Effects of citrate on the different phases of calcium oxalate crystallization

Urinary citrate appears to be an important factor in the crystallization process of calcium oxalate and calcium phosphate. The urinary excretion of citrate was found to be significantly lower in patients with calcium oxalate stone disease as compared with normal subjects, and about 30 per cent of the calcium stone formers can be considered as hypocitraturic. The lowest excretion of citrate was recorded in urine collected during the night. Citrate has significant effects on supersaturation with respect to both calcium oxalate and calcium phosphate, it also inhibits the growth of these crystals. In addition, citrate appears to be capable of inhibiting the aggregation of crystals composed of calcium oxalate, brushite, and hydroxyapatite. The heterogenous growth of calcium oxalate on calcium phosphate is also counteracted by citrate. As a consequence of the crucial role of citrate in these processes, stone prevention with alkaline citrate has become an attractive form of treatment in patients with recurrent stone formation. Single evening dose administration of sodium potassium citrate resulted in an of sodium potassium citrate resulted in an increased excretion of citrate, reduced levels of the calcium/citrate ratio as well as supersaturation with respect to calcium oxalate and a decreased rate of stone formation. However, conflicting results of stone preventive treatment with alkaline citrate have been reported by different groups, and long-term follow-up of patients treated in a randomized way is necessary to definitely assess the efficacy of alkaline citrate.     

Histone deacetylase. A key enzyme for the binding of regulatory proteins to chromatin

Stone and urine composition were analysed in 75 men and 40 women with recurrent calcium oxalate stone disease (group R) and in 48 men and 19 women who had formed only one calcium-oxalate-containing stone (group S). Patients who had developed stones with a large fraction of calcium phosphate were significantly more frequent in group R than in group S. There was furthermore a higher excretion of calcium and higher calcium oxalate supersaturation levels in patients with stones containing more than 25% calcium phosphate. It was concluded from these observations that the calcium phosphate content of renal stones might be a useful factor in predicting the future course of the disease.     

Urinary calcium oxalate saturation in healthy infants and children

PURPOSE: A number of factors influence the development of renal calculi, the most essential of which is the supersaturation of urine with lithogenic substances. Calcium oxalate stones occur most frequently in adult and pediatric patients with urolithiasis. Therefore, we established normal age and sex related data for urinary calcium oxalate saturation in infancy and childhood to allow a more specific prediction of the risk of (recurrent) stone disease. MATERIALS AND METHODS: We collected 24-hour urine samples from 473 healthy infants and children without a history of renal stones. Urinary lithogenic and stone inhibitory substances were measured, and the urinary calcium oxalate saturation was calculated using a computer program. RESULTS: Mean urinary calcium oxalate saturation was always higher in boys than in girls, which was significant in infancy (5.22 versus 2.03, p < 0.05) and at ages 7 to 9 years (8.84 versus 5.47, p < 0.05). The saturation first increased (p < 0.05) until age 7 to 9 years in boys and girls, and remained at high levels at ages 10 to 12 years (7.03 versus 5.49, p < 0.05 compared to infancy). Calcium oxalate saturation then decreased until adolescence when values were comparable to those of infancy (5.29 versus 3.35). CONCLUSIONS: We recommend calculating urinary calcium oxalate saturation for diagnostic purposes as well as for therapy control. Normal age and sex related values must be considered.     

Idiopathic calcium oxalate urolithiasis and endogenous oxalate production

Despite the great effort that has gone into investigating urolithiasis, this condition still persists as one of the major ailments of the urinary tract. Calcium oxalate urolithiasis is the most common form, accounting for some 60 to 80% of total stones. This review examines the elements (i.e., urine volume and pH and urinary excretion of calcium, oxalate, citrate, urate, magnesium, pyrophosphate, and glycosaminoglycans) that give rise to idiopathic calcium oxalate urolithiasis. Treatment strategies for idiopathic calcium oxalate urolithiasis, including lithotripsy, also are discussed. Urinary oxalate excretion is a major risk factor for calcium oxalate urolithiasis, with 85 to 95% of the urinary load derived endogenously. The factors controlling endogenous oxalate production are reviewed, including pathways for the diversion of glyoxylate from oxalate production. The use of beta-aminothiols and other substances to reduce endogenous oxalate production in subjects with idiopathic calcium oxalate urolithiasis is also discussed. A review of current methodologies for the determination of urinary oxalate is also included.     

