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.

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.

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.

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.

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.