Dietary and urinary risk factors for stones in idiopathic calcium stone formers compared with healthy subjects

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 underlie the combined role of genetic and nutritional factors in the pathogenesis of urinary stone formation.     

Dietary management of urinary risk factors in renal stone formers

Three hundred and ninety-two stone formers were investigated to exclude systemic disorders and to define the presence of haematological and urinary abnormality commonly associated with stone disease. Increased urinary excretion of calcium, oxalate or uric acid was found in 40% and there was more than one abnormality in 16% of the patients. The dietary habit of stone formers did not differ significantly from that of control subjects. Dietary advice to increase the consumption of fibre and reduce the consumption of sugar, refined carbohydrates and animal protein produced a significant reduction in the urinary excretion of calcium, oxalate and uric acid. We consider that reduction of the nutrient density of the diet by this means is the first line of management of idiopathic stone formers.     

Intestinal oxalate and calcium absorption in recurrent renal stone formers and healthy subjects

The fractional intestinal absorption of oxalate and calcium was investigated by isotope techniques in 20 normal subjects and in 12 idiopathic calcium oxalate stone formers. The greatest amount of 14C-oxalate was excreted during the first six hour period in controls as well as in stone formers. The stone formers had a greater intestinal uptake of oxalate (11 +/- 5.1%) than the controls (6.2 +/- 3.7%; p less than 0.01). There was no significant relationship between the fractional absorption of oxalate and the total urinary oxalate excretion. The stone formers also had a higher fractional uptake of calcium compared to the controls (55 +/- 11% vs. 47 +/- 9.1%; p less than 0.05). There was a positive relationship (r = 0.47) between the urinary excretions of calcium and oxalate in the stone formers. During these conditions no correlation could be demonstrated between the fractional absorptions of oxalate and calcium, neither in the stone formers nor in the controls. In conclusion, patients with recurrent formation of calcium oxalate containing stones appear to have an enhanced intestinal uptake of both oxalate and calcium. This disturbance could be of primary pathogenic importance for their stone forming propensity.     

Evidence for altered renal tubule function in idiopathic calcium stone formers

Patients who form calcium kidney stones often have metabolic disorders such as idiopathic hypercalciuria (IH) that reflect abnormalities in mineral handling in the kidney. Renal handling of calcium is altered by ingestion of nutrients such as carbohydrates, protein, and sodium, and patients with IH appear to be more sensitive to these stimuli. Studies using probes such as diuretics or lithium clearance have the ability to clarify which nephron segments are involved in the altered renal calcium transport with nutrient seen in IH. Studies in the genetic hypercalciuric rat demonstrate alterations in both proximal tubule and thick ascending limb calcium reabsorption. Similar studies in humans have begun to provide evidence about the corresponding abnormalities in stone formers with IH. A pattern of altered renal tubule transport in calcium stone formers is suggested by the frequency of such findings as decreased tubular maximal reabsorption of phosphate and abnormal urine acidification as well as hypercalciuria in such patients, not explained by monogenic transport abnormalities.     

Effect of oral calcium loading on intact PTH and calcitriol in idiopathic renal calcium stone formers and healthy controls

The calciuric response after an oral calcium load (l000 mg elementalcalcium together with a standard breakfast) was studied in 13healthy male controls and 21 recurrent idiopathic renal calciumstone formers, 12 with hypercalciuria (U_CaxV>7.50 mmol/24h) and nine with normocalciuria. In controls, serum 1,25(OH)₂vitamin D3 (calcitriol) remained unchanged 6 h after oral calciumload (50.6±5.1 versus 50.9±5.0 pg/ml), whereasit tended to increase in hypercalciuric (from 53.6±3.2to 60.6±5.4 pg/ml, P=0.182) and fell in normocalciuricstone formers (from 45.9±2.6 to 38.1±3.3 pg/ml,P=0.011). The total amount of urinary calcium excreted afterOCL was 2.50±0.20 mmol in controls, 2.27±0.27mmol in normocalciuric and 3.62±0.32 mmol in hypercalciuricstone formers (P=0.005 versus controls and normocalciuric stoneformers respectively); it positively correlated with serum calcitriol6 h after calcium load (r=0.392, P=0.024). Maximum increasein urinary calcium excretion rate, Ca-E_max, was inversely relatedto intact PTH levels in the first 4 h after calcium load, i.e.more pronounced PTH suppression predicted a steeper increasein urinary calcium excretion rate. Twenty-four-hour urine calciumexcretion rate was inversely related to the ratio of calcitriol/PTH_maxafter calcium load (r=–0.653, P=0.0001), indicating thatan abnormally up-regulated synthesis of calcitriol and consecutiverelative PTH suppression induce hypercalciuria. Finally, lateabsorption of calcium as suggested by maximum urinary calciumexcretion beyond 4 h after oral calcium load was as rare inhypercalciuric stone formers (2 of 12) as in controls (1 of13) and did not occur in normocalciuric stone formers.     