External beam irradiation inhibits neointimal hyperplasia after injury-induced arterial smooth muscle cell proliferation

BACKGROUND: The high social-economic cost of nephrolithiasis wholly justifies the attempts to understand its mechanism and avoid recurrences. The influence of dietary habits and urinary risk factors has been evaluated, but the results were discrepant, probably because of differences in the methodologies used to compare patients and controls. METHODS: The aim was to assess dietary and urinary risk factors for urinary stones by comparison between 108 calcium stone formers (SF) and 210 healthy subjects (HS). All subjects were recruited during the same 1 year period. Personal characteristics, dietary habits (evaluated through a food frequency questionnaire) and urinary biochemical parameters were collected. The high predominance of men in the SF group led us to focus on the 79 SF and the 96 HS men. RESULTS: A familial history of stones was reported more frequently in SF than in HS, 42.9% vs 17.6%, P<0.005. Body weight was higher in SF, 76.8+/-12.2 kg vs 72.8+/-9.6 kg, P=0.02; and calcium intake was lower in SF, 794.8+/-294.1 mg vs 943.6+/-345.4 mg, P<0.01. For urinary parameters, calcium and oxalate output were significantly higher in SF. Urinary urea, as a reflection of daily protein intake, and uric acid were also higher in SF. Urinary citrate excretion related to body weight was lower in SF. Calciuria was significantly correlated with urinary urea in both SF and HS, but the correlation was stronger for SF. Calciuria correlated significantly with natriuria only in HS. CONCLUSIONS: The main differences between SF and HS were that SF had a family history of stones, a higher body weight, a lower daily intake of calcium, and a higher urinary output of calcium and oxalate. These results underline the combined role of genetic and nutritional factors in the pathogenesis of urinary stone formation.     

Experimental nephrolithiasis in rats: the effect of ethylene glycol and vitamin D3 on the induction of renal calcium oxalate crystals

Using ethylene glycol (EG) and vitamin D3 as crystal-inducing diet (CID) in rats, we investigated the effect of the dosage of EG on the generation of chronic calcium oxalate (CaOx) nephrolithiasis. We collected weekly 24 hour urines and measured herein the amount of oxalate, calcium, glycosaminoglycans (GAG's), creatinine, protein, alkaline phosphatase (AP), gamma-glutamyl transpeptidase (gamma-GT), and N-acetyl-beta-glucosaminidase (NAG). The potential of these urines to inhibit crystal growth and agglomeration was also evaluated. After four weeks, the kidneys were screened by histology and radiography for the presence of CaOx crystals and the amount of kidney-associated oxalate was biochemically measured. Using 0.5 vol.% EG, only a part of the rats showed CaOx deposition in the renal cortex and/or medulla, without obvious differences between Wistar and Sprague-Dawley (SD) rats. If a dietary EG concentration of 0.75, 1.0, or 1.5 vol.% was used, the amount of kidney-associated oxalate was proportionally higher and CaOx crystal formation was consistently found in all rats. Most crystals were encountered in the cortex, whereas in the medulla and the papillary region, crystals were only occasionally detected. From these data, we conclude that in the chronic rat model, based on EG and vitamin D3, a consistent deposition of CaOx crystals is obtained using a EG concentration of at least 0.75%.     

