The Efficacy of Polyunsaturated Fatty Acids as Protectors against Calcium Oxalate Renal Stone Formation: A Review.

In the pathogenesis of hypercalciuria and hyperoxaluria, n-6 polyunsaturated fatty acids (PUFAs) have been implicated by virtue of their metabolic links with arachidonic acid (AA) and prostaglandin PGE2. Studies have also shown that n-3 PUFAs, particularly those in fish oil-eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)-can serve as competitive substrates for AA in the n-6 series and can be incorporated into cell membrane phospholipids in the latter's place, thereby reducing urinary excretions of calcium and oxalate. The present review interrogates several different types of study which address the question of the potential roles played by dietary PUFAs in modulating stone formation. Included among these are human trials that have investigated the effects of dietary PUFA interventions. We identified 16 such trials. Besides fish oil (EPA+DHA), other supplements such as evening primrose oil containing n-6 FAs linoleic acid (LA) and γ-linolenic acid (GLA) were tested. Urinary excretion of calcium or oxalate or both decreased in most trials. However, these decreases were most prominent in the fish oil trials. We recommend the administration of fish oil containing EPA and DHA in the management of calcium oxalate urolithiasis.

Exploring the Potential Relationship Between Phytate Ingestion, Urinary Phytate Excretion, and Renal Stone Risk in a Unique Human Model: No Hard Evidence in Support of Phytate as a Stone Inhibitor.

OBJECTIVE: Dietary phytate (IP6) enjoys a reputation as an inhibitor of calcium renal stone formation, although there are very few human studies to support this notion. In South Africa, urolithiasis occurs in the white (W) but is rare in the black (B) population. We undertook this unique human model to further investigate the IP6 theory. METHODS: Healthy W and B males completed baseline food-frequency recall questionnaires. Dietary intake of IP6 was restricted for 18 days. An IP6 dietary supplement was ingested on days 15-18. Twenty-four-hour urinary phytate and other urinary components were determined. Relative supersaturations of calcium salts were calculated. The urinary metastable limit (MSL) of calcium oxalate (CaOx) and its crystallisation kinetics were determined experimentally. RESULTS: Habitual dietary intake of IP6 and its urinary excretion were significantly higher in B than in W (1650 ± 202 vs. 640 ± 134 mg/d, P = .0002 and 1.13 ± 0.12 vs. 0.75 ± 0.13 µM, P <.05, respectively). In B, urinary phytate decreased significantly after 15 days of IP6 restriction, but in W, its excretion remained constant. After supplementation, urinary IP6 increased significantly in both groups reaching levels commensurate with the baseline value in B. No significant differences occurred in B in any of the routine urinary risk factors throughout the trial. However, in W, urinary citrate excretion increased on day 18 relative to day 0. There were no significant intragroup or intergroup changes in relative supersaturation, metastable limit, or crystallization kinetics. CONCLUSIONS: Despite notable differences in the renal handling of ingested IP6, there were no changes in any of the well-established urinary risk factors for calcium renal stone formation in either of our uniquely different test groups. We conclude that, in the absence of hard evidence, claims that IP6 is a stone inhibitor remain unproven.

Correction to: Different effects of γ-linolenic acid (GLA) supplementation on plasma and red blood cell phospholipid fatty acid composition and calcium oxalate kidney stone risk factors in healthy subjects from two race groups with different risk profiles pose questions about the GLA-arachidonic acid-oxaluria metabolic pathway: pilot study.

The authors would like to add the following paragraph in the acknowledgement section of the original version of the paper.

Different effects of γ-linolenic acid (GLA) supplementation on plasma and red blood cell phospholipid fatty acid composition and calcium oxalate kidney stone risk factors in healthy subjects from two race groups with different risk profiles pose questions about the GLA-arachidonic acid-oxaluria metabolic pathway: pilot study.

