Molecular basis of inherited renal lithiasis

Idiopathic calcium oxalate stone formation results from an interaction between genetic and environmental factors. Clearly identifiable risk factors for the disease that have a significant genetic influence are the excretions of calcium, oxalate and citrate. Candidate genes that may be responsible for these effects have been proposed. With the large-scale sequencing of the human genome and the identification of genetic polymorphisms, it is only a matter of time before these genes and the sequence differences within them that are associated with susceptibility to the disease are conclusively identified.     

Artificial neural networks for assessing the risk of urinary calcium stone among men

The pathophysiology of idiopathic calcium oxalate nephrolithiasis involves metabolic abnormalities. Previous studies gave conflicting results about the metabolic factors in stone formers. Artificial neural networks (ANN) are new methods based on computer programming that have outperformed conventional methods in prediction of outcomes in different medical applications. The aim of our study was to compare with ANN the clinical and biochemical parameters implicated in urinary calcium stone between stone formers (SF) and controls (C). We compared 11 clinical and biochemical variables among 119 male idiopathic calcium oxalate SF and 96 C by univariate and multivariate statistical analyses. Univariate analyses included discriminant analysis, logistic regression analysis, and ANN. For multivariate analyses, stepwise discriminant analysis and ANN were performed. Variables included age, body mass index (BMI), family history of nephrolithiasis, supersaturation with respect to calcium oxalate, calcemia, and 24-h urinary calcium, oxalate, uric acid, urea, sodium, and citrate. With univariate and multivariate analyses, ANN were as efficient as classical statistical analyses in discriminating the different parameters. The sensitivity, the specificity, and the percentage of correctly classified patients were similar in all analyses. With ANN, supersaturation (receiver operating characteristic, ROC curves index 0.73) and urea (ROC 0.72) were the most discriminant followed by family history and urinary calcium (ROC 0.67). ROC index was 0.63 for citrate, 0.61 for oxalate and urate, 0.60 for sodium and calcemia, 0.58 for age, and 0.56 for BMI, but these parameters were not statistically different between SF and C. ANN gave additional information since they made it possible to determine the cut-off values of the parameters and their predictive power. Cut-off values for being a stone former were 8.9 for supersaturation and 363 mmol/day for urinary urea with a predictive power of 0.69 and 0.70, respectively. Univariate and multivariate analysis evidenced supersaturation and 24-h urinary urea excretion as the most discriminant parameters between the two populations. In addition to high supersaturation, the negative impact of protein intake was confirmed.     

Vascular endothelial growth factor gene polymorphism is associated with calcium oxalate stone disease

Growth factor-related genes regulate cell growth, differentiation and apoptosis in the kidney in response to cellular injury. One of the theories of stone formation is that cellular injury, and thus growth factors, play a role. We therefore investigated the association between growth factor genes and calcium oxalate stone disease. The most frequently seen polymorphism of the vascular endothelial growth factor (VEGF) gene is Bst U I C/T, which is located upstream at the -460th nucleotide. Other growth factor-related gene polymorphisms include the cytochrome P450c17alpha enzyme (CYP17) gene MspA I C/T polymorphism at the 5'-UTR promoter region, the epidermal growth factor receptor (EGFR) gene Bsr I polymorphism (A to T) at position 2,073, and the insulin-like growth factor-2 (IGF-2) gene Apa I A/G at exon 9. All four polymorphisms were used as genetic markers in this study in the search for an association between stone disease and growth factor related genes. A normal control group of 230 healthy people, and 230 patients with calcium oxalate stone, were examined. The polymorphism was seen following polymerase chain reaction based restriction analysis. The result revealed a significant difference between normal individuals and stone patients (P=0.0003, Fisher's exact test) in the distribution of the VEGF gene polymorphism as well as an odds ratio of 1.30 (95% confidence interval=0.993-1.715) per copy of the "T" allele. Whereas, the IGF-2, EGFR and CYP17 gene polymorphisms did not reveal a significant association with stone disease. We conclude that the VEGF gene Bst U I polymorphism is a suitable genetic marker of urolithiasis.     

