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Background and Purpose: We used computer modeling to investigate the influence of physicochemical stone risk factors on urinary supersaturation (SS) of calcium oxalate (CaOx) in patients with severe hyperoxaluria, relative hypocalciuria, hypocitraturia, and CaOx nephrolithiasis after extensive small bowel resection, usually performed for Crohn's disease. We also simulated different treatment strategies, including oral calcium supplements and citrate, in such patients., Materials and Methods: A baseline urine model was derived by consolidating data acquired by ourselves with those from another patient cohort. Calcium and oxalate excretions in this model were altered to obtain an extreme case. For comparison, additional models were based on published urine data from normal subjects (N) and idiopathic CaOx stone formers (SF). The Joint Expert Speciation System was used to simulate different urine situations based on reported compositional values., Results: [Ca(2+)][Ox(2-)] ionic concentration products and SS(CaOx) are substantially higher in enteric hyperoxaluric patients than in N and SF, despite their relatively lower calcium excretions. Molar Ca:Ox ratios are substantially lower in enteric hyperoxalurics than in N and SF. Oral calcium supplements can reduce SS(CaOx), but monitoring is required to avoid exceeding a safe dosing threshold. A simple calculation can alert the clinician that this threshold is being approached or even exceeded. Increasing urinary pH and citrate decreases SS(CaOx) but not to the same extent as decreasing Ox excretion., Conclusions: Calcium supplements can help reduce stone risk in patients with severe enteric hyperoxaluria, but initial efforts should be directed toward reducing urinary oxalate by reducing dietary oxalate. Citrate therapy that increases both urine pH and urinary citrate provides an additional therapeutic benefit.

Background: Urinary sulfate (SO4(2-)) and thiosulfate (S2O3(2-)) can potentially bind with calcium and decrease kidney stone risk. We modeled the effects of these species on the concentration of ionized calcium (iCa) and on supersaturation (SS) of calcium oxalate (CaOx) and calcium phosphate (CaP), and measured their in vitro effects on iCa and the upper limit of stability (ULM) of these salts., Methods: Urine data from 4 different types of stone patients were obtained from the Mayo Nephrology Clinic (Model 1). A second data set was obtained from healthy controls and hypercalciuric stone formers in the literature who had been treated with sodium thiosulfate (STS) (Model 2). The Joint Expert Speciation System (JESS) was used to calculate iCa and SS. In Model 1, these parameters were calculated as a function of sulfate and thiosulfate concentrations. In Model 2, data from pre- and post STS urines were analyzed. ULM and iCa were determined in human urine as a function of sulfate and thiosulfate concentrations., Results: Calculated iCa and SS values for all calcium salts decreased with increasing sulfate concentration. Thiosulfate had no effect on these parameters. In Model 2, calculated iCa and CaOx SS increased after STS treatment, but CaP SS decreased, perhaps due to a decrease in pH after STS treatment. In confirmatory in vitro experiments supplemental sulfate, but not thiosulfate, significantly increased the calcium needed to achieve the ULM of CaP and tended to increase the oxalate needed to reach the ULM of CaOx. Sulfate also significantly decreased iCa in human urine, while thiosulfate had no effect., Conclusion: Increasing urinary sulfate could theoretically reduce CaOx and CaP stone risk. Although STS may reduce CaP stone risk by decreasing urinary pH, it might also paradoxically increase iCa and CaOx SS. As such, STS may not be a viable treatment option for stone disease.

It has been demonstrated that vitamin E supplementation reduces calciuria and oxaluria and that it may also prevent oxalate-mediated peroxidative injury, all of which reduce the risk of calcium oxalate urolithiasis. In view of the significant difference in stone occurrence in black (B) and white (W) South Africans, we undertook to investigate the effects of vitamin E supplementation in subjects from these two groups. Five healthy males from each group ingested one capsule (400 IU) of vitamin E daily for 60 days. Blood and 24 h urine samples were collected at baseline and on day 60; 24 h dietary questionnaires were simultaneously completed. Urine composition was determined by routine analyses. Urinary and plasma TBARS were determined using a commercially available assay kit while plasma vitamin E was determined by reverse phase HPLC. Plasma vitamin E increased significantly in W but not in B. Urinary and plasma TBARS did not increase in either group. Urinary citrate increased significantly in both groups but the percentage increase in W (169%) was greater than that in B (82%). No other urinary parameter changed significantly. The increase in plasma vitamin E in W but not in B suggests either that the mechanism by which it is packaged into chylomicrons, which are secreted into the systemic circulation, is suppressed in the latter group or that it is differentially absorbed in the two groups. Similarly, to explain the greater increase in citraturia in W compared to B, we speculate that inhibition of lipogenesis of arachidonic acid by vitamin E, ultimately leading to an increase in citraturia, occurs to a lesser extent in B than in W.