Fatty acid (FA) composition of phospholipids in plasma and red blood cells (RBC) can influence calciuria, oxaluria and renal stone formation. In this regard, the ratio of arachidonic acid (AA) and its precursor linoleic acid (LA) appears to be important. Administration of γ-linolenic acid (GLA) has been shown to increase the concentration of dihomo-gamma linoleic acid (DGLA) relative to AA indicating that it may attenuate biosynthesis of the latter. Such effects have not been investigated in race groups having difference stone occurrence rates. Black (B) and white (W) healthy males ingested capsules containing linoleic acid (LA) and GLA, for 30 days. Plasma and RBC total phospholipid (TPL) FA profiles, serum and 24 h urine biomarkers of hypercalciuria and urinary stone risk factors were determined on days 0 and 30. Data were tested for statistical significance using GraphPadInstat version 3.02. Concentration and percentage content of DGLA in plasma TPL increased in W but not in B. Arachidonic acid (AA) did not change in either group. There was no change in calcium excretion in either group but oxalate and citrate excretion increased in W. We suggest that elongation of GLA to DGLA may occur more rapidly than desaturation of DGLA to AA in W and that depressed activity of the enzyme elongase may occur in B. Calciuric and citraturic effects may be dependent on the quantity of LA or on the mass ratio of LA/GLA in the FA supplement. Questions about the mooted DGLA-AA-oxaluria pathway arise. We speculate that there exists a potential for using GLA as a conservative treatment for hypocitraturia. The observation of different responses in B and W indicates that such differences may play a role in stone formation and prevention.

Stress-stones-stress-recurrent stones: a self-propagating cycle? Difficulties in solving this dichotomy.

Numerous studies have reported an association between stress and urolithiasis. Although urinary risk factors have been measured in several of these, compelling evidence of a causal relationship has not been established. A shortcoming is that alterations in single urinary parameters rather than ratios and quotients, which provide a more synergistic risk evaluation, have been measured. Recently, we speculated about a possible association between chronic stress and stone recurrence. This presents an intriguing dichotomy of whether stress causes stones or vice versa, or whether they are linked in a self-propagating stress-stones-stress-recurrence cycle. We investigated the latter hypothesis in a retrospective case-control designed study in which we calculated urinary ratios and quotients which are regarded as diagnostic indicators of stone risk. These included Ca/Cr, Ox/Cr, Mg/Cr, Cit/Cr, urate/Cr and citrate-magnesium-calcium ratios, activity product quotient for calcium oxalate (CaOx) and relative supersaturation of CaOx, brushite and uric acid. Overnight urinary data from 128 participants comprising 31 first time (FS), 33 recurrent (RS) CaOx stone formers and 64 controls were used. All subjects had been previously assessed for chronic stress dimensions, as well as for stress caused by their stone episodes per se. Conditional and unconditional logistic regression (with a Bonferroni correction for multiple tests) and simple linear regression were used to analyse various components of the data. Although RS had more stressful life events, with greater intensity of perception than FS, there were no significant differences between the groups regarding any of the urinary risk factors. No significant association between stressful life events and any of the urinary ratios or quotients was observed. A direct causal link between stress and stone recurrence was not indicated. We believe that future studies should shift their focus from traditional urinary risk factors to other stone-forming mechanisms. However, we recognize that there is an inherent problem in attempting to solve the stress-stones dichotomy as it would be impossible to disentangle alterations in risk factors which arise from lifestyle stress and those arising from stone episodes themselves.

Folium pyrrosiae ingestion has no effect on the thermodynamic or kinetic urinary risk factors for calcium oxalate urolithiasis in healthy subjects: a poor prognosis for alternative treatment in this type of stone former.

Kidney stone disease occurs throughout the world. Conservative treatments involving herbal preparations have been used in traditional Chinese medicine. In vitro studies have suggested that Folium pyrrosiae (FP) has therapeutic potential in this context. The present study was undertaken to investigate the effects of ingested FP on urinary thermodynamic and kinetic risk factors for calcium oxalate (CaOx) stone formation in subjects from two different population groups. Healthy white (n = 9) and black (n = 9) males ingested 1.5 g FP each day for 7 days. 24 h urines (baseline and day 7) and blood samples (baseline and day 3) were collected. Urines were analyzed for lithogenic risk factors and were subjected to CaOx crystallization experiments in which the metastable limit (MSL), particle size-volume distribution and crystal deposition kinetics were determined. Urine composition values were used to calculate the relative supersaturation (RS) of CaOx and other urinary salts. Blood samples were analyzed for liver enzymes to monitor the safety of the protocol. Food diaries were recorded on days 0 and 7. Data were analyzed statistically using standard software. Nutrient intakes and the concentration of liver enzymes did not change during the study. No side effects were reported. There were no statistically significant differences in any of the thermodynamic (RS, MSL) or kinetic (particle volume-size distribution, crystal deposition rate) risk factors for CaOx stone formation in either of the groups following ingestion of FP relative to baseline values. FP does not have potential as a therapeutic agent in the management of CaOx kidney stone disease.

