Increased dietary oxalate does not increase urinary calcium oxalate saturation in hypercalciuric rats

BACKGROUND: Human calcium oxalate (CaOx) nephrolithiasis may occur if urine is supersaturated with respect to the solid-phase CaOx. In these patients, dietary oxalate is often restricted to reduce its absorption and subsequent excretion in an effort to lower supersaturation and to decrease stone formation. However, dietary oxalate also binds intestinal calcium which lowers calcium absorption and excretion. The effect of increasing dietary oxalate on urinary CaOx supersaturation is difficult to predict. METHODS: To determine the effect of dietary oxalate intake on