Alendronate decreases urine calcium and supersaturation in genetic hypercalciuric rats

BACKGROUND: The mechanism of excess urine calcium excretion in human idiopathic hypercalciuria (IH) has not been determined but may be secondary to enhanced intestinal calcium absorption, decreased renal calcium reabsorption, and/or enhanced bone demineralization. We have developed a strain of genetic hypercalciuric stone-forming (GHS) rats as an animal model of human IH. When these GHS rats are placed on a low-calcium diet (LCD), urinary calcium (UCa) excretion exceeds dietary calcium intake, suggesting that bone may contribute to the excess UCa excretion. We used the GHS rats to test the hypothesis that bone contributes to the persistent IH when they are fed an LCD by determining if alendronate (Aln), which inhibits bone resorption, would decrease UCa excretion. METHODS: GHS rats (N = 16) and the parent strain (Ctl, N = 16) were fed 13 g/day of a normal (1.2%) calcium diet (NCD) for seven days and were then switched to a LCD (0. 02%) for seven days. Ctl and GHS rats in each group were then continued on LCD for an additional seven days, with or without injection of Aln (50 micrograms/kg/24 hrs). UCa excretion was measured daily during the last five days of each seven-day period. To determine the effects of Aln on urine supersaturation, the experiment was repeated. All relevant ions were measured, and supersaturation with respect to calcium oxalate and calcium hydrogen phosphate was determined at the end of each period. RESULTS: UCa was greater in GHS than in Ctl on NCD (7.4 +/- 0.5 mg/24 hrs vs. 1.2 +/- 0.1, GHS vs. Ctl, P < 0.01) and on LCD (3.9 +/- 0.2 mg/24 hrs vs. 0. 7 +/- 0.1, GHS vs. Ctl, P < 0.01). LCD provides 2.6 mg of calcium/24 hrs, indicating that GHS rats are excreting more calcium than they are consuming. On LCD, Aln caused a significant decrease in UCa in GHS rats and brought GHS UCa well below calcium intake. Aln caused a marked decrease in calcium oxalate and calcium hydrogen phosphate supersaturation. CONCLUSION: Thus, on a LCD, there is a significant contribution of bone calcium to the increased UCa in this model of IH. Aln is effective in decreasing both UCa and supersaturation. The Aln-induced decrease in urine supersaturation should be beneficial in preventing stone formation in humans, if these results, observed in a short-term study using the hypercalciuric stone-forming rat can be confirmed in longer term human studies.     

Calcium phosphate/calcium oxalate crystal association in urinary stones: implications for heterogeneous nucleation of calcium oxalate

PURPOSE: Most stones contain more than one type of crystals, and some combinations, such as calcium phosphate/calcium oxalate, are more common than others. Epitaxy between the crystals has been suggested to play a role in growth of such stones. The specific aim of this study is to investigate the involvement of calcium phosphate in crystallization of calcium oxalate. MATERIALS AND METHODS: Twenty calcium oxalate stones or stone fragments were examined using various microscopic techniques, including scanning, transmission and back-scattered electron microscopy. Similarly, calcium oxalate stones induced on a plastic foreign body implanted inside urinary bladders of laboratory rats were also investigated. Examination of the interface between calcium phosphate and calcium oxalate crystals was emphasized. RESULTS: Close association between crystals of calcium phosphate and calcium oxalate were found in both the human and rat stones. All crystals examined were associated with an organic matrix on the surface and contained copious amounts of organic material within the crystalline entities. Interface between the crystals also appeared to be occupied by organic matrix. CONCLUSIONS: Results of this and other studies from our laboratory indicate that epitaxy between various crystals, even though theoretically possible, appears unlikely in vivo. The appearance of specific crystalline combinations in stones is probably a result of the urinary environment being conducive for crystallization of those components. Heterogeneous nucleation of calcium oxalate is most probably induced by biological elements, including membranous cellular degradation products.     