Dietary risk factors for hyperoxaluria in calcium oxalate stone formers

BACKGROUND: Hyperoxaluria is a major predisposing factor in calcium oxalate urolithiasis. The aim of the present study was to clarify the role of dietary oxalate in urinary oxalate excretion and to assess dietary risk factors for hyperoxaluria in calcium oxalate stone patients. METHODS: Dietary intakes of 186 calcium oxalate stone formers, 93 with hyperoxaluria (>or=0.5 mmol/day) and 93 with normal oxalate excretion (<0.4 mmol/day), were assessed by a 24-hour weighed dietary record. Each subject collected 24-hour urine during the completion of the food record. Oxalate content of foods was measured by a recently developed analytical method. RESULTS: The mean daily intakes of energy, total protein, fat and carbohydrates were similar in both groups. The diets of the patients with hyperoxaluria were estimated to contain 130 mg/day oxalate and 812 mg/day calcium as compared to 101 mg/day oxalate and 845 mg/day calcium among patients without hyperoxaluria. These differences were not significant. The mean daily intakes of water (in food and beverages), magnesium, potassium, dietary fiber and ascorbic acid were greater in patients with hyperoxaluria than in stone formers with normal oxalate excretion. Multiple logistic regression analysis revealed that urinary oxalate excretion was significantly associated with dietary ascorbate and fluid intake, and inversely related to calcium intake. Differences of estimated diet composition of both groups corresponded to differences in urinary parameters. CONCLUSIONS: These findings suggest that hyperoxaluria predominantly results from increased endogenous production and from intestinal hyperabsorption of oxalate, partly caused by an insufficient supply or low availability of calcium for complexation with oxalate in the intestinal lumen.     

Studies of dietary influence on urinary oxalate in calcium oxalate stone formers

In order to examine the effect of diet on the urinary excretion of oxalate, a spinach loading and milk loading experiment was performed in normal subjects and patients with single calcium oxalate stones and recurrent calcium oxalate stones after a rat experiment. When spinach (100 g, total oxalate 642.57 mg, insoluble oxalate 282.21 mg, taken oxalate 444.57 mg) was given with a low calcium diet to the patients, the increase of urinary oxalate was more prominent in those with recurrent stones; the mean urinary oxalate increased from 39.84 to 84.18 mg/day (P less than 0.01) in the group with recurrent stones, from 36.95 to 55.12 mg/day (P less than 0.05) in the group with single stones and from 33.99 to 42.78 mg/day in the control group. These increases in oxalate excretion could be ameliorated by the concurrent oral administration of milk (calcium 343 mg). Moreover, diurnal variation in oxalate excretion was observed. It was more evident under spinach load in the group with recurrent stones than in the control group. Urinary oxalate increased promptly, reaching peak levels between 4 and 6 hours after loading in the group with recurrent stones and single stones, and between 2 and 4 hours in the control group. The influence of the spinach load disappeared within 24 hours.     

The influence of a high-oxalate/low-calcium diet on calcium oxalate renal stone risk factors in non-stone-forming black and white South African subjects