Interleukin-1β gene and receptor antagonist gene polymorphisms in patients with calcium oxalate stones

Interleukin-1 (IL-1) might play a role in the process of bone loss and hypercalciuria and is therefore considered to be involved in the formation of urinary stones. The aim of this study is to test whether the IL-1beta promoter region, exon 5 region and IL-1 receptor antagonist gene intron 2 polymorphisms could be genetic markers for the susceptibility to the formation of urinary stones. A control group of 152 healthy people and a group of 105 patients with recurrent calcium oxalate stone were examined in this study. Polymerase chain reaction (PCR) analyzed the variable number tandem repeats at intron 2 of the IL-1Ra gene for the polymorphisms. PCR-based restriction analysis was done for the IL-1beta gene polymorphisms of the promoter region and exon 5 by the endonucleases Ava I and Taq I, respectively. The polymorphisms studied in the IL-1beta genes did not reveal a strong association with calcium oxalate stone disease when compared with the control group (promoter region by chi-square test, P=0.627: exon 5 region by Fisher's exact test, P = 0.403). Only two frequent alleles of the IL-1Ra gene corresponding to one and two copies of an 86-bp sequence repeat were identified by PCR. The result revealed significant differences between control individuals and stone patients (P < 0.01. Fisher's exact test). In addition, the frequency of the type I allele in the stone group (99.0%) was higher than in the control group (94.0%). The odds ratio for the type I allele of the IL-1Ra gene in calcium oxalate stone disease is 6.041 (95% CI: 1.683 approximately 21.687). There is an association between urolithiasis and polymorphism in the IL-1Ra gene. No significant difference was found when dividing the stone patients into groups with normocalciuria and hypercalciuria in relation to these genetic polymorphisms. Further studies of the type I allele of the IL-IRa gene are worthwhile because of its correlation with stone disease. In our study, neither the IL-1beta promoter region nor the exon 5 polymorphisms were significantly different when comparing control subjects and calcium oxalate stone patients.     

Artificial neural networks for assessing the risk factors for urinary calcium stones according to gender and family history of stone

OBJECTIVE: In a previous work, we evidenced that artificial neural networks (ANNs) were more informative than classical statistical analyses for assessing the risk of idiopathic calcium nephrolithiasis in male stone-formers. MATERIAL AND METHODS: We compared risk factors for idiopathic calcium nephrolithiasis (age, body mass index, calcemia, calcium oxalate supersaturation, and 24-h calciuria, oxaluria, uricosuria, citraturia, urea, and sodium) in four populations: men and women with and without a family history of stone (FHS). A total of 119 males (58 with an FHS, 61 without) and 59 females (30 with an FHS, 29 without) were compared to healthy controls. For each variable, receiver operating characteristic (ROC) curve indices were calculated by means of ANNs. RESULTS: In men without an FHS, the most discriminant variables were 24-h urea (ROC curve index 0.76), supersaturation (ROC curve index 0.72), 24-h calciuria (ROC curve index 0.68), 24-h uricosuria (ROC curve index 0.64), 24-h oxaluria (ROC curve index 0.63), 24-h sodium (ROC curve index 0.62), and calcemia (ROC curve index 0.60). In men with an FHS, only supersaturation (ROC curve index 0.67) was discriminant. In women without FHS, calcemia (ROC curve index 0.67), 24-h calciuria (ROC curve index 0.64), and 24-h uricosuria (ROC curve index 0.62) were discriminant. In women with an FHS, supersaturation (ROC curve index 0.70), 24-h uricosuria (ROC curve index 0.69), 24-h urea (ROC curve index 0.68), and 24-h calciuria (ROC curve index 0.67) were discriminant. CONCLUSIONS: Risk factors for idiopathic calcium nephrolithiasis were roughly the same in men with or without an FHS, and in women with an FHS. In these patients, calcium oxalate supersaturation and 24-h urea were the most discriminant factors. Conversely, in women without an FHS, calcium abnormalities (calcemia, 24-h calciuria) were discriminant and should prompt a search for infraclinical primary hyperparathyroidism or sarcoidosis.     

