Urinary Citrate Excretion Research Articles

Associations between renal sodium‐citrate cotransporter (hNaDC‐1) gene polymorphism and urinary citrate excretion in recurrent renal calcium stone formers and normal controls

Urinary citrate is a potent inhibitor of renal stone formation. Its excretion is regulated by Na(+)/dicarboxylate cotransporter-1 (NaDC-1), which is expressed on the apical membrane of renal proximal tubules. Many patients with calcium urolithiasis exhibit hypocitraturia, however, the mechanisms are not perfectly understood. We examined whether or not the I550V polymorphism in human NaDC-1 gene (hNaDC-1) influenced urinary citrate excretion. I550V polymorphism was investigated in 105 patients with recurrent renal calcium stone formation (RSF) and 107 age-matched healthy volunteers with non-renal stone formation (NSF), using polymerase chain reaction (PCR) restriction fragment length polymorphism analysis and two 24-h urine samples. Overall and in the RSF groups, subjects with a BB (homozygous for the digested Bcl-I allele) genotype exhibited a significantly lower urinary citrate excretion level than subjects with a bb (homozygous for the undigested allele) genotype. Genotype distributions between subjects with hypocitraturia and normocitraturia were significantly different, with the BB genotype being more frequently observed in subjects with hypocitraturia - both overall and in each of the RSF and NSF groups. Although the BB genotype was observed more frequently in the RSF group than in the NSF group, no statistical differences among the distributions of the three genotypes (BB, Bb [heterozygous] and bb) were observed between the RSF and NSF groups. These results suggest that the B allele of I550V polymorphism of hNaDC-1 may be associated with a reduction in urinary citrate excretion and contribute to hypocitraturia in recurrent renal stone formers.

Differences in 24-Hour Urine Composition between Black and White Women

Black women are less likely to develop kidney stones and have greater bone mass than white women. However, little is known about racial differences in urine composition. Urine pH, volume, and 24-h urinary excretion of calcium, citrate, oxalate, uric acid, sodium, potassium, magnesium, phosphate, sulfate, and creatinine of 146 black women were compared with 330 white women in the Nurses' Health Study. All participants were postmenopausal non-stone formers. ANOVA was used to compare mean urinary values. Linear regression models were adjusted for age, body mass index, dietary intake, and urinary factors. On average, black women excreted 65 mg less urinary calcium (P < 0.001), 4 mg more oxalate (P < 0.001), 9 mEq less potassium (P < 0.001), 11 mg less magnesium (P = 0.003), 120 mg less phosphate (P < 0.001), and 3 mmol less sulfate (P < 0.001) per day than did white women. The urine pH of black women was 0.11 units higher (P = 0.03) and urine volume was 0.24 L less (P = 0.001). The urinary relative supersaturations of calcium oxalate (P = 0.03) and brushite (P = 0.002) were lower in black women. No other significant differences were observed. Differences in urinary calcium and pH persisted after multivariate adjustment and after exclusion of participants who were taking thiazide diuretics or those with diabetes. In conclusion, black women excrete less urinary calcium and have a higher urinary pH than do white women. These differences are not explained by differences in age, body mass index, or diet and may account for the lower incidence of both nephrolithiasis and osteoporosis in black women.

Vitamin B6 deficiency augments endogenous oxalogenesis after intravenous l-hydroxyproline loading in rats

The effects of an intravenous hydroxyproline load on endogenous oxalogenesis were compared in rats fed a standard diet or a vitamin B6-deficient diet. Twelve male Wistar rats were randomized to two groups and were fed either a standard diet (control group) or a vitamin B6-deficient diet for 3 weeks. Then the animals were intravenously administered 100 mg (762.6 micromol)/ml hydroxyproline. In the control group, infusion of hydroxyproline increased the 5-h urinary oxalate and glycolate excretion above baseline to 0.27% (2.02 +/- 1.11 micromol) and 0.32% (2.43 +/- 1.60 micromol) of the administered dose (mol/mol), while it was respectively 2.01% (15.24 +/- 2.13 micromol) and 0.00% (-0.02 +/- 0.19 micromol) of the dose in the vitamin B6-deficient group. Therefore, vitamin B6 deficiency augmented endogenous synthesis of oxalate from hydroxyproline by 7.56-fold (15.24/2.02) compared with that in the control group. Urinary citrate excretion was significantly lower at baseline and all other times in the vitamin B6-deficient group compared with the control group. In conclusions, L-hydroxyproline loading augmented endogenous oxalogenesis in the vitamin B6-deficient group without causing hyperglycolic aciduria, and also led to significant hypocitraturia. These findings suggest that hydroxyproline is not metabolized to oxalate via glycolate, but rather via the 4-hydroxyglutamate to glyoxylate pathway (usually requiring vitamin B6-dependent enzymes) even in the presence of vitamin B6 deficiency.

