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Idiopathic calcium nephrolithiasis is a multifactorial disease with a pathogenesis that involves a complex interaction of environmental and individual factors. This review discusses what is known, about monogenic renal calcium stone-related disorders, provides an update on genetic research in calcium nephrolithlasis and such intermediate phenotypes as idiopathic hypercalciuria, discusses the problems that these conditions pose to clinicians and geneticists interested in their pathogenesis, and proposes some method tools potentially useful in this research frame of reference.

While bone involvement is more evident in case of secondary calcium calculosis, such as hyperparathyroidism, medullary sponge disease, hypercalcemic systemic illness and chronic diarrhea syndrome, less known and more controversial is still the link between bone loss and idiopathic calcium nephrolithiasis. In this study 46 patients with idiopathic calcium nephrolithiasis were consecutively enrolled at their customer diet. Our data show that dietary habits, especially an high sodium and animal protein intake, could seem to influence bone loss of the lumbar spine and of the neck. Furthemore a negative correlation has been found between citrate urinary excretion and bone loss, that suggests a protective role of potassium citrate not only on prevention of recurrent calcium nephrolithiasis, but also on bone loss.

Growing evidence has assigned to oxalate a pivotal role in calcium nephrolithiasis pathophysiology. A better understanding of the mechanisms behind intestinal absorption and renal excretion has led to the identification of new treatments. Among these, diet and probiotics appear promising in terms of safety and rationale. However, the discrepancy between in vitro and in vivo results requires further studies to identify the right patient target, the correct dosage, and the real modification of natural and clinical history of nephrolithiasis.

Objective: The object of this study was to investigate the role for measurement of 24-h renal oxalate excretion in the evaluation of idiopathic calcium stone formers. Materials and Methods: Renal excretion rates of oxalate and creatinine were measured in 24-h urines in 46 consecutive male recurrent idiopathic calcium stone formers and 61 healthy males. Furthermore, day-to-day variation in renal oxalate excretion in 10 male recurrent stone formers and 10 healthy males were evaluated by measuring 24-h oxalate excretion on 5 different days in each individual. Concentrations of oxalate in urine were measured using an enzymatic method without ascorbate interference. Results: The cumulative frequency distribution curves of 24-h renal oxalate excretion rates of stone formers and controls were congruent, and there were no statistically significant differences in oxalate excretion rates between stone formers and controls. Mean 24-h oxalate excretion (95%-confidence intervals) was 0.22 (0.18-0.25) mmol and 0.21 (0....

IntroductionThe genetics underlying the idiopath-ic hypercalciuria leading to calcium-containing renal stones remains elus-ive. The discovery of rare monogenic tubulopathies, often leading to hype-rcalciuria, has increased our underst-anding of tubular physiology and pat-ho-physiology. However, insights int-o idiopathic calcium stone formation have not been gained from these dis-orders. The aim of this study is to ex-amine CYP24A1 mutations in cohorts of patients with calcium nephrolithi-asis.Materials and MethodsWe examined two cohorts of stone-forming patients for mutations in CYP24A1, which encodes the vitamin D24-hydroxylase enzyme. The first cohort had a biochemical phenotype of suppressed parathyroid hormone and high normal serum calcium, whilst the second cohort had a hypercalciuria phenotype. We did not identify bi-allelic sequence variants in CYP24A1 in our cohorts.ResultsIn cohort 1, we identified 9 known s-equence variants. In cohort 2 we ide-ntified 7 known sequence variants.ConclusionCYP24A1 mutations remain a rare cause of calcium nephrolithiasis and hypercalciuria.

Background Because the causes of stones are uncertain, interventions to prevent recurrence have an insecure foundation. Progress depends on careful evaluation of stone formers. Methods A descriptive retrospective database study of 1983 men and 816 women from the Southampton stones clinic from 1990 to March 2007. Anonymized data from the first attendance were analysed using non-parametric statistical tests. Results Sex ratio (2.43:1), age (median 49 y, 2.5th-97.5th percentiles, 23-77 y men, 20-79 y women), recurrent stone formers (30%) and type of stone were similar to other centres. Women more often had a positive family history (24% versus 19% men), previous urinary infection (31% versus 5%) and structural urinary tract abnormality (14% versus 7%); more men had gout (5% versus 1%) and bladder outlet obstruction (3% versus 4/GFR) < 0.70 mmol/L); 6% men and 1.6% women also had low plasma phosphate. Many variables correlated significantly but often weakly with age. Creatinine clearance, pH and (men) TmPO4/GFR decreased from 50 y, urine creatinine, calcium and citrate from 60 y. Conclusions Risk factors for stones differ between men and women, change with ageing and in some may have a genetic basis. The role of phosphaturia merits further exploration.