OBJECTIVE: To evaluate the influence of a high-oxalate/low-calcium diet on calcium oxalate stone risk factors in both black South Africans (who are largely immune to kidney stones) and white South Africans (in whom stones are more common). SUBJECTS AND METHODS: Urinary and dietary variables were examined in 11 black and 11 white South African men. None of the subjects had had a kidney stone or any metabolic illness. Their normal domestic food intake was assessed using a semiquantitative food frequency questionnaire. Subjects were given a standardized high-oxalate/low-calcium diet for 3 days; 24-h urine samples were collected before the protocol and during the final day. The samples were analysed using routine modern laboratory techniques. The urine analysis data were used to calculate the Tiselius risk index and the relative urinary supersaturations of calcium oxalate, uric acid and calcium phosphate. RESULTS: Urine analysis showed an intriguing anomaly; black subjects had significantly higher urinary pH and oxalate values than whites (6.50 vs 6.21 and 0.23 vs 0.14 mmol/24 h, respectively), while their urinary citrate was lower (1.47 vs 3.69 mmol/24 h). In addition, the Tiselius risk index and relative supersaturation of calcium oxalate were higher in black subjects. These results are contrary to those which might have been reasonably expected when comparing stone-free and stone-prone groups. After the dietary protocol, the only urinary variable which changed significantly was urinary oxalate, which increased by 57% in whites. CONCLUSION: Factors which are conventionally used to assess stone risk (pH, oxaluria, citraturia, relative supersaturation) are not helpful in identifying why South African blacks are relatively immune to stones. We suggest that relatively lower oxalate absorption rates may be a physiological feature of this racial group.     

Calcitonin secretion in idiopathic renal stone formers

Several studies demonstrated a reduction in bone mineral content (BMC) in idiopathic renal stone formers (RSF). We found this reduction in association with a chronic low-calcium diet. Low calcium intake could theoretically result in calcitonin deficiency, responsible for increased bone resorption. This hypothesis was tested in 22 male RSF eating a low-calcium diet (350 +/- 72 SD mg/day) for 2 years or more, who showed a significant reduction in their BMC. When compared to 15 normal male subjects eating a free diet, RSF showed increases in serum alkaline phosphatase activity and fasting urinary excretion of hydroxyproline and calcium, suggesting increased bone turnover. Plasma calcitonin levels were measured by radioimmunoassay following an extraction-concentration technique (exCT). Basal plasma exCT levels were higher (P less than 0.005) in RSF (4.1 +/- 0.8 SEM pg/ml) than in normal subjects (2.8 +/- 0.4). Following a 5 minute infusion of 2 mg elemental calcium per kg, levels of plasma exCT tended to increase more, although not significantly, in RSF (51.3 +/- 9.4 pg/ml) than in normal subjects (36.6 +/- 9.7). The CT secretory response, taking into account changes in serum calcium concentration (delta exCT/delta Ca), was higher (P less than 0.05) in RSF (50.0 +/- 10.0) than in normal subjects (25.6 +/- 6.6). Our study thus demonstrates that RSF chronically fed a low-calcium diet have increased basal plasma CT levels and increased CT cells responsiveness. CT deficiency cannot therefore be considered a cause for the low BMC associated with a chronic low-calcium diet in RSF.     

Proteins in renal stones and urine of stone formers

Knowledge of the essential characteristics of macromolecules constituting the organic matrix of the nidus of urinary stones is required to understand the mechanism of urolithogenesis. The aim of this study was to isolate and characterise those stone nidus proteins. Using an extraction buffer containing SDS and β-mercaptoethanol, we were able to overcome known problems of protein isolation from urinary stone matrix. These proteins were characterised by a strong tendency to aggregate under reducing and denaturing conditions. On SDS-PAGE, their molecular weights range from ≤12 to 66 kDa. Antisera raised against stone matrix proteins showed a cross-reactivity between proteins isolated from different stones irrespective of their origin or mineral composition. Moreover, urinary proteins from stone formers also cross-reacted with these whereas there was no reaction with urinary proteins of non-stone formers. Western blotting confirmed these findings. Given the above summarised properties, it can be safely concluded that these proteins are prevalent in urines of stone formers, that they are selectively incorporated into renal stones of all aetiologies, and that they most likely have a role in nidus and, therefore, early stone formation. Received: 4 February 1998 / Accepted: 4 May 1998     

Crystalline composition of urinary stones in recurrent stone formers

175 stones from 70 recurrent stone formers with each at least two stones available for analysis were studied crystallographically. The chance that a subsequent stone belonged to the same of five major stone groups was 65% but rose to 91% if three of these groups were considered as one (calcium stones). Other findings, however, indicate that distinction between the three groups of calcium stones is of interest. Thus, pure calcium oxalate stones (Ox) did not occur in the same patients as pure calcium phosphate stones (P). In comparable stones containing both the above types of components (OxP), the calcium phosphate content was significantly lower (average apatite content per stone 9%) in stones from patients who also had Ox stones than (37%) in those who had associated P stones. Also, the stone nucleus was frequently Ox in the OxP stones from the former and usually P in the OxP stones of the latter patients. Brushite occurred in 10% of the stones, which is more frequent than in unselected stone materials and largely due to a tendency for it to recur in a few patients. Patients who provide more than one stone for analysis appear to differ considerably in stone composition from stone patients in general, and inclusion of several stones from some patients will lead to bias in materials purporting to reflect stone composition in a population. When available, several stones from each patient should preferably be analysed. Exceptions may be made for cystine and, possibly, pure uric acid stone patients.     