The efficacy of dietary intervention on urinary risk factors for stone formation in recurrent calcium oxalate stone patients

PURPOSE: Nutrition is suggested to be the major environmental risk factor in idiopathic calcium oxalate stone disease. The study was designed to evaluate the effect of dietary intervention on urinary risk factors for recurrence in calcium oxalate stone formers. MATERIALS AND METHODS: A total of 76 men and 31 women with idiopathic calcium oxalate stone disease collected 24-hour urine on their habitual, self-selected diets and after 7 days on a balanced standardized diet according to the recommendations for calcium oxalate stone formers. RESULTS: On the usual diet, a urine volume of less than 2.0 l per 24 hours was present in 57.9%, hypercalciuria in 25.2%, hypomagnesuria in 18.7%, hyperoxaluria in 14.0%, hyperuricosuria in 41.3% and hypocitraturia in 57.0% of patients. The frequency of metabolic abnormalities and the risk of calcium oxalate stone formation decreased significantly on the ingestion of the balanced diet, due to the significant increase in urinary volume, pH and citrate excretion and the significant decrease in urinary calcium and uric acid excretion. No change occurred in urinary oxalate and magnesium excretion. CONCLUSIONS: The evaluation of urinary risk profiles of the patients on their usual dietary habits revealed a high risk for calcium oxalate stone formation. A low fluid intake and an increased intake of protein and alcohol were identified as the most important dietary risk factors. The shift to a nutritionally balanced diet according to the recommendations for calcium oxalate stone formers significantly reduced the stone forming potential.     

Nephrolithiasis in identical twins: the impact of nature vs nurture

OBJECTIVE: To assess possible underlying metabolic abnormalities in three sets of monozygotic twins, to evaluate the interplay among the factors of kidney stone formation, a complex multifactorial process influenced by environmental, genetic and anatomical factors. PATIENTS AND METHODS: Three sets of identical twins with either cystine or calcium oxalate stones were identified. Demographic data, medical histories and the results of 24-h urine testing, with samples collected on self-selected diets, were reviewed and analysed. RESULTS: The cystinuric twins had very similar cystine excretion rates, while stone activity was significantly more pronounced in one. Metabolic abnormalities were concordant in one set of twins with calcium oxalate stones, both being hypercalciuric and hyperuricosuric. However, metabolic abnormalities were discordant in the other pair, one twin with hypercalciuria and the other with hypocitraturia. Two of the three pairs had low urinary volume. CONCLUSIONS: These results support previous observations that environmental, genetic and potentially, anatomical factors play roles in kidney-stone formation. Additional controlled studies of monozygotic stone-forming twins might help to define the interplay between environmental and genetic factors, and allow the identification of susceptibility genes involved in stone generation.     

Calcitonin receptor gene polymorphism: a possible genetic marker for patients with calcium oxalate stones.

OBJECTIVES: The formation of urinary stones is hypothesized to be associated with calcitonin receptors. The most commonly seen polymorphism is C/T at the 1377th nucleotide. Hence, these polymorphisms are being used as a genetic marker in the search for the cause of urolithiasis. METHODS: A normal control group of 105 healthy people and 102 patients with recurrent calcium oxalate stones were examined. The polymorphism was detected following a polymerase chain reaction-based and restriction analysis by AluI. An uncuttable length is 228 bp (CC) whereas two fragments of 120 and 108 bp are shown as cuttable lengths (TT). RESULTS: The results revealed significant differences between the normal individuals and the stone patients (p<0.01). The distribution of leucine (cuttable) homozygote in the stone group (2.0%) was higher than in the control group (0.0%). The odds ratio for the leucine allele of the calcitonin receptor gene in calcium oxalate stone disease is 5.634 (95% CI: 2.286--13.885). CONCLUSIONS: Results show that the polymorphism in the calcitonin receptor gene could be a genetic marker for urinary stone disease and therefore it is worthwhile pursuing further studies of the leucine allele of calcitonin receptor gene due to it is strongly correlated with stone disease.     