BACKGROUND: CaSR gene is a candidate for calcium nephrolithiasis. Single-nucleotide polymorphisms (SNPs) encompassing its regulatory region were associated with calcium nephrolithiasis. AIMS: We tested SNPs in the CaSR gene regulatory region associated with calcium nephrolithiasis and their effects in kidney. SUBJECTS AND METHODS: One hundred sixty-seven idiopathic calcium stone formers and 214 healthy controls were genotyped for four CaSR gene SNPs identified by bioinformatics analysis as modifying transcription factor binding sites. Strontium excretion after an oral load was tested in 55 stone formers. Transcriptional activity induced by variant alleles at CaSR gene promoters was compared by luciferase reporter gene assay in HEK-293 and HKC-8 cells. CaSR and claudin-14 mRNA levels were measured by real-time PCR in 107 normal kidney medulla samples and compared in patients with different CaSR genotype. RESULTS: Only rs6776158 (A>G), located in the promoter 1, was associated with nephrolithiasis. Its minor G allele was more frequent in stone formers than controls (37.8% vs 26.4%, P = .001). A reduced strontium excretion was observed in GG homozygous stone formers. Luciferase fluorescent activity was lower in cells transfected with the promoter 1 including G allele at rs6776158 than cells transfected with the A allele. CaSR mRNA levels were lower in kidney medulla samples from homozygous carriers for the G allele at rs6776158 than carriers for the A allele. Claudin-14 mRNA levels were also lower in GG homozygous subjects. CONCLUSIONS: Minor allele at rs6776158 may predispose to calcium stones by decreasing transcriptional activity of the CaSR gene promoter 1 and CaSR expression in kidney tubules.

Nephrolithiasis is a common disorder, with a rising prevalence in the general population. Its pathogenesis is still unclear, but a role for genetics has long been recognized, especially in cases of the more common calcium nephrolithiasis. Although relatively rare, monogenic causes of hypercalciuria and nephrolithiasis do exist and their timely recognition is important from a prognostic and therapeutic viewpoint. This article reviews the clinical and laboratory findings characterizing inherited causes of nephrolithiasis with a view to helping clinicians to recognize and manage these rare conditions.

Sakhaee et al in this issue have investigated whether the risk of the common calcium nephrolithiasis is associated with the metabolic syndrome (MS). This question is interesting since it deals with a more general problem on whether calcium nephrolithiasis is a ‘systemic disorder’ and entails a cardiovascular risk..

■ Objective: To review dietary factors implicated in the pathogenesis of calcium nephrolithiasis and the pathophysiological mechanisms proposed for each. ■ Data sources: Data were obtained from English language articles published between 1950 and 1991 addressing the evaluation and therapy of patients with nephrolithiasis. The articles are indexed in the National Library of Medicine's MEDLINE data base. ■ Study selection: Studies selected for inclusion in this review were those that identified and discussed dietary factors in the pathophysiology of calcium nephrolithiasis. ■ Data extraction: References were reviewed by the authors with emphasis on study size, randomization, and statistical analysis. ■ Data synthesis: Renal stone formation is the result of genetic, metabolic, and environmental factors. The most important environmental factors relate to diet. Assessment of dietary sodium, calcium, phosphorus, oxalate, protein, fiber, fluid, and exogenous vitamins is mandatory in the initial evaluation of the patient with renal stones. Instruction to correct identified dietary excesses or deficiencies is the first therapeutic intervention for all patients, including those in whom additional drug therapy is ultimately required. ■ Conclusions: Nutritional intervention is central to the evaluation, therapy, and long-term monitoring of the patient with calcium nephrolithiasis.