Effect of urinary macromolecules on aggregation of calcium oxalate in recurrent calcium stone formers and healthy

Summary The inhibitory activity of urinary macromolecules on the aggregation of calcium oxalate crystals was studied using an aggregometer originally devised to measure thrombocyte aggregation capacity by means of the optical turbidity at 660 nm. The macromolecular fraction of the urine (molecular weight above 5000) of recurrent calcium stone formers showed much less inhibitory activity than that of healthy controls (P0.05). It was speculated on the basis of the results of gel filtration that there were some proteins (molecular weight about 10000–30000) which had inhibitory activities for the aggregation of calcium oxalate. This gives support to the assumption that macromolecules are important during the phase of aggregation of calcium oxalate crystals.     

Influence of the calcium content of the diet on the incidence of mild hyperoxaluria in idiopathic renal stone formers

Urinary oxalate excretion was measured in 101 male idiopathic calcium (Ca) stone formers studied on 3 dietary conditions (free-choice, Ca-enriched, and low-Ca diet). The population consisted of 38 normocalciuric and 63 hypercalciuric patients. Mean oxalate excretion was similar in normocalciuric and in hypercalciuric patients, on free-choice as well as on Ca-enriched diet. In both conditions the incidence of hyperoxaluria (greater than or equal to 435 mumol/24 h) within each group of stone formers was also similar, ranging from 11 to 22%. On low-Ca diet, however, mean oxalate excretion increased significantly (p less than 0.01) in hypercalciurics but not in normocalciurics; on this diet, the incidence of hyperoxaluria was particularly high in the hypercalciurics (33%), compared with the normocalciurics (13%). On low-Ca diet, oxalate excretion was positively correlated with the estimated degree of intestinal absorption of calcium (p = 0.01). These results show that among idiopathic stone formers, mild hyperoxaluria is not a rare finding and that this disorder can be encountered in each group of patients; its incidence, however, is influenced by the calcium content of the diet. On a low-Ca diet, patients with intestinal Ca hyperabsorption are particularly prone to develop hyperoxaluria, an observation which leads to question the relevance of such a dietary advice unless oxalate intake is simultaneously reduced.     

Rice-bran treatment for calcium stone formers with idiopathic hypercalciuria

The efficacy of rice-bran therapy was studied in patients with hypercalciuria who were suffering from calcium stones. The frequency of stone episodes was reduced dramatically, especially in "active recurrent stone formers". Urinary calcium excretion was considerably reduced, while urinary phosphate and oxalate were slightly increased. Urinary magnesium, uric acid, serum calcium, phosphate, magnesium and uric acid were not affected. There were no changes in serum iron, copper and zinc even when patients were treated for long periods. The treatment was tolerated well and there were no serious side effects. Rice-bran therapy is particularly useful in patients with hyperabsorptive hypercalciuria and it is effective in the prevention of recurrent urinary stone disease.     

Urinary stone risk factors in the siblings of patients with calcium renal stones

PURPOSE: We determined which, if any, urinary stone risk factors accurately discriminate stone forming and nonstone forming siblings of patients with calcium renal stones. MATERIALS AND METHODS: A total of 252 siblings of stone formers provided 2, 24-hour urine samples, which were sent overnight and analyzed at a central laboratory. Standard stone risk factors were measured and the supersaturation of calcium oxalate, calcium phosphate and uric acid was calculated. RESULTS: Discriminant functions were derived for each gender by multivariate analysis. In stone forming sisters higher urinary calcium and pH discriminated with a success rate of 70%. In stone forming brothers higher urinary calcium, lower urinary potassium and older age discriminated with a success rate of 79%. CONCLUSIONS: Select urinary measurements as well as age classify siblings into those with and without stones with fair accuracy. Calcium excretion and urinary pH in females, and calcium excretion, urinary potassium and age in males are feasible identifiers of stone forming siblings. To determine whether these measurements can be used to predict new stone onset may require years of observation of our current cohort.     