The genetic composition of Oxalobacter formigenes and its relationship to colonization and calcium oxalate stone disease

Oxalobacter formigenes is a unique intestinal organism that relies on oxalate degradation to meet most of its energy and carbon needs. A lack of colonization is a risk factor for calcium oxalate stone disease. Protection against calcium oxalate stone disease appears to be due to the oxalate degradation that occurs in the gut on low calcium diets with a possible further contribution from intestinal oxalate secretion. Much remains to be learned about how the organism establishes and maintains gut colonization and the precise mechanisms by which it modifies stone risk. The sequencing and annotation of the genomes of a Group 1 and a Group 2 strain of O. formigenes should provide the informatic tools required for the identification of the genes and pathways associated with colonization and survival. In this review we have identified genes that may be involved and where appropriate suggested how they may be important in calcium oxalate stone disease. Elaborating the functional roles of these genes should accelerate our understanding of the organism and clarify its role in preventing stone formation.     

Calcium oxalate monohydrate binding protein: a diagnostic biomarker for calcium oxalate kidney stone formers

Urinary oxalate is a biomarker for calcium oxalate kidney stone disease; however, its assay is insensitive and nonspecific. Calcium oxalate monohydrate (COM) binding protein (45 kDa) is a promoter of calcium oxalate kidney disease, which is markedly upregulated by oxalate induced oxidative stress. The current study was carried out to evaluate whether COM binding protein can serve as a diagnostic marker for calcium oxalate kidney stone formers. COM binding protein was isolated, purified and antibody was raised against it in rabbits. Urine samples (24 h) were collected from patients suffering from various kidney diseases such as acute nephritis, chronic nephritis, nephrotic syndrome, calcium oxalate (CaOx) stone formers, uric acid stone formers, struvite stone formers and calcium phosphate stone formers. This COM binding protein was quantified by an in house ELISA method and the excretion was found to lie between 2 and 3 mg in control samples, while in CaOx stone formers it was detected between 11 and 19 mg. Urinary risk factors were assayed. We conclude that COM binding protein can serve as a diagnostic marker for CaOx stone formers.     

A twin study of genetic and dietary influences on nephrolithiasis: a report from the Vietnam Era Twin (VET) Registry

BACKGROUND: Nephrolithiasis is a complex phenotype that is influenced by both genetic and environmental factors. We conducted a large twin study to examine genetic and nongenetic factors associated with stones. METHODS: The VET Registry includes approximately 7500 male-male twin pairs born between 1939 to 1955 with both twins having served in the military from 1965 to 1975. In 1990, a mail and telephone health survey was sent to 11,959 VET Registry members; 8870 (74.2%) provided responses. The survey included a question asking if the individual had ever been told of having a kidney stone by a physician. Detailed dietary habits were elicited. In a classic twin study analysis, we compared concordance rates in monozygotic (MZ) and dizygotic (DZ) twins. We also conducted a cotwin control study of dietary risk factors in twins discordant for stones. RESULTS: Among dizygotic twins, there were 17 concordant pairs and 162 discordant pairs for kidney stones. Among monozygotic twins, there were 39 concordant pairs and 163 discordant pairs. The proband concordance rate in MZ twins (32.4%) was significantly greater than the rate in DZ twins (17.3%) (chi(2)= 12.8; P < 0.001), consistent with a genetic influence. The heritability of the risk for stones was 56%. In the multivariate analysis of twin pairs discordant for kidney stones, we found a protective dose-response pattern of coffee drinking (P= 0.03); those who drank 5 or more cups of coffee were half as likely to develop kidney stones as those who did not drink coffee (OR = 0.4, 95% CI 0.2, 0.9). Those who drank at least 1 cup of milk per day were half as likely to report kidney stones (OR = 0.5, 95% CI 0.3, 0.8). There were also marginally significant protective effects of increasing numbers of cups of tea per day and frequent consumption of fruits and vegetables. Other factors such as the use of calcium supplements, alcohol drinking, consumption of solid dairy products, and the amount of animal protein consumed were not significantly related to kidney stones in the multivariate model. Conclusion: These results confirm that nephrolithiasis is at least in part a heritable disease. Coffee, and perhaps tea, fruits, and vegetables were found to be protective for stone disease. This is the first twin study of kidney stones, and represents a new approach to elucidating the relative roles of genetic and environmental factors associated with stone formation.     