Efficacy of Standard Diet Therapy for Patients with Urolithiasis

Purpose: To determine the effectiveness of standard diet therapy as a preventive measure against urinary stone recurrence, we compared the metabolic parameters before and after diet recommendation in the patients with urolithiasis. Materials and Methods: A total of 40 stone formers participated in this study and none of them had other metabolic disorders. The dietary recommendations for them included the following: large amounts of water and fruit juice, and restriction of animal protein, salt and oxalate-rich foods. Simplified metabolic evaluations were performed before and after the dietary therapy and compared using the Wilcoxon signed rank test and McNemar’s test. The urinary volume and creatinine differences between the two tests were also considered for determining the patients' compliance and appropriate 24-hour urine collection. Results: There was no significant change in the patients blood chemistry before and after the diet therapy. Among the urinary parameters, the excretion of citrate (p=0.005) was significantly increased, but the rest of the parameters remained unchanged. With respect to occurrence of urinary metabolic abnormalities, only the frequency of hypocitraturia showed a statistically significant decrease after diet therapy (p=0.039). The results concerning the changes in the urinary volume and creatinine level showed no difference before and after the therapy. Conclusions: The standard diet therapy applied to the patients with urolithiasis showed a favorable effect on the excretion of urinary citrate, which is an important protective factor against stone formation. However, we could not found any significant changes in the other urinary lithogenic parameters during this short-term evaluation. (Korean J Urol 2007;48: 608-614) 󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏󰠏

Chronic acid ingestion promotes renal stone formation in rats treated with vitamin D3

Although hypercalciuria, a well-established adverse effect of vitamin D3, can be a risk factor of renal stone formation, the risk of nephrolithiasis has not been well defined. The consumption of a diet high in acid precursors is often cited as a risk factor for the development of calcium-based kidney stones. In the present study, we investigated the effect of chronic acid ingestion on kidney stone formation in rats treated with calcitriol (1-25[OH]2 D3). Control rats (C-C), calcitriol-treated rats (C-V; three treatments of 0.5 microg of calcitriol per week) and acid-ingested (water containing 0.21 mol/L NH4Cl), calcitriol-treated (three treatments of 0.5 microg of calcitriol per week) rats (A-V) were fed in metabolic cages. After 1 month, urine, blood, kidney and bone samples were analyzed. The A-V rats exhibited elevated serum calcium concentrations, urinary calcium and phosphate excretion, urinary type I collagen cross-linked N-peptide (NTx)/creatinine values, mRNA expression of osteopontin in the kidney, and renal calcium contents as well as decreased bone mineral densities, compared with the C-C and C-V rats. Urinary citrate excretion was lower and NaDC-1 mRNA expression in the kidney was higher in the A-V rats than in the C-C and C-V rats. Calcium phosphate kidney stones were found in the A-V rats. The ingestion of NH4Cl, an acid precursor, promotes calcium phosphate kidney stone formation in calcitriol-treated rats. The chronic intake of a diet rich in acid precursors may be a risk factor for the development of kidney stones in subjects who are being treated with calcitriol.