Sulfate but not thiosulfate reduces calculated and measured urinary ionized calcium and supersaturation: implications for the treatment of calcium renal stones.

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.

Enteric hyperoxaluria secondary to small bowel resection: use of computer simulation to characterize urinary risk factors for stone formation and assess potential treatment protocols.

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.

Herbal preparations affect the kinetic factors of calcium oxalate crystallization in synthetic urine: implications for kidney stone therapy.

Herbal remedies are increasingly being considered as suitable long-term treatments for renal dysfunction. The objective of the present study was to investigate the effect of some herbal extracts, all previously identified in published studies as influencing kidney stone formation, on the crystallization characteristics of calcium oxalate (CaOx) in synthetic urine (SU). Five herbal extracts were selected for the study: Folium pyrrosiae, Desmodium styracifolium, Phyllanthus niruri, Orthosiphon stamineus and Cystone(®). Concentrated stock solutions of each herbal extract were prepared and were tested at their recommended dosages in in vitro crystallization studies in SU. CaOx crystallization experiments were performed in which the metastable limit (MSL), average particle size, and nucleation and growth rates were determined. The CaOx MSL of SU was unaltered by the five herbal extracts. Three of the herbs (Desmodium styracifolium, Orthosiphon stamineus and Cystone(®)) significantly reduced the average particle size of precipitated crystals relative to undosed SU. All of the extracts increased the rate of nucleation and decreased the rate of growth significantly in SU. Cystone(®) showed the greatest effect on the measured risk factors. It is concluded that all of the herbs have the potential to serve as inhibitors of calcium oxalate stone formation and warrant investigation in clinical trials.

Malic acid supplementation increases urinary citrate excretion and urinary pH: implications for the potential treatment of calcium oxalate stone disease.

BACKGROUND AND PURPOSE: Raising urinary pH and citrate excretion with alkali citrate therapy has been a widely used treatment in calcium nephrolithiasis. Citrate lowers ionized Ca(+2) concentrations and inhibits calcium salt precipitation. Conservative alternatives containing citrate such as fruit juices have been investigated and recommended. Any compound that induces systemic alkalosis will increase citraturia. Malate, a polycarboxylic anion like citrate, is a potential candidate for chelating Ca(+2) and for inducing systemic alkalinization. We undertook to investigate these possibilities. MATERIALS AND METHODS: Theoretical modeling of malic acid's effects on urinary Ca(+2) concentration and supersaturation (SS) of calcium salts was achieved using the speciation program JESS. Malic acid (1200 mg/day) was ingested for 7 days by eight healthy subjects. Urines (24 hours) were collected at baseline and on day 7. They were analyzed for routine lithogenic components, including pH and citrate. Chemical speciation and SS were calculated in both urines. RESULTS: Modeling showed that complexation between calcium and malate at physiological concentrations of the latter would have no effect on SS. Administration of the supplement induced statistically significant increases in pH and citraturia. The calculated concentration of Ca(+2) and concomitant SS calcium oxalate (CaOx) decreased after supplementation, but these were not statistically significant. SS for the calcium phosphate salts hydroxyapatite and tricalcium phosphate increased significantly as a consequence of the elevation in pH, but values for brushite and octacalcium phosphate did not change significantly. CONCLUSIONS: We speculate that consumption of malic acid induced systemic alkalinization leading to reduced renal tubular reabsorption and metabolism of citrate, and an increase in excretion of the latter. The decrease in SS(CaOx) was caused by enhanced complexation of Ca(+2) by citrate. We conclude that malic acid supplementation may be useful for conservative treatment of calcium renal stone disease by virtue of its capacity to induce these effects.

Effects of vitamin E ingestion on plasma and urinary risk factors for calcium oxalate urolithiasis in two population groups having different stone-risk profiles: evidence of different physiological handling mechanisms.

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.

Evening primrose oil supplementation increases citraturia and decreases other urinary risk factors for calcium oxalate urolithiasis.

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.

Calcium oxalate stone formation risk - a case of disturbed relative concentrations of urinary components.

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.

Renal response to lithogenic and anti-lithogenic supplement challenges in a stone-free population group.