The impact of dietary oxalate on kidney stone formation

The role of dietary oxalate in calcium oxalate kidney stone formation remains unclear. However, due to the risk for stone disease that is associated with a low calcium intake, dietary oxalate is believed to be an important contributing factor. In this review, we have examined the available evidence related to the ingestion of dietary oxalate, its intestinal absorption, and its handling by the kidney. The only difference identified to date between normal individuals and those who form stones is in the intestinal absorption of oxalate. Differences in dietary oxalate intake and in renal oxalate excretion are two other parameters that are likely to receive close scrutiny in the near future, because the research tools required for these investigations are now available. Such research, together with more extensive examinations of intestinal oxalate absorption, should help clarify the role of dietary oxalate in stone formation.     

Heterozygous cystinuria and calcium oxalate urolithiasis.

Many variables are known to be associated with the formation of calcium oxalate urolithiasis but none is essential for the initiation or growth of stones. It is likely that the predisposition to stone formation is related to multiple factors. We herein describe still another metabolic state that seems to predispose to calcium oxalate stone disease, namely heterozygosity for cystinuria. Cystine screening tests were done on 24-hour urine specimens obtained from 126 patients in whom recurrent calcium oxalate stones form and 84 controls and quantitative amino acid determinations were done on all positive specimens. Of those studied 17 of 126 stone patients and 1 of 84 controls were heterozygous cystinurics. A test of the differences between the relative frequencies of cystinuria heterozygotes in the 2 groups with Fisher's exact test revealed them to be highly significant (p less than 0.001). Our study indicates that carrier status for 1 of the cystinuria genes predisposes to calcium oxalate stone formation but, like other factors related to urolithiasis, it is not a necessary cause of stone disease.     

Genetic and dietary influences on urinary oxalate excretion

Several genes contribute to the development of calcium oxalate nephrolithiasis as it is a polygenic disease. To explore the influence of genetic factors on oxalate excretion we have examined the distribution of oxalate excretions in 101 normal individuals who consumed self-selected diets. The distribution was apparently trimodal, consistent with the existence of three classes of oxalate excretors reflecting two allelic genes determining high and low oxalate excretion occurring with frequencies of 0.32 and 0.68 respectively. The pattern of inheritance in eight families was compatible with the expression of a pair of codominant alleles. A comparison of the distribution of excretory classes among the 101 normal individuals with that of 101 calcium oxalate stone formers suggests that high oxalate excretion may be associated with a 4-fold increased risk of stone disease and intermediate excretion with a 1.6-fold increase. Control of dietary factors influencing oxalate excretion apparently improved the discrimination between excretory classes in 17 individuals but the intra-individual variability in oxalate excretion was not reduced in four of nine individuals in whom this parameter was evaluated. More stringent dietary control than that applied in this study may be required before more extensive genotyping of individuals is attempted. Received: 4 February 1997 / Accepted: 22 October 1997     

Association of E-cadherin gene 3'-UTR C/T polymorphism with calcium oxalate stone disease