尿路結石形成と食事との関係を明らかにする目的で尿路結石患者の食事調査を行った.36例(男24例, 女12例)のカルシウム結石患者の栄養摂取量を調べ, 日本人の栄養所要量と比べ, つぎのごとき結果をえた.結石患者は男女別でも, また全体でも栄養所要量に比べて, 総蛋白質, 動物性蛋白質, 動物蛋白比すべて有意に高かった.食塩摂取量は男および全体で結石患者に有意に高く, 女でもその傾向がみられた.カルシウムおよび炭水化物は男および全体で結石患者の摂取量が所要量より有意に低く, また女でもその傾向がみられた, To clarify the relationship between renal stone formation and the diet, the consumption of various nutrients of calcium stone formers was investigated. The study included 24 male and 12 female stone formers, between 20 and 78 years old (mean 42 years). The daily consumption of nutrients was compared to the daily nutritive requirement for the Japanese. The amounts of total and animal protein ingested by all the patients were significantly larger than the daily nutritive requirements. The animal protein ratio was also significantly higher. Concerning the total protein, animal protein and animal protein ratio, male and female patients showed similar results. Salt consumption was significantly larger for all the patients and the male patients than the daily nutritive requirement for the Japanese. Female stone formers also showed this tendency. Consumption of calcium and carbohydrate by all the patients and the male patients was significantly smaller than the daily nutritive requirement. This tendency was observed for the female patients.

Background: The purpose of this trial was to evaluate the efficacy of a low-animal-protein diet (LAPD) or a high-fiber diet (HFD) for the prevention of calcium nephrolithiasis recurrence. Methods: We conducted a 4-year randomized trial comparing the effect of 2 diets in 175 idiopathic calcium stone formers. Fifty-five were assigned to a LAPD (25 g/day fiber) and 60 were placed on a normal diet (control group). The primary outcome measure was the time to the first recurrence of calcium nephrolithiasis. Daily urine compositions were analyzed at baseline, at month 4 (M4), M12, M24, M36 and M48. Results: Seventy-three patients completed the trial (23 in the LAPD group, 27 in the HFD group and 23 in the control group). Recurrence was 48% (11/23) in the LAPD group, 63% (17/27) in the HFD group and 48% (11/23) in the control group (p = not significant). During follow-up, urinary calcium levels and other urine parameters did not change significantly in the 3 groups, except for a significant decrease in 24-hour urinary sulfate in the LAPD group. Conclusions: In idiopathic calcium stone formers, neither a LAPD nor a HFD appeared to provide protection against recurrence.

Objective: Urolithiasis has a strong familial component. However, to date, no specific genetic abnormality has been identified. It has been reported that allelic variation in the vitamin D receptor (VDR) gene may affect calcium absorption and excretion. Urolithiasis is a multifactorial disease in which both genetic and environmental factors have an effect on onset and severity of disease. In the present study, the role of Taq I polymorphism of vitamin D receptor gene in urolithiasis was studied. Methods: Eighty children with calcium stone disease (40 with single episode of stone disease and 40 with recurrence) and 40 controls were enrolled. Polymorphic sites were amplified by polymerase chain reaction, digested with Taq I restriction enzymes and analyzed by gel electrophoresis. Allelic or genotypic frequencies were calculated and associations between them and the presence of hypercalciuria, family history and stone recurrence were evaluated. Results: Incidence of Taq I tt genotypes was significantly higher in patients with recurrent calcium-stone disease compared to the controls. In addition, the frequency of the 't' allele was higher in recurrent calcium-stone formers. Taq I t allele was found to be associated with increased risk of recurrence. No association between Taq I polymorphism and a positive family history was found in the present study. The frequency of hypercalciuria was higher in patients with the 'tt' genotype. Conclusion: Taq I t allele of the VDR gene may be a risk factor for severe urolithiasis and recurrent stone disease.

To the Editor: In their interesting review on Randall's plaque, Evan et al.1 go through a number of rodent models where hypercalciuria with/without stones or nephrocalcinosis have been observed, but do not form Randall's plaque-like structures. The list is incomplete, as they themselves pointed out. In our opinion, the Nuf rat model should be added:2 this rat has an activating mutation of the calcium-sensing receptor, which leads to calcifications at various renal levels and – of particular interest – in papillary ducts in up to 63% of heterozygous animals. Whether Randall's plaques exist in such a model is not known and cannot be ascertained from published pictures. Calcification interestingly occurs with no associated hypercalciuria. This model is attractive in relation to human idiopathic calcium stone disease (idiopathic calcium nephrolithiasis). Quite recently, Soldati et al.3 showed that an activating polymorphism of the calcium-sensing receptor is associated with hypercalciuria in idiopathic calcium nephrolithiasis, and Terranegra et al.4 have reported that calcium-sensing receptor SNPs form a haplotype block associated with idiopathic calcium nephrolithiasis and increase the risk of stones by as much as 3.36 times. Looking for the occurrence of Randall's plaques in the Nuf rat might therefore be highly rewarding.