Dietary calcium, dietary protein, and kidney stone formation

Kidney stone disease is common and is a major cause of morbidity involving the urinary tract. Rising incidence rates of calcium oxalate stone disease, the most common type of kidney stone, have focused attention on dietary habits and their potential role in the development of nephrolithiasis. Traditionally, calcium restriction had been recommended to reduce the likelihood of calcium stone formation, but recent evidence suggests that dietary calcium restriction may actually increase the risk. Observational and experimental data suggest that restriction of animal protein may lower the risk of stone formation, but a randomized trial did not confirm this finding. Dietary modification may play an important role in reducing the likelihood of stone recurrence. Notably, dietary calcium restriction should be avoided in patients who have had a calcium oxalate kidney stone.     

Uropontin in urinary calcium stone formation

Normal urine is frequently supersaturated with respect to calcium oxalate. Thus, urinary inhibitors of crystallization appear to have an important role in preventing urinary stone formation. Uropontin was isolated by monoclonal antibody immunoaffinity chromatography and has the same N-terminal sequence as osteopontin derived from bone. This urinary form of osteopontin is a potent inhibitor of calcium oxalate monohydrate crystal growth at concentrations (approximately 0.1 microM) that normally prevail in human urine. Interaction with calcium oxalate monohydrate in vivo was shown by analysis of EDTA extracts of calcium stones. Uropontin is an abundant component of calcium oxalate monohydrate stones and present in only trace quantities in calcium oxalate dihydrate and hydroxyapatite stones. However, the precise role of uropontin in the pathogenesis of urinary stone formation is not known and is the subject of ongoing investigations.     

Pathological and immunocytochemical changes in chronic calcium oxalate nephrolithiasis in the rat

In the present study, we exposed rats to a crystal-inducing diet (CID) consisting of vitamin D3 and 0.5% ethylene glycol (EG), and we investigated histologically the kidney damage induced by the deposition of calcium oxalate (CaOx) crystals. After 28 days, 50% of the animals had renal CaOx crystals, of which 60% also had small papillary stones. Most crystals were present in the cortex. The occurrence of these crystals coincided with morphological and cytochemical changes: glomerular damage, tubular dilatation and necrosis, and an enlargement of the interstitium. The number of epithelial and interstitial cells positive for the proliferating cell nuclear antigen (PCNA) was increased. Tamm-Horsfall protein (THP) was not only demonstrable in the thick ascending limb of the loop of Henle (TAL), but also frequently in glomeruli, in the proximal tubular epithelium, and in the papilla. In the lumen of the tubular system, it was associated with urinary casts. Reflection contrast microscopy (RCM) showed that the crystals were coated with a thin layer of THP. In spite of the high urinary oxalate concentrations, the above described cellular changes were not observed in CID-fed rats without renal crystals. We conclude, therefore, that in the kidney, the retained CaOx crystals rather than the urinary oxalate ions are responsible for the observed morphological and immunocytochemical changes.     

Hyperuricosuria and urolithiasis

Hyperuricosuria with or without hypercalciuria amounted to about 23% of the possible cause of urolithiasis in my clinical experience. Approximately three forth of urolithiasis caused by hyperuricosuria was calcium oxalate stones and the rest was uric acid stones. Uric acid is one of the composition of urinary stones itself, but it has an activity of calcium oxalate stone formation. The hypotheses why the uric acid induced calcium oxalate stones were introduced. The preventive effect of allopurinol on the recurrent calcium oxalate stone formers was proved in our previous study which may revealed the urinary uric acid promoted calcium oxalate stone formation or masked the inhibitory activity of urinary macromolecular inhibitors. On the basis of above statement, I emphasize the importance of the treatment of hyperuricosuria in preventing urinary stones.     