INTRODUCTION: Urinary stone disease is one of the most commonly seen urological diseases in Taiwan. Single nucleotide polymorphisms (SNPs) are commonly used for the investigation of genetic markers for stone disease. E-cadherin (CDH-1) is one of the cellular junction proteins related to the integrity of epithelial cells. Our aim was to investigate a polymorphism of the CDH-1 gene 3'-UTR as a possible genetic marker in the search for the genetic causes. MATERIALS AND METHODS: 148 patients with calcium oxalate stone were compared with 103 healthy controls for the frequency of CDH-1 3'-UTR polymorphisms. The polymorphism was detected by polymerase chain reaction-based restriction analysis (PML I endonuclease). RESULTS AND CONCLUSIONS: The results revealed significant differences between normal individuals and calcium stone disease patients (p = 0.0013). The distribution of genotype TT homozygote was higher in stone patients (51.5%) than in the control group (43.4%). The odds ratio for T allele compared to C allele was 2.0. We have concluded that polymorphisms of CDH-1 3'-UTR is a valid genetic marker for calcium stone disease.     

Prevalence of hyperoxaluria in idiopathic calcium oxalate kidney stone disease

Urinary excretion of oxalate, calcium and urate has been investigated in 88 patients affected by idiopathic calcium oxalate stone disease and in 20 normal subjects. Of these ions, only oxalate was found significantly higher in stone formers. Defining hyperoxaluria as urinary oxalate excretion greater than 2 SD above normal, 50% of stone-forming people were found to be hyperoxaluric. When stone formers were classified in normo- and hyperoxaluric, the prevalence of hypercalciuria, hyperuricuria, family history of stone disease and recurrencies in stone formation was the same in both groups. It is concluded that hyperoxaluria is a frequent finding in finding in idiopathic calcium oxalate renal stone disease.     

Arginine form of p21 gene codon 31 is less prominent in patients with calcium oxalate stone

The formation of urinary stones is associated with cell death in response to various injuries. P21 (WAF1/CIP1) is a downstream protein of P53 and can arrest the cell cycle at G1/S with resulting cell death. We aimed to investigate the polymorphism of p21 gene codon 31 as the genetic marker in searching for the association of urolithiasis. One hundred and nineteen healthy controls and 95 patients with calcium oxalate stone were examined in this study. The polymorphism was seen from the result of polymerase chain reaction-based restriction analysis. The result revealed significant differences between normal individuals and stone patients (P < 0.05) and the distribution of arginine homozygote in the control group (31.9%) was higher than in the patient group (16.8%). It is concluded that polymorphisms of p21 codon 31 can be a genetic marker for urinary stone disease. Individuals possessing arginine form of p21 codon 31 have less risk of developing calcium stone disease. Received: 15 June 2000 / Accepted: 6 December 2000     

Kalciumoxalatharnsteine und Hyperoxalurie

Approximately 4 million Germans suffer from stone disease. In the majority of cases (70-75%) it is calcium oxalate. Its pathophysiology is complex and comprises disorders such as hypercalciuria, hyperoxaluria, hypocitraturia, hyperuricosuria, and hypomagnesuria. These biochemical changes in urine are well known as "classic" risk factors of calcium oxalate stone formation. However, studies in the last decade showed that calcium oxalate stones are strongly related with other diseases or disorders such as overweight, hypertension, or a lack of oxalate-degrading bacteria in the gut. The evidence for these "new" risk factors in the literature is very strong. It is particularly important in regard to effective treatment and aftercare of patients with calcium oxalate stones to be familiar with both the "classic" and the new risk factors.     

Essential arterial hypertension and stone disease.