Idiopathic calcium nephrolithiasis and hypercalciuria are multifactorial disease conditions, the pathogenesis of which involves the interaction of environmental and individual factors. Data support a strong role of genes in the pathogenesis of these two conditions. Findings obtained in monogenic disorders characterized by renal calcium stones, and/or hypercalciuria, and/or nephrocalcinosis have proposed a number of genes as candidate genes in the pathogenesis of the common idiopathic calcium nephrolithiasis and hypercalciuria. The physiological role of these genes, and findings in monogenic disorders and idiopathic, multifactorial disorders will be presented.

In two earlier publications we reported excellent therapeutic results in patients with recurrent calcium nephrolithiasis, using oral or intravenous i.v. sodium thiosulfate on the one hand, and on treatment of tumorus-soft periarticular tissues calcifications on the other. Thus, we considered useful to measure endogenous thiosulfaturia, using a specific HPLC method, in 25 healthy adult males and 25 patients with recurrent calcium nephrolithiasis. Healthy adult males excreted between 11 and 16 μ M/24 hour of endogenous thiosulfate, while patients with recurrent calcium nephrolithiasis excreted significantly lower amounts of 6 and 10 μ M/24 hour, except one patient, who did not excrete endogenous thiosulfate, reflecting probably a genetic abnormality. Thiosulfate is a unique agent for treatment of recurrent calcium nephrolithiasis as well as some other abnormal calcium depositions. Two doses of 5 mM sodium thiosulfate daily are therapeutically sufficient. © 2004 Kluwer Academic Publishers.

Purpose: Pharmacological treatment of hypocitraturic calcium nephrolithiasis requires as many as 12 tablets, or numerous crystal packages or liquid supplements taken throughout the day. In addition to added cost, this cumbersome regimen decreases patient compliance, which may increase stone recurrence rates. We evaluated the urinary biochemical effects of dietary citrate supplementation in hypocitraturic calcium stone formers in an attempt to decrease or eliminate the need for pharmacological therapy.Materials and Methods: A total of 12 patients who were either noncompliant with or intolerant of pharmacological citrate therapy supplemented their routine diet with citrate in the form of lemonade, consisting of 4 ounces of reconstituted lemon juice (5.9 gm. citric acid) mixed with tap water to a total volume of 2 1. and consumed at uniform intervals throughout the day. Urine specimens (24-hour) were obtained for biochemical analysis after 6 days of lemonade therapy and compared to pre-lemonade basel...

Nephrolithiasis seems to be the result of crystal formation, aggregation and retention in the kidney during crystalluria. These processes have to occur within the short urinary transit time through the kidney being in the order of few minutes. Recently much work was done on rather qualitative aspects of nephrolithiasis like genetics, metabolism and morphology. In this review we try to provide some quantitative information on urinary supersaturation with respect to stone minerals, especially Ca oxalate (CaOx), on the formation and aggregation of CaOx crystals and on crystal retention in the kidney. The paper is centered on idiopathic Ca nephrolithiasis being the most frequent stone disease with only partially known pathogenesis. New aspects of the role of urinary macromolecules in stone formation and of the mechanism of crystal aggregation are provided.

Many studies indicate that up-regulated production of 1,25(OH)2-vitamin D3 (calcitriol) with increased intestinal absorption of calcium is the primary event causing idiopathic hypercalciuria. Thus, a low calcium diet appears to be a straightforward strategy in calcium stone formers with hypercalciuria (HCSF). However, the efficacy of such a regimen has never been established, and lowering calcium intake from 1000 to 400 mg/day further enhances calcitriol production. On a diet chronically restricted in calcium, many stone formers increase their intake of animal flesh protein. The latter is known to increase renal mass, and calcitriol levels indeed are positively correlated with renal mass in animals as well as in HCSF. Thus, low calcium and high animal flesh protein consumption are independent stimuli for further up-regulation of calcitriol production. The rise in calcitriol suppresses parathyroid hormone synthesis thereby diminishing renal tubular calcium reabsorption, and increasing urinary calcium losses. Since calcitriol up-regulation also increases bone resorption, the combination of low calcium and high protein intake is particularly likely to induce negative calcium balance and thus osteopenia. Finally, low calcium intake carries the risk of insufficient intestinal binding of oxalate with subsequent increases in intestinal absorption and urinary excretion of oxalate. Indeed, most recent studies suggest that high amounts of calcium, when ingested simultaneously with oxalate-containing meals, are able to prevent hyperoxaluria during severe oral oxalate loading.