Theoretical modeling of urinary crystallization processes affords opportunities to create and investigate scenarios which would be extremely difficult or impossible to achieve in in vivo experiments. Researchers have previously hypothesized that calcium renal stone formation commences in the nephron. In the present study, concentrations of urinary components and pH ranges in different regions of the nephron were estimated from concentrations in blood combined with a knowledge of the renal handling of individual ions. These were used in the chemical speciation program JESS to determine the nature of the solution complexes in the different regions of the nephron and the saturation index (SI) of the stone-forming salts calcium oxalate (CaOx), brushite (Bru), hydroxyapatite (HAP) and octacalcium phosphate (OCP). The effect of independent precipitation of each of the latter on the SI values of other salts was also investigated. HAP was the only salt which was supersaturated throughout the nephron. All of the other salts were supersaturated only in the middle and distal regions of the collecting duct. Supersaturations were pH sensitive. When precipitation of CaOx, Bru and OCP was simulated in the distal part of the collecting duct, little or no effect on the SI values of the other stone forming salts was observed. However, simulation of HAP precipitation caused all other salts to become unsaturated. This suggests that if HAP precipitates, a pure stone comprising this component will ensue while if any of the other salts precipitates, a mixed CaOx/CaP stone will be formed. Application of Ostwald's Rule of Stages predicts that the mixed stone is likely to be CaOx and Bru. Our modelling demonstrates that precipitation of stone-forming salts in the nephron is highly dependent on the delicate nature of the chemical equilibria which prevail and which are themselves highly dependent on pH and component concentrations.

Purpose: We investigated the effects of gamma-linolenic acid (an omega-6 polyunsaturated fatty acid) in the form of evening primrose oil on calcium oxalate urinary stone risk factors in 2 ethnic groups., Materials and Methods: Eight black and 8 white healthy male subjects ingested 1,000 mg evening primrose oil (Natrodale, Kuils River, South Africa) daily for 20 days while following a free diet. Arachidonic acid content was determined by a dietary questionnaire. On days 0, 10 and 20, and 4 days after protocol 24-hour urine samples were collected. Samples were analyzed using routine assays., Results: Citraturia increased significantly in each group. Urinary oxalate showed a tendency to decrease in black subjects. Calciuria and the Tiselius risk index decreased significantly in each group. Carryover effects were observed., Conclusions: To our knowledge increased citraturia has not been previously reported for any essential fatty acid. We hypothesize that evening primrose oil inhibits lipogenesis, thereby decreasing citrate consumption. For the decrease in oxaluria we suggest that evening primrose oil alters membrane fatty acid composition, thereby inhibiting the modulation of protein kinases that lead to hyperoxaluria. In regard to decreased calciuria we suggest that evening primrose oil modulates delta-5 and/or delta-6-desaturase, thereby inhibiting the production of arachidonic acid and prostaglandin E2, which influence calciuria. The different response in the 2 groups with respect to oxaluria confirms previously reported differences in sensitivity toward supplemental ingestion. Data suggest that evening primrose oil supplementation should be investigated as a possible conservative treatment for calcium oxalate urolithiasis.