BACKGROUND: Cross-sectional studies have shown that nephrolithiasis is more frequently found in hypertensive patients than in normotensive subjects, but the pathogenic link between hypertension and stone disease is still not clear. METHODS: Between 1984 and 1991, we studied the baseline stone risk profile, including supersaturation of lithogenic salts, in 132 patients with stable essential hypertension (diastolic blood pressure of more than 95 mm Hg) without stone disease and 135 normotensive subjects (diastolic blood pressure less than 85 mm Hg) without stone disease who were matched for age and sex (controls). Subsequently, both controls and hypertensives were followed up for at least five years to check on the eventual formation of kidney stones. RESULTS: Baseline urine levels in hypertensive males were different from that of normotensive males with regards to calcium (263 vs. 199 mg/day), magnesium (100 vs. 85 mg/day), uric acid (707 vs. 586 mg/day), and oxalate (34.8 vs. 26.5 mg/day). Moreover, the urine of hypertensive males was more supersaturated for calcium oxalate (8.9 vs. 6.1) and calcium phosphate (1.39 vs. 0.74). Baseline urine levels in hypertensive females were different from that of normotensive females with regards to calcium (212 vs. 154 mg/day), phosphorus (696 vs. 614 mg/day), and oxalate (26.2 vs. 21.7 mg/day), and the urine of hypertensive females was more supersaturated for calcium oxalate (7.1 vs. 4.8). These urinary alterations were only partially dependent on the greater body mass index in hypertensive patients. During the follow-up, 19 out of 132 hypertensive patients and 4 out of 135 normotensive patients had stone episodes (14.3 vs. 2.9%, chi-square 11.07, P = 0.001; odds ratio 5.5, 95% CI, 1.82 to 16.66). Of the 19 stone-former hypertensive patients, 12 formed calcium calculi, 5 formed uric acid calculi, and 2 formed nondetermined calculi. Of the urinary factors for lithogenous risk, those with the greatest predictive value were supersaturation of calcium oxalate for calcium calculi and uric acid supersaturation for uric acid calculi. CONCLUSIONS: A significant percentage of hypertensive subjects has a greater risk of renal stone formation, especially when hypertension is associated with excessive body weight. Higher oxaluria and calciuria as well as supersaturation of calcium oxalate and uric acid appear to be the most important factors. Excessive weight and consumption of salt and animal proteins may also play an important role.     

Analytical epidemiology of urolithiasis

In this paper, urolithiasis is reviewed from the standpoint of analytical epidemiology, which examines a statistical association between a given disease and a hypothesized factor with an aim of inferring its causality. Factors incriminated epidemiologically for stone formation include age, sex, occupation, social class (level of affluence), season of the year and climate, dietary and fluid intake and genetic prodisposition. Since some of these factors are interlinked, they are broadly classified into five categories and epidemiologically looked over here. Genetic predisposition is essentially endorsed by the more frequent episodes of stone formation in the family members of stone formers, as compared to non-stone formers. Nevertheless, some environmental factors (likely to be dietary habits) shared by family members are believed to be relatively more important than genetic predisposition. A hot, sunny climate may influence stone formation through inducing dehydration with increased perspiration and increased solute concentration with decreased urine volume, coupled with inadequate liquid intake, and possibly through the greater exposure to ultraviolet radiation which eventually results in an increased vitamin D production, conceivably correlated with seasonal variation in calcium and oxalate excretion to the urine. Urinary tract infections are importantly involved in the formation of magnesium ammonium phosphate stones in particular. The association with regional water hardness is still in controversy. Excessive intake of coffee, tea and alcoholic beverages seemingly increase the risk of renal calculi, though not consistently confirmed. Many dietary elements have been suggested by numerous clinical and experimental investigations, but a few elements are substantiated by analytical epidemiological investigations. An increased ingestion of animal protein and sugar and a decreased ingestion of dietary fiber and green-yellow vegetables are linked with the higher probability of stone formation in the industrialized countries. No trace elements in foodstuffs and liquids have been epidemiologically associated. The dietary guidelines for avoiding stone formation and/or recurrence are summarized in this paper, including other daily-life recommendations.