Effect of high-calcium diet on urinary oxalate excretion in urinary stone formers

The effect of mild high-calcium diet or regular-calcium diet on urinary calcium excretion, urinary oxalate excretion, urinary calcium/creatinine ratio, urinary oxalate/creatinine ratio, and the probability of being a stone former (PSF) were studied in 85 patients with idiopathic urolithiasis. Intake of high-calcium diet for 5-6 days reduced (p less than 0.01-p less than 0.001) urinary oxalate excretion, urinary oxalate/creatine ratio and PSF in patients with idiopathic hypercalciuria. Under the regular-calcium diet, administration of 60 mg/day of pyridoxal phosphate for 3 months lowered (p less than 0.05-p less than 0.01) urinary oxalate excretion, urinary oxalate/creatinine ratio and PSF in patients with idiopathic hypercalciuria alone. From these findings, intake of mild high-calcium diet appears to be beneficial to decrease the urinary oxalate excretion and PSF in patients with idiopathic hypercalciuria. Pyridoxal phosphate has all the features of suppressing such risk factors for stone formation in patients with idiopathic hypercalciuria.     

The relation between urinary tract infections and stone composition in renal stone formers

During a seven-year period (1975-1981) a total of 1325 patients hospitalized for stone disease were studied as to the occurrence of positive urine cultures. Urinary stones from 535 surgically treated patients were analyzed with infrared spectrophotometry and the relationships between stone composition, level of surgery and bacteriological strains were studied. Positive urinary cultures were found in 34% of the surgically treated patients and in 21% of those not operated upon. Among the surgically treated patients with urinary tract infection (UTI) E. coli was the most frequent microorganism (35%), followed by Proteus (28%). Patients with Proteus infection had the highest frequency of UTI episodes, most of which occurred before hospitalization. There was a higher frequency of magnesium ammonium phosphate (MAP) calculi among patients with Proteus infection than among those with non-Proteus infection, in whom no difference in stone composition was found. Patients infected with E. coli had more phosphate-containing stones (CaP+MAP) than non-infected patients. The highest frequency of oxalate calculi (CaOx+CaOx/CaP) was found among patients without infection. No E. coli infections were seen in male patients with CaP and MAP calculi. MAP stones were most often found in the kidney and oxalate stones in the ureter.     

Comparison of urinary proteins in calcium stone formers and healthy individuals: a case-control study

OBJECTIVE: This study aimed at comparing the urinary protein levels in calcium stone formers with those of healthy individuals. PATIENTS AND METHODS: From January 2002 until June 2004, 100 calcium stone formers (mean age 38.6 +/- 10.3 years), who had at least two episodes of calcium stone formation, were compared with 100 healthy individuals (mean age 33.8 +/- 9.7 years). Their 24-hour urinary protein levels, using SDS-PAGE, were measured. RESULTS: The mean 24-hour urinary Tamm-Horsfall protein (THP) levels were 3.3 +/- 0.8 mg in the case group and 4.6 +/- 1.9 mg in the controls, and the difference was not statistically significant (p = 0.53). However, the THP levels in individuals with and without bacteriuria were significantly different (15.8 +/- 3.3 mg vs. 2.6 +/- 1.0 mg, p = 0.0001). The mean 24-hour urinary albumin concentrations were 163.31 +/- 15.1 mg in the case group and 74.26 +/- 4.6 mg in the controls. The mean 24-hour urinary transferrin levels were 8.09 +/- 2.7 mg in the case group and 0.40 +/- 0.3 mg in the controls. The differences were statistically significant for both albumin and transferrin (p < 0.0001 and p = 0.0063, respectively). There were no significant differences in any other mean urinary protein concentrations between cases and controls. CONCLUSIONS: The THP level in the urine of stone formers is not quantitatively different from that of healthy individuals, but it increases in association with bacteriuria. Albumin and transferrin may play a presumptive role in stone formation.     

Bone mineral content in calcium renal stone formers

Idiopathic renal calcium stone disease often presents with reduced bone mineral content. Investigations using non-invasive methods for the measurement of bone mineral content (single and dual-photon absorptiometry, dual-energy x-ray absorptiometry, quantitative computed tomodensitometry) show a slight decrease in skeletal mineral content of idiopathic renal stone formers (RSFs).The alterations in bone mineral content in RSFs have different explanations: prostaglandin-mediated bone resorption, subtle metabolic acidosis and 1–25 vitamin D disorders. Bone mineral content is worsened by insufficient dietary calcium leading to a negative calcium balance.