Insulin resistance and low urinary citrate excretion in calcium stone formers

Epidemiological data suggest an association between kidney stones and some features of metabolic syndrome such as an overweight condition, arterial hypertension or glucose intolerance. However, mechanisms remain to be elucidated. This study aimed to evaluate insulin resistance, as assessed by homeostasis model assessment (HOMA-IR), and urine composition analysis in patients affected by calcium nephrolithiasis. A cohort of 61 (38 male, 29–57 years of age) non-diabetic calcium stone formers was studied. Data about body mass index, arterial blood pressure, serum biochemistry including parathyroid hormone and calcitriol were recorded in all the patients; fasting glucose and insulin were determined to calculate HOMA-IR value and accordingly the patients were grouped into tertiles. Urine pH and urinary excretion of calcium, citrate, phosphate, oxalate, uric acid, urea and creatinine were measured on 24 h urine samples. Patients of the highest HOMA-IR tertile showed lower urine citrate levels than patients of the lowest HOMA-IR tertile (475 ± 243 vs. 630 ± 187 mg/24 h, p < 0.05), whereas no difference was detected as far as urinary oxalate, calcium, uric acid, phosphate, and urine pH and urine volume output were concerned. HOMA-IR values were positively related to uric acid serum levels ( r = 0.31, p < 0.05) and negatively to urinary citrate excretion ( r = −0.26, p < 0.05). Hypocitraturic patients showed higher levels of HOMA-IR than normocitraturic ones (3.03 ± 0.92 vs. 2.25 ± 1.19, p < 0.05). This study shows that a higher level of insulin resistance is associated with lower urinary citrate excretion, and that hypocitraturic patients show a greater insulin resistance than normocitraturic calcium stone formers. This may be related to changes in citrate, Na +–K + and H + renal tubule transports, which have been described in insulin resistance. In conclusion, insulin resistance may contribute to an increased risk of calcium stone formation by lowering urinary citrate excretion. This finding suggests the need for a careful metabolic assessment in patients known to form calcium stones in order to ensure stone recurrence prevention and cardiovascular protection.

Body Size and 24-Hour Urine Composition

Greater body mass index (BMI) is a risk factor for kidney stones. However, the relation between BMI and the urinary excretion of many lithogenic factors remains unclear. We studied urine pH, urine volume, and 24-hour urinary excretion of calcium, oxalate, citrate, uric acid, sodium, magnesium, potassium, phosphate, and creatinine in stone-forming and non-stone-forming participants in the Health Professionals Follow-Up Study (599 stone-forming and 404 non-stone-forming men), Nurses' Health Study (888 stone-forming and 398 non-stone-forming older women), and Nurses' Health Study II (689 stone-forming and 295 non-stone-forming younger women). Each cohort was divided into quintiles of BMI. Tests of linear trend were conducted by 1-way analysis of variance. Linear regression models were adjusted for age, history of stone disease, dietary intake, and urinary factors. Participants with greater BMIs excreted more urinary oxalate (P for trend <or= 0.04), uric acid (P < 0.001), sodium (P < 0.001), and phosphate (P < 0.001) than participants with lower BMIs. There was an inverse relation between BMI and urine pH (P <or= 0.02). Positive associations between BMI and urinary calcium excretion in men and stone-forming younger women (P <or= 0.02) did not persist after adjustment for urinary sodium and phosphate excretion. Because of differences in urinary volume and excretion of inhibitors such as citrate, we observed no relation between BMI and urinary supersaturation of calcium oxalate. Urinary supersaturation of uric acid increased with BMI (P <or= 0.01). Positive associations between BMI and urinary calcium excretion likely are due to differences in animal protein and sodium intake. The greater incidence of kidney stones in the obese may be due to an increase in uric acid nephrolithiasis.

PD-04.04: Vitamin B6 deficiency causes hypocitraturia within one week in rats

Citrate is an effective inhibitor of the nucleation, growth, and aggregation of calcium oxalate crystals. Several citrate-containing compounds have been used in the treatment and management of urolithiasis. Changes of the acid-base balance are known to induce marked changes in the urinary citrate level, e.g., hypocitraturia is associated with acidosis, potassium depletion, and starvation. We have previously shown that vitamin B6 deficiency causes hypocitraturia as well as hyperoxaluria in rats. Here we investigated the effects of vitamin B6 deficiency on urinary citrate and oxalate excretion in rats over time.

Partial Neutralization of the Acidogenic Western Diet with Potassium Citrate Increases Bone Mass in Postmenopausal Women with Osteopenia

