxalate crystalluria does not qualify as a diagnostic aid. (2) The co-existence of the isotropic phase and mixed stones may indicate that the formation of these concretions is characteristic for a major RCU subgroup. (3) On the basis of clinical chemistry and physicochemical data in urine and of crystalluria, it appears that the pathogenesis of RCU differs in male and female subjects.     

Magnesium excretion in recurrent calcium urolithiasis

Patients with recurrent non-infectious calcium urolithiasis were classified metabolically (122 patients). When the magnesium excretion was measured in the metabolic subgroups, a subset of patients (21.6%) could be identified with marked hypomagnesuria as the only metabolic abnormality. A significantly reduced rate of magnesium excretion was found in these normocalciuric stone formers while assessing the overall 24-h urine magnesium excretion or the 24-h urine and fasting urine magnesium to calcium ratio. These differences were apparently not due to factors that might modify renal magnesium excretion, such as parathyroid function, hypercalcemia, hypophosphatemia, alimentary sodium load, age and sex.     

Risk formulas in calcium oxalate urolithiasis

In order to reflect the risk of calcium stone formation, risk formulas have been described in the literature with the objective of being able to predict the further course of the stone disease. Some of these formulas are reviewed in this paper. Various results were obtained when different risk expressions were related to the severity of the stone disease. Although a reliable prediction of the future course of the disease most certainly cannot be made by analysis of the variables included in these expressions, several of the risk formulas differed significantly between patients with and without recurrent stone formation during a reasonable follow-up period. Some risk formulas might thus be helpful, at least to some extent, in selecting those patients in whom continuous stone formation can be anticipated and in whom active therapeutic measures should be beneficial and worthwhile. With an increased understanding of the mechanisms of calcium oxalate stone formation and our possibilities of measuring the relevant risk factors, it is likely that improved risk formulas with an increased predictive power can be developed. Until this becomes a reality, in most cases we have to combine important information on the history and clinical observations of the disease with a risk formula that offers a high degree of discrimination with respect to the risk of further stone formation.     

Citrate and recurrent idiopathic calcium urolithiasis

Summary In idiopathic recurrent calcium urolithiasis (RCU) in men (n=37) the metabolic effects of oral tripotassium citrate (PC) were investigated in a longitudinal field study. The patients were either normo- (n=22) or hypocitraturic (n=15). Laboratory examinations were performed before, and after 3, 6, and more than 12 months of medication. Acceptance of PC was poor, mainly because of the salty taste of the tablet preparation chosen, and a number of participants dropped out of the study. In the remaining participants, compliance was acceptable when evaluated on the basis of urinary potassium and undesired side effects did not occur. In the short term (up to 3 months), PC evoked compensated metabolic alkalosis (pH and citrate in urine increased; blood gases remained normal), a drop in urinary calcium, together with increasing oxaluria, hydroxyapatite supersaturation, and calcium phosphate crystalluria. In the long term (>12 months) PC urinary pH and citrate dissociated, in that pH returned to pretreatment baseline values, whereas citrate stayed at high levels. In normocitraturics but not in hypocitraturics, urinary urea and sodium in creased with PC. Hypocitraturics appeared to be less sensitive to the effects of PC, as reflected by the relatively small rise in urinary pH and citrate, and they maintained higher mean levels of indicators of bone metabolism (osteocalcin, alkaline phosphatase, hydroxyproline) despite continuous administration of PC. It was concluded that although the PC tablet preparation was effective it may not be an ideal anti-stone drug treatment in the long term and that, especially in hypocitraturiecs, the intrinsic metabolic defect of RCU may not be sufficiently well controlled.     

Urinary enzymes and calcium oxalate urolithiasis

Male Sprague-Dawley rats were challenged with various hyperoxaluric agents including ammonium oxalate, hydroxy-L-proline, and ethylene glycol. All treatments resulted in increased urinary oxalate. Associated with hyperoxaluria was an increase in urinary levels of renal enzymes, gamma-glutamyl transpeptidase, N-acetyl-beta-glucosaminidase, and alkaline phosphatase. Most of the rats did not demonstrate any significant change in urinary levels of beta-galactosidase. There was a highly significant positive correlation between urinary oxalate and N-acetyl-beta-glucosaminidase.     

Magnesium excretion and calcium oxalate urolithiasis

One hundred fifty-five recurrent noninfectious calcium oxalate stone formers were evaluated in an effort to assess the importance of magnesium excretion on calcium oxalate stone formation. All patients evaluated had normal urinary magnesium excretion, and any elevation of the calcium/magnesium ratio was related to the presence of hypercalciuria. The findings indicate that magnesium deficiency does not appear to be a significant cause of calcium oxalate urolithiasis. If magnesium supplement is of value in some patients, it is likely related to its inhibitory effect on calcium oxalate crystallization.     

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.