Calcium oxalate crystallization in urine of healthy men and women: a comparative study

This study aimed to compare calcium oxalate (CaOx) crystallization in undiluted urine from healthy men and women with the object of clarifying the difference in stone incidence between the two sexes. Twenty-four hour urine specimens were collected from 37 men and 28 women. Urinary pH, and concentrations of Ca, oxalate and urate were measured, and indices of crystallization determined by Coulter Counter particle analysis following induction of CaOx crystallization by addition of oxalate. The amount of oxalate required to induce crystallization was significantly (p < 0.01) higher in females than in males, as was the overall particle volume deposited after 90 minutes incubation (p < 0.006). Scanning electron microscopy revealed larger individual crystals in female urine, and a greater degree of crystal aggregation in male urine, although the average overall size of the precipitated crystal particles did not differ between the two sexes. There were no significant differences between men and women with regard to median pH, or Ca and oxalate concentrations, but the median urate concentrations were slightly, but significantly, higher (p < 0.05) in the women's urines than in the men's. It was concluded that the greater risk of CaOx stones in men is related to an increased propensity to nucleate CaOx crystals per se, rather than to a tendency to form larger crystalline particles.     

Circadian variations in the risk of urinary calcium oxalate stone formation

OBJECTIVE: To evaluate the circadian fluctuations in the risk of urinary calcium oxalate stone formation with regard to critical periods of crystallization. PATIENTS AND METHODS: Over a given time period, the Tiselius index depends on urine volume and urinary excretion of oxalate, calcium, citrate and magnesium. This crystallization potential was evaluated during three successive periods spread over 24 h for 25 recurrent stone-formers aged 16-76 years (mean 50) and 25 control subjects aged 27-71 years (mean 44). RESULTS: There was no significant difference in the value of the Tiselius index for all equivalent time periods in both groups of patients. The minimum value was recorded in the afternoon and the circadian pattern of the index illustrated the predominant importance of urinary output in its determination. Morning urinary concentrations and excretions of citrate, and nocturnal levels of magnesium were significantly higher in the stone-formers when compared with the control subjects. CONCLUSION: The lithogenic risk for calcium oxalate stones was maximal at the end of the night or during the early morning, when urinary output was minimal. This circadian study revealed abnormalities that are not apparent from non-fractionated 24 h urine samples, and which were potentially relevant to therapy.     

Reduction of urinary stone recurrence by dietary counseling after SWL

To reduce the recurrence rate of or urolithiasis, dietary counseling was conducted for calcium-stone patients. Sixty-six patients received dietary counseling and were in principle instructed to use the Recommended Dietary Allowance for Japanese as their goal. Seventy-three patients did not undergo the counseling. Comparison of the dietary intake of the patients with the dietary requirements for Japanese revealed that protein intake, especially animal protein intake, was higher and calcium intake lower in the patients. As a result of the counseling, intakes of total protein, animal protein, fat, and carbohydrates were all reduced. Patients in the stone recurrence-free group excreted less oxalate than those in the recurrent one. The excretion of oxalate was then reduced and urine volume increased owing to the diet counseling program. The stone recurrence rate of the group participating in the diet counseling was lower than that of the group not taking part. The recurrence rate of the hyperoxaluric group was higher, with statistical significance, than that of the normooxaluric group among those not receiving the dietary counseling. With dietary counseling, the recurrence rate significantly decreased in the hyperoxaluric patients. Thus, the reduction in the rate of stone recurrence resulting from participation in the diet counseling program seemed to be attributable to the decrease in urinary oxalate excretion. Dietary counseling seems to be a useful measure to prevent urinary stone recurrence.     

Further evidence linking urolithiasis and blood coagulation: urinary prothrombin fragment 1 is present in stone matrix

The fact that organic material is always present and distributed throughout each renal calculus suggests that it may play a role in stone formation. The organic matrix of calcium oxalate (CaOx) crystals freshly generated in urine in vitro contains urinary prothrombin fragment 1 (UPTF1) as the principal protein. In this initial study, matrix was extracted from 12 renal calculi and evaluated for the presence of UPTF1 using Western blotting. UPTF1 was present in all eight stones whose principal component was CaOx, and in one of two stones which consisted mainly of calcium phosphate (CaP). UPTF1 was absent from the two struvite calculi examined. The relationship between CaP and UPTF1 was explored further. Matrix harvested from CaP crystals freshly generated in urine in vitro was also shown to contain UPTF1 as its principal component. Our inability to detect UPTF1 in one mixed CaOx/CaP stone may be related to our methods of matrix retrieval, while its absence from two struvite stones argues against it being present in the other stones merely as a consequence of passive inclusion. This absence may be related to the alkaline environment typical of struvite stone growth. The finding that UPTF1 is present in some renal stones provides the first direct evidence that links blood coagulation proteins with urolithiasis.     