OBJECTIVE: In South Africa, urolithiasis is extremely rare in the black population, but is common in the white population. The objective of this study was to investigate the individual effects of 5 different dietary and supplemental challenges (high dietary calcium, calcium supplement, vitamin B6 supplement, L-glutamine supplement, and L-cysteine supplement) on the urinary risk factors for calcium oxalate urolithiasis in subjects from both race groups. DESIGN: Complete Latin Square design. SETTING: University research laboratory. SUBJECTS: Subjects were recruited from the student cohort of the University of Cape Town (10 male subjects from each race group). Selection criteria were no history of renal or metabolic diseases, and no chronic or acute medication. Subjects served as their own controls. INTERVENTION: After 7 days on a self-selected standardized diet, a 24-hour baseline urine sample was collected. A second 24-hour urine sample was collected after 5 days on the prescribed dietary or supplemental challenge. These were analyzed for biochemical and physicochemical risk factors. Additionally, 24-hour dietary recall questionnaires were recorded at baseline and after the 5-day test period, and were analyzed using a food analysis program. Statistical analysis of variance was performed on all of the data. MAIN OUTCOME MEASURES: Urine composition, relative supersaturation of urinary salts, calcium oxalate metastable limit, and Tiselius risk index. RESULTS: None of the protocols altered any of the urinary biochemical or physicochemical risk factors in black subjects. In white subjects, the calcium diet significantly increased urinary potassium (P =.0001) and decreased the relative supersaturation of brushite (P =.035); the calcium supplement significantly decreased the Tiselius risk index (P =.014); vitamin B6 supplement significantly decreased urinary calcium (P =.016), urinary phosphate (P =.027), and the relative supersaturation of brushite (P =.004); L-glutamine supplement significantly decreased relative supersaturation of calcium oxalate (P =.01); L-cystine supplement significantly decreased urinary calcium (P =.031) and the Tiselius risk index (P =.013). CONCLUSIONS: Because none of the challenges had an effect on the urinary risk factors in black subjects, it is speculated that a renal or gastrointestinal homeostatic adjustment occurs in this group, thereby keeping urinary concentration of substances in balance.

Idiopathic calcium oxalate urolithiasis: risk factors and conservative treatment.

Idiopathic calcium oxalate urolithiasis is a frequent and recurrent multifactorial disease. This review focuses on urinary and dietary risk factors for this disease and conservative strategies for rectifying them. Dietary oxalate and calcium and their respective urinary excretions have been extensively investigated during the last 10 years. Urinary oxalate has emerged as the most important determinant of calcium oxalate crystallization while the role of urinary calcium has shifted to bone balance and osteoporosis. Dietary calcium restriction increases urinary oxalate and contributes to a negative bone balance. It has therefore been abandoned as a means to reduce the risk of calcium oxalate kidney stone formation. Calcium oxalate kidney stone patients are advised to increase their fluid intake to achieve a urine volume of 2 l or more; the recommended calcium intake is 800-1200 mg/day; high oxalate foods should be restricted; daily protein intake should be between 0.8 and 1 g/kg body weight/day; essential fats should be included; vegetable and fruit (except oxalate-rich vegetables) intake should be increased. The use of calcium supplements has potential benefits but needs to be examined further.

Effects of calcium carbonate, magnesium oxide and sodium citrate bicarbonate health supplements on the urinary risk factors for kidney stone formation.

We describe a model to illustrate different chemical interactions that can occur in urine following ingestion of individual and combined health supplements. Two types of interactions are defined: synergism and addition. The model was applied to eight healthy males who participated in a study to investigate the chemical interactions between calcium carbonate, magnesium oxide and sodium citrate-bicarbonate health supplements on calcium oxalate urinary stone risk factors. Subjects ingested these components individually and in combination for 7 days. Twenty-four-hour urines were collected at baseline and during the final day of supplementation. These were analysed using standard laboratory techniques. Three different chemical interactions, all involving citrate, were identified: magnesium and citrate exerted a synergistic effect on lowering the relative superaturation (RS) of brushite; the same two components produced a synergistic effect on raising pH; finally, calcium and citrate exerted an additive effect on lowering the RS of uric acid. We propose that the novel approach described in this paper allows for the evaluation of individual, additive and synergistic interactions in the assessment of the efficacy of stone-risk reducing preparations.