Chronic acid loads are an obligate consequence of the high animal/grain protein content of the Western diet. The effect of this diet-induced metabolic acidosis on bone mass is controversial. In a randomized, prospective, controlled, double-blind trial, 161 postmenopausal women (age 58.6 +/- 4.8 yr) with low bone mass (T score -1 to -4) were randomly assigned to 30 mEq of oral potassium (K) citrate (Kcitrate) or 30 mEq of K chloride (KCl) daily. The primary end point was the intergroup difference in mean percentage change in bone mineral density (BMD) at lumbar spine (L2 through L4) after 12 mo. Compared with the women who received KCl, women who received Kcitrate exhibited an intergroup increase in BMD (+/-SE) of 1.87 +/- 0.50% at L2 through L4 (P < 0.001), of 1.39 +/- 0.48% (P < 0.001) at femoral neck, and of 1.98 +/- 0.51% (P < 0.001) at total hip. Significant secondary end point intragroup changes also were found: Kcitrate increased L2 through L4 BMD significantly from baseline at months 3, 9, and 12 and reached a month 12 increase of 0.89 +/- 0.30% (P < 0.05), whereas the KCl arm showed a decreased L2 through L4 BMD by -0.98 +/- 0.38% (P < 0.05), significant only at month 12. Intergroup differences for distal radius and total body were NS. The Kcitrate-treated group demonstrated a sustained and significant reduction in urinary calcium excretion and a significant increase in urinary citrate excretion, with increased citrate excretion indicative of sustained systemic alkalization. Urinary bone resorption marker excretion rates were significantly reduced by Kcitrate, and for deoxypyridinoline, the intergroup difference was significant. Urinary net acid excretion correlated inversely and significantly with the change in BMD in a subset of patients. Large and significant reductions in BP were observed for both K supplements during the entire 12 mo. Bone mass can be increased significantly in postmenopausal women with osteopenia by increasing their daily alkali intake as citrate, and the effect is independent of reported skeletal effects of K.

Causes of Hypocitraturia in Recurrent Calcium Stone Formers: Focusing on Urinary Potassium Excretion

Multiple factors associated with hypocitraturia have been identified. However, limited studies addressing the causal relationship to hypocitraturia are available. We therefore conducted this study to determine factors associated with hypocitraturia and show their causal relationship in recurrent calcium stone formers. Dietary review and 24-hour urine samples were obtained from all recurrent calcium stone formers referred for metabolic workup in the stone clinic. One month of oral potassium chloride supplementation was prescribed to stone formers to determine the causal relationship between urinary potassium and citrate levels. Eighty-three subjects, 44 men and 39 women, were recruited to participate in this study. Hypocitraturia (citrate < 300 mg/d [<1.43 mmol/d]) was found in 50.6% of subjects. Four independent urinary variables associated with hypocitraturia were identified, including potassium level, net gastrointestinal alkaline absorption, calcium level, and titratable acid. Urinary potassium level was the strongest predictor of urinary citrate level. Hypocitraturic subjects also had lower fruit intake compared with subjects with high urinary citrate levels. Potassium chloride supplementation to a subgroup of this population (n = 58) resulted in a significant increase in urinary citrate excretion (350.73 +/- 27.25 versus 304.15 +/- 30.00 mg/d [1.67 +/- 0.13 versus 1.45 +/- 0.14 mmol/d]; P < 0.02), but no alteration in fractional excretion of citrate (19.7% +/- 2.7% versus 23.1% +/- 2.4%; P > 0.05). Hypocitraturia was found to be a common risk factor associated with recurrent calcium stone formation and low urinary potassium level, low alkaline absorption, low urinary calcium level, and high titratable acid excretion. Hypocitraturia is predominantly of dietary origin. Estimation of fruit intake should be included in the metabolic evaluation for recurrent calcium stone formation.

Biochemical and Stone-Risk Profiles With Topiramate Treatment

Topiramate is a novel neuromodulatory agent commonly prescribed for the treatment of seizure disorders and for migraine headache prophylaxis. Calcium phosphate kidney stones have been observed with topiramate treatment, but a comprehensive elucidation of stone-risk profile was not reported previously. This study explores the relationship between topiramate treatment and propensity for kidney stone formation. Thirty-two topiramate-treated subjects and 50 healthy volunteers participated in a cross-sectional study in which serum chemistry test and 24-hour urine collection results were evaluated for stone risk. Furthermore, a short-term longitudinal study was conducted in 7 patients to assess stone risk before and 3 months after topiramate treatment. Serum bicarbonate levels were lower with topiramate treatment. Urinary pH, urinary bicarbonate excretion, and fractional excretion of bicarbonate increased, whereas urinary citrate excretion was significantly lower (737 +/- 329 versus 278 +/- 226 mg/d; P < 0.001). Net acid excretion did not change. The relative saturation ratio for brushite increased with topiramate treatment (3.14 +/- 1.69 versus 1.27 +/- 1.26; P < 0.001) because of urinary alkalinization and decreased urinary citrate levels. Urinary saturation of undissociated uric acid decreased (41 +/- 52 versus 76 +/- 60 mg/d; P < 0.001). Treatment with topiramate causes systemic metabolic acidosis, markedly lower urinary citrate excretion, and increased urinary pH. These changes increase the propensity to form calcium phosphate stones.

Nefrolitiasis en un paciente con fibrosis quística

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Defects in the CFTR gene cause abnormal chloride conductance across the apical membrane of epithelial cells, which results in progressive lung disease and also affects other organs. Because life expectancy has increased, other complications of CF have become more apparent. We present a patient with CF and symptomatic nephrolithiasis. Several stones were evident in both kidneys. A 24-hour urine sample showed hyperoxaluria (141 mg/24 h/ 1.73 m(2)) and hypocitraturia and (206 mg/24 h/1.73 m(2), 177 mg citrate/g creatinine). Nephrolithiasis should be included in the differential diagnosis of patients with CF and abdominal pain; urinary excretion of oxalate and citrate should be investigated.

Association of Prevalent Hypertension With 24-Hour Urinary Excretion of Calcium, Citrate, and Other Factors

The relation between hypertension and the urinary excretion of calcium, citrate, and other factors is unclear. It has been proposed that increased urinary calcium excretion is a central feature of essential hypertension. Metabolic acidosis also may be associated with hypertension and decreases urinary citrate levels. To compare the urine composition of individuals with and without hypertension, we studied 24-hour urinary excretion of calcium, citrate, oxalate, uric acid, sodium, magnesium, potassium, phosphorus, and creatinine and pH in a subset of participants with and without nephrolithiasis in the Nurses' Health Study I (older women; N = 1,284), Nurses' Health Study II (younger women; N = 952), and the Health Professionals Follow-up Study (men; N = 788). Logistic regression models adjusted for age, weight, dietary intake, and urinary factors. In participants with and without nephrolithiasis, citrate was the only urinary factor consistently related to hypertension. Compared with those in the lowest quartile of urinary citrate excretion, multivariate odds ratios of prevalent hypertension in the highest quartile were 0.37 (95% confidence interval [CI], 0.24 to 0.55; P trend < 0.001) for older women, 0.54 (95% CI, 0.32 to 0.92; P trend = 0.03) for younger women, and 0.27 (95% CI, 0.16 to 0.45; P trend < 0.001) for men. Urinary calcium levels were not related consistently to hypertension. Excluding participants with single 24-hour urine collections and those administered thiazide diuretics or angiotensin-converting enzyme inhibitors did not change the results. Lower urinary citrate excretion is associated independently with prevalent hypertension. Factors that regulate urinary citrate excretion may play a role in hypertension.

Study of a novel indolin-2-ketone compound Z24 induced hepatotoxicity by NMR-spectroscopy-based metabonomics of rat urine, blood plasma, and liver extracts

Antiangiogenic compound has been believed to be an ideal drug in the current cancer biological therapy, but the angiogenesis inhibitors suffer setback for unknown toxicity now. A novel synthetic indolin-s-ketone small molecular compound, 3Z-3-[((1)H-pyrrol-2-yl)-methylidene]-1-(1-piperidinylmethyl)-1,3-2H-indol-2-one (Z24) can inhibit angiogenesis in new blood vessels. The hepatotoxicity effects of Z24 oral administration (dosed at 60, 130 and 200 mg/kg) have been investigated in female Wistar rats by using metabonomic analysis of (1)H NMR spectra of urine, plasma and liver extracts, as well as by clinical chemistry analysis, liver histopathology and electron micrographs examination. The (1)H NMR spectra of the biofluids were analyzed visually and via pattern recognition by using principal component analysis. The metabonomic trajectory analysis on the time-related hepatotoxicity of Z24 was carried out based on the (1)H NMR spectra of urine samples, which were collected daily predose and postdose over an 8-day period. Urinary excretion of citrate, lactate, 2-oxo-glutarate and succinate increased following Z24 dosing. Increased plasma levels of lactate, TMAO and lipid were observed, with concomitant decrease in the level of glucose and phosphatidylcholine. Metabolic profiling on aqueous soluble extracts of liver tissues with the high dose level of Z24 showed an increase in lactate and glutamine, together with a decrease in glucose, glycogen and choline. On the other hand, studies on lipid soluble extracts of liver tissues with the high dose level of Z24 showed increased level in lipid triglycerides and decreased level in unsaturated fatty acids and phosphatidylcholine. Moreover, the most notable effect of Z24 on the metabolism was the reduction in the urinary levels of creatinine and TMAO and the increase in acetate, citrate, succinate and 2-oxo-glutamate with time dependence. The results indicate that in rats Z24 inhibits mitochondrial function through altering the energy and lipid metabolism, which results in the accumulation of free fatty acids and lactate because of the lack of aerobic respiration. These data show that the metabonomic approach represents a promising new technology for the toxicological mechanism study.