Metocurine pharmacokinetics and pharmacodynamics in goats

Crystalluria is important in the evaluation of patients with urinary stone and is more frequently encountered in elderly than in younger adults. After noting that calcium oxalate monohydrate crystalluria was higher in elderly patients, we undertook a study to determine if oral treatment with naftidrofuryl oxalate, a drug frequently prescribed for elderly patients in France, was associated with crystalluria. The presence of early morning crystalluria was assessed in non-stone-forming patients hospitalized in a geriatric department. We studied 251 patients without a history of nephrolithiasis (mean age; 81.6 +/- 8.5 years) of whom 49 had been treated orally with naftidrofuryl oxalate at a mean dosage of 485 +/- 120 mg/24h. We identified and quantified the crystals in one early morning urine sample kept at room temperature. The frequency of crystalluria in elderly patients without stones who were not taking naftidrofuryl oxalate was 31.7% compared with only 6% in the general adult population. In this group, mainly calcium phosphate crystals were found. In patients who received naftidrofuryl oxalate, the frequency of crystalluria was 51% of which the major component was calcium oxalate monohydrate and not calcium phosphate. Naftidrofuryl oxalate may enhance crystal formation in elderly patients. This should be taken into account, particularly when other predisposing factors for nephrolithiasis are present, and a preventive increase in fluid intake considered.     

Uric acid-related nephrolithiasis

Abnormalities in uric acid metabolism are associated with uric acid and calcium oxalate urolithiasis. Clinical stone formation depends on multiple identifiable risk factors that affect uric acid and calcium oxalate solubility. The understanding of urinary pH is critical to direct appropriate treatment of uric acid-related nephrolithiasis. Understanding uric acid metabolism and the pathophysiology of uric acid and calcium oxalate stone formation leads to a rational treatment approach to uric acid and hyperuricosuric calcium oxalate stone disease.     