Idiopathic calcium nephrolithiasis (ICN) and hypertension (HY) are both common in affluent countries. Hypercalciuria is reported to be associated with HY1 and hypertensive subjects tend to develop renal stones more often than normals3. Our aim was to evaluate possible differences in blood pressure (BP) between ICN patients and normals and to find possible relationships between BP and metabolic parameters in ICN patients and normals.

The pathogenesis of idiopathic calcium nephrolithiasis most likely involves an imbalance between factors promoting and inhibiting calcium crystal growth and aggregation in the urine. Among many factors able to cause this disorder, urine concentration induced by chronic dehydration seems to be an important condition that increases the risk of stone formation1. To verify the effect of drastic dehydration on lithogenic risk, we carried out this study.

Urinary tract infection (UTI) is well known to be a primary factor in the pathogenesis of struvite stones1, yet little data exist on the effect of UTI on idiopathic calcium nephrolithiasis (ICN)2. The aim of this study was to evaluate the prevalence of UTI among patients with ICN and to determine the effect of UTI on the urinary risk factors in ICN.

In an attempt to document the efficacy of potassium citrate in stone formation, 57 patients with active lithiasis (2 or more stones during the preceding 2 years) and hypocitraturia were randomly allocated into 2 groups, with 1 group taking 30 to 60 mEq. potassium citrate daily in wax matrix tablet formation and the other group receiving placebo. In 18 patients receiving potassium citrate for 3 years stone formation significantly declined after treatment from 1.2 +/- 0.6 to 0.1 +/- 0.2 per patient year (p0.0001), in 13 patients (72%) the disease was in remission and all patients showed a reduced stone formation rate individually. In contrast, 20 patients taking placebo medication for 3 years showed no significant change in stone formation rate (1.1 +/- 0.4 to 1.1 +/- 0.3 per patient year) and in only 4 patients (20%) was the disease in remission. The stone formation rate during potassium citrate treatment was significantly lower than during the placebo treatment (0.1 +/- 0.2 versus 1.1 +/- 0.3 per patient year, p0.001). Potassium citrate therapy caused a significant increase in urinary citrate, pH and potassium, whereas placebo did not. Adverse reactions to potassium citrate were mild causing only 2 patients in the potassium citrate group and 1 in the placebo group to withdraw from the study. In summary, our randomized trial showed the efficacy of potassium citrate in preventing new stone formation in idiopathic hypocitraturic calcium nephrolithiasis.

Clinical and biochemical parameters were investigated in a group of patients with medullary sponge kidney (MSK) and compared with tho se of 2 groups of patients with idiopathic calcium nephrolithiasis, single and recurrent stone-formers (SSF and RSF). No sex differences, a more common family history of nephrolithiasis, no tendency to over weight and a higher urinary magnesium excretion were found to be the distinctive features of the patients with MSK with respect to SSF and RSF. Although the high magnesium excretion has been postulated to inhibit calcium oxalate crystallization, its protective effect in MSK is probably overwhelmed by other risk factors such as distal aci dification defects and prolonged transit time in the ectatic ducts.

To clarify the relationship between renal stone formation and the diet, the consumption of various nutrients of calcium stone formers was investigated. The study included 24 male and 12 female stone formers, between 20 and 78 years old (mean 42 years). The daily consumption of nutrients was compared to the daily nutritive requirement for the Japanese. The amounts of total and animal protein ingested by all the patients were significantly larger than the daily nutritive requirements. The animal protein ratio was also significantly higher. Concerning the total protein, animal protein and animal protein ratio, male and female patients showed similar results. Salt consumption was significantly larger for all the patients and the male patients than the daily nutritive requirement for the Japanese. Female stone formers also showed this tendency. Consumption of calcium and carbohydrate by all the patients and the male patients was significantly smaller than the daily nutritive requirement. This tendency was observed for the female patients.

Stone disease is a common medical problem, frequently recurs, and is associated with significant morbidity. Because appropriate medical therapy significantly decreases stone recurrence, this disorder must not be ignored by nonurologists. Even the single stone-former should be offered a metabolic evaluation.