1538: Evaluation of a Novel Nutritional Supplement to Improve Urinary Magnesium and Citrate Excretion

1538: Evaluation of a Novel Nutritional Supplement to Improve Urinary Magnesium and Citrate Excretion

Probing gender-specific metabolism differences in humans by nuclear magnetic resonance-based metabonomics

The measurement of metabolite profiles that are interpreted to yield biomarkers using multivariate data analysis is now a well-established approach for gaining an improved understanding of the impact of genetic modifications, toxicological and therapeutic interventions, and exposure to stimuli (e.g., noxious agents, stressors, nutrients) on the network of transcripts, proteins, and metabolites present in cells, tissues, or whole organisms. This has been termed metabonomics. In this study, multivariate analysis of 1H nuclear magnetic resonance (NMR) spectra of metabolite profiles of urine and plasma from 150 healthy humans revealed that in young people and/or individuals with low body mass indexes, females had higher rates of lipid biosynthesis than did males, whereas males had higher rates of protein turnover than did females. With increasing age, overall lipid biosynthesis decreased in females, whereas metabolism increasingly favored lipid synthesis over protein turnover in males. By relating the derived metabonomic data to known metabolic pathways and published biochemical data, it appears that females synthesize relatively more lipoproteins and unsaturated lipids than do males. Furthermore, the changes in lipid biosynthesis and urinary citrate excretion in females showed a positive correlation. Estrogen most likely plays an essential role in the regulation of, and communication between, protein and lipid biosynthesis by controlling pH in mitochondria and the cytoplasm and hence the observed altered citrate levels.

The increased risk of urinary stone disease in betel quid chewers

The chewing of betel quid is a common practice in many countries of the world, particularly in Southeast Asia. The quid consists of a preparation of areca nut, betel leaf and calcium hydroxide "lime" paste ("chuna"). For the first time, we present a study that links its use to urinary stone disease. Eight patients (seven male and one female) who presented to our Stone Unit with recurrent urinary stones were included in the study. All were from the Indian subcontinent and were found to regularly chew betel. The patients underwent metabolic screening including blood, random urine and 24-h urine tests, quantitative chemical analysis of their calculi (where possible) and each completed a 7-day Diet Diary on his/her free, home diet. The study demonstrated a high incidence of hypercalciuria, a tendency to pass an alkaline urine and low urinary citrate excretion among the patients. Together these urinary risk factors increase the probability of developing both calcium phosphate-containing and calcium oxalate-containing stones. In support of this hypothesis, the patients were found to form stones consisting mainly of calcium phosphate but mixed with calcium oxalate. It is concluded that the use of calcium hydroxide "chuna" in the betel quid is the major contributor to the cause of urinary stones in its users. Moreover, the development of urinary lithiasis in such patients may be a precursor to milk-alkali syndrome in those individuals whose chewing habit is more extensive than in the patients in this study and who do not seek to decrease their habit over the long term.

Rosiglitazone induces renal cellular acidosis.