Sodium excretion in children with lithogenic disorders

INTRODUCTION: The causes of nephrolithisis are multifactorial and have not yet been enough investigated [1]. Hypercalciuria is the most common cause of metabolic nephrolithiasis [2-4]. Close relationship between urinary calcium and urinary sodium has been a subject of reported observations in the past, showing that high urinary sodium is associated with high urinary calcium [5-7]. Hyperoxaluria, hyperuricosuria and cystinuria are also metabolic disorders that can lead to nephrolithiasis. Recent studies have indicated that urinary elimination of cystine is influenced by urinary sodium excretion. Based on these observations it has been hypothesised that patients with high urinary sodium excretion are at high risk of urinary stone disease. The purpose of the study was to investigate sodium excretion in a 24-hour urine and first morning urine collected from children with lithogenic metabolic abnormalities (hypercalciuria, hyperoxaluria, hyperuricosuria, cystinuria), both with nephrolithiasis and without it, in order to determine its significance in urinary calculi formation. PATIENTS AND METHODS: Urinary sodium excretion was investigated in 2 groups of children: patients with lithogenic metabolic abnormalities, but without urinary stone disease (L group) and patients with nephrolithiasis (C group). Both groups were divided into 2 subgroups: patients with hypercalciuria and without it. There were 22 patients in group L (mean age 11.97 +/- 4.13 years), of whom 17 formed a hypercalciuric subgroup and 5 formed a non-hypercalciuric subgroup (3 patients with hyperuricosuria and 2 patients with hyperoxaluria). Group C consisted of 21 patients with nephrolithiasis (mean age 12.67 +/- 3.44 years), of whom 6 formed a hypercalciuric subgroup and 15 formed a non-hypercalciuric group (2 patients with cystinuria and 13 patients without lithogenic metabolic abnormalities). Control group consisted of 42 healthy age-matched children. All subjects had a normal renal function. A detailed history and clinical examination were done, and ultrasonography was performed in all patients. A 24-hour urine, first morning urine and serum specimen were analysed for sodium, potassium, calcium, uric acid, urea and creatinine. Fractional excretion of sodium, as well as urinary sodium to creatinin ratio and urinary sodium to potassium ratio, were calculated from the findings. Sodium and potassium levels were determined by flame photometry, calcium was measured by atomic absorption technique (Beckman Atomic Spectrophotometer, Synchron CX-5 model, USA), uric acid by carbonate method and creatinine by Jaffe technique. Cystine and dibasic amino acids were quantified by ion chromatography. Urinary oxalate excretion was determined by enzyme spectrophotometry. Hypercalciuria was defined by 24-hour calcium excretion greater than 3.5 mg/kg per day and/or calcium to creatinine ratio greater than 0.20 [8]. Uric acid excretion was expressed as uric acid excretion factored for glomerular filtration, according to Stapleton's and Nash's formula [9]. Normal values were lower than 0.57 mg/dl of glomerular filtration rate in 24-hour samples. Mean values were statistically analyzed by Pearson's linear correlation and analysis of variance (ANOVA). RESULTS: Urinary sodium concentration values including urinary sodium to potassium ratios, are shown in Table 1. We found that urinary sodium excretion was significantly increased in patients of both L and C groups when compared with controls (p < 0.05). Further analysis of the subgroups showed that urinary sodium excretion was significantly higher only in patients with hypercalciuria of both L and C groups in comparison to controls (p < 0.05) (Table 2). A significant positive correlation was found between 24-hour urinary sodium to creatinine ratio and urinary calcium to creatinine ratio (r = 0.31; p < 0.001) (Graph 1), as well as between urinary sodium to potassium ratio in 24-hour and first morning urine (r = 0.69; p < 0.001) (Graph 2). (A     

A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones

BACKGROUND: A high dietary calcium intake is strongly suspected of increasing the risk of kidney stones. However, a high intake of calcium can reduce the urinary excretion of oxalate, which is thought to lower the risk. The concept that a higher dietary calcium intake increases the risk of kidney stones therefore requires examination. METHODS: We conducted a prospective study of the relation between dietary calcium intake and the risk of symptomatic kidney stones in a cohort of 45,619 men, 40 to 75 years of age, who had no history of kidney stones. Dietary calcium was measured by means of a semiquantitative food-frequency questionnaire in 1986. During four years of follow-up, 505 cases of kidney stones were documented. RESULTS: After adjustment for age, dietary calcium intake was inversely associated with the risk of kidney stones; the relative risk of kidney stones for men in the highest as compared with the lowest quintile group for calcium intake was 0.56 (95 percent confidence interval, 0.43 to 0.73; P for trend, < 0.001). This reduction in risk decreased only slightly (relative risk, 0.66; 95 percent confidence interval, 0.49 to 0.90) after further adjustment for other potential risk factors, including alcohol consumption and dietary intake of animal protein, potassium, and fluid. Intake of animal protein was directly associated with the risk of stone formation (relative risk for men with the highest intake as compared with those with the lowest, 1.33; 95 percent confidence interval, 1.00 to 1.77); potassium intake (relative risk, 0.49; 95 percent confidence interval, 0.35 to 0.68) and fluid intake (relative risk, 0.71; 95 percent confidence interval, 0.52 to 0.97) were inversely related to the risk of kidney stones. CONCLUSIONS: A high dietary calcium intake decreases the risk of symptomatic kidney stones.