Objectives: The different susceptibility to renal stone disease of white and black people has been previously explained in terms of intrinsic (genetics) and extrinsic (diet, lifestyle) factors. However, in South Africa, the absence of stone disease in the black population has not yet been fully explained by either of these. The aim of the present study was to identify potential differences between black and white subjects in South Africa and white subjects in Europe with respect to their relative dietary and urinary risk factors for renal stone formation., Materials and Methods: A total of 72 healthy subjects (45 males and 27 females, age range 21-30 years) with no previous history of renal stone disease or specific diseases predisposing to renal stone formation were recruited in South Africa (SA) and in Italy (IT). They were divided in three groups: South African blacks (SA-B), South African whites (SA-W) and Italian whites (IT-W). Each participant provided a 24-hour dietary record and 24-hour urine sample taken over the same period. Nutrients and calories were calculated by means of food composition tables using a computerised procedure. Urinary concentrations of potassium, sodium, calcium, phosphate, oxalate, urate, citrate, magnesium, and creatinine, together with the pH and urinary volumes, were measured., Results: The mean carbohydrate intake was significantly higher in SA-B (293+90 g/day) than in both SA-W (194+74, p = 0.002) and IT-W (212 +/- 81; p = 0.000). Daily magnesium intake was higher in SA-B (290+124 mg/day) than in IT-W (176+73 mg/day, p = 0.002). The mean daily urinary excretion of calcium was significantly (p = 0.029) lower in SA-B (3.07 +/- 1.68 mmol/day) with respect to SA-W (4.65 +/- 2.44 mmol/day) and IT-W (4.51 +/- 1.89 mmol/day) whereas mean daily urinary excretion of citrate was significantly (P = 0.012) higher in SA-B (3.36 +/- 1.4 mmol/day) than in SA-W (3.09 +/- 1.45 mmol/day) and IT-W (2.36 +/- 0.98 mmol/day)., Conclusion: Although the carbohydrate intake and the percent of energy from carbohydrate of black subjects in this study were higher with respect to white controls, we were not able to show any other relevant difference of the known dietary stone risk patterns between black and white subjects. On the other hand the urinary patterns of black controls seem to be more favourable in term of risk for stone formation than those of white controls showing a lower calcium excretion and a higher citrate excretion in the urine. Our result of higher carbohydrate intake in black subjects is counter-intuitive as it suggests a higher risk of stone formation in this group. This puzzling result may have arisen because our subjects were recruited from the urban population rather than from rural areas, suggesting that western diets and lifestyles may ultimately change the stone incidence profile in the black population.

Background: Although afflicted with stone formation, urolithiasis patients often present with normal renal excretions of lithogenic and inhibitory substances. In this study, crystal formation is not interpreted as the result of urinary excretions simply exceeding the static limits of normal ranges but rather as the consequence of relative combinations of such parameters which convert urine into becoming potentially lithogenic. Our model embraces different triplet combinations of fundamental urinary risk factors for calcium oxalate (CaOx) crystallization, to characterize different levels of urinary stone formation risk., Methods: Urinalyses and BONN-Risk-Indices (BRI) were determined for CaOx patients under home conditions, after 1 week of hospitalization, and for healthy controls. The relative urinary concentrations and interdependences of, inter alia, free ionized Ca (Ca2+), bound Ca (Ca b), and oxalic acid (OA) were compared., Results: Three levels of CaOx formation risk can be distinguished: (I): low stone formation risk with an increase in (Ca2+) and concomitant decrease in (Ca b), while (OA) remains almost constant, BRI increases simultaneously; (II) moderate risk at (Ca2+)/(Ca b) approximately 1; and (III) high risk with decrease in (Ca2+)/(Ca b) and simultaneous increase in (OA)., Conclusions: The proposed approach of urinalysis interpretation allows complementary strategy of identification of patterns of disturbed urinary composites leading to calculus formation.

Background: The therapeutic action of citrate in the management of calcium oxalate urolithiasis has been attributed to the depletion of free calcium ions by complexation of the latter by citrate itself. However, little attention has been given to the nature of such complexes and the chemical conditions which control their formation because it is very difficult to measure them in solution. We therefore modelled the theoretical formation of these complexes in urine following administration of a citrate-containing preparation, using a powerful speciation program, JESS (Joint Expert Speciation System), which has been widely used to model metal-ligand equilibria in biological systems but which has hitherto not been applied in urolithiasis research. This program has an extensive database of thermodynamic constants and is able to calculate mixed ligand speciation., Methods: Urine data obtained before and after citrate administration in four groups of subjects (male and female normals and stone formers) were used as input for JESS to calculate the speciation of calcium, citrate and oxalate. The program was also used to examine the effects of varying different urinary components on the nature and concentration of the various species., Results: The speciation predicted the formation of a key calcium-citrate-phosphate species (previously unreported in urolithiasis research), which accounts for a significant percentage of the complexation of the free calcium. Moreover, the formation of this complex was found to be dependent on an increase in urinary pH rather than on an increase in urinary citrate concentration per se., Conclusion: The therapeutic action of citrate in the management of calcium oxalate urolithiasis is due to the formation of a pH dependent calcium-citrate-phosphate complex which reduces the concentration of the free calcium ion species, thereby reducing the risk of stone formation.

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.