We studied the effect of RGZ treatment on urinary ammonium and citrate excretion as noninvasive indices of proximal tubular cell pH. Male Sprague Dawley rats fed RGZ 9.4mg/kg diet for 3 days increased their ammonium excretion by 120%(42.6± 3 vs 19.4 ±2umol/mg, p=0.01) and decreased their citrate excretion by 66%(5.8 ± 0.9 vs 17.4± 4.7 mg/mg creatinine, p=0.03) as urine pH decreased (6.16± 0.06 vs 6.33± 0.07, p=0.04). Serum bicarbonate remained unchanged (27 ± 1 and 27±1mM) suggesting enhanced systemic metabolic acid production. In a healthy human subject, RGZ, 6mg x 2days increased UV NH4+ by 186%(33 vs 17umol/min, avg of 3-1h clearance periods), decreased urine pH (5.7 vs 6.4) and increased plasma bicarbonate(24.8 to 28.1mM). In proximal tubule-like OKP cells RGZ (20uM) induced a spontaneous acidosis (6.98± 0.03 vs 7.29± 0.05, p=0.01 after 8minutes measured by BCECF assay) and increased ammonium production from glutamine by 176%(2,421± 147 vs 1,376± 67 nmol/mg protein/18h, p<0.005). Since NHE 3 protein increased 50% and sodium excretion decreased (2JPET 308:426,2004), these results are consonant with increased NH4+/Na+ exchange contributing to sodium retention observed with RGZ and that either cellular acidosis or PPARγ upregulating NHE3 activity in the proximal tubule.

Effect of potential renal acid load of foods on urinary citrate excretion in calcium renal stone formers

The aim of this study was to investigate the influence of the potential renal acid load (PRAL) of the diet on the urinary risk factors for renal stone formation. The present series comprises 187 consecutive renal calcium stone patients (114 males, 73 females) who were studied in our stone clinic. Each patient was subjected to an investigation including a 24-h dietary record and 24-h urine sample taken over the same period. Nutrients and calories were calculated by means of food composition tables using a computerized procedure. Daily PRAL was calculated considering the mineral and protein composition of foods, the mean intestinal absorption rate for each nutrient and the metabolism of sulfur-containing amino acids. Sodium, potassium, calcium, magnesium, phosphate, oxalate, urate, citrate, and creatinine levels were measured in the urine. The mean daily PRAL was higher in male than in female patients (24.1+/-24.0 vs 16.1+/-20.1 mEq/day, P=0.000). A significantly (P=0.01) negative correlation (R=-0.18) was found between daily PRAL and daily urinary citrate, but no correlation between PRAL and urinary calcium, oxalate, and urate was shown. Daily urinary calcium (R=0.186, P=0.011) and uric acid (R=0.157, P=0.033) were significantly related to the dietary intake of protein. Daily urinary citrate was significantly related to the intakes of copper (R=0.178, P=0.015), riboflavin (R=0.20, P=0.006), piridoxine (R=0.169, P=0.021) and biotin (R=0.196, P=0.007). The regression analysis by stepwise selection confirmed the significant negative correlation between PRAL and urinary citrate (P=0.002) and the significant positive correlation between riboflavin and urinary citrate (P=0.000). Urinary citrate excretion of renal stone formers (RSFs) is highly dependent from dietary acid load. The computation of the renal acid load is advisable to investigate the role of diet in the pathogenesis of calcium stone disease and it is also a useful tool to evaluate the lithogenic potential of the diet of the individual patient.

Épidémiologie actuelle de la lithiase rénale en France

Nephrolithiasis is a frequent disease that affects about 10% of people in western countries. The prevalence of calcium oxalate stones has been constantly increasing during the past fifty years in France as well as in other industrialized countries. Stone composition varies depending to gender and age of patients and also underlines the role of other risk factors and associated pathologies such as body mass index and diabetes mellitus. The decrease in struvite frequency in female patients is the result of a significantly improved diagnostic and treatment of urinary tract infections by urea-splitting bacteria. In contrast, the increasing occurrence of weddellite calculi in stone forming women aged more than 50 years could be the consequence of post-menopausal therapy. A high prevalence of uric acid was found in overweight and obese stone formers and in diabetic ones as well. Another important finding was the increased occurrence with time of calcium oxalate stones formed from papillary Randall's plaques, especially in young patients. Nutritional risk factors for stone disease are well known: they include excessive consumption of animal proteins, sodium chloride and rapidly absorbed glucides, and insufficient dietary intake of fruits and potassium-rich vegetables, which provide an alkaline load. As a consequence, an excessive production of hydrogen ions may induce several urinary disorders including low urine pH, high urine calcium and uric acid excretion and low urine citrate excretion. Excess in calorie intake, high chocolate consumption inducing hyperoxaluria and low water intake are other factors, which favour excessive urine concentration of solutes. Restoring the dietary balance is the first advice to prevent stone recurrence. However, the striking increase of some types of calculi, such as calcium oxalate stones developed from Randall's plaque, should alert to peculiar lithogenetic risk factors and suggests that specific advices should be given to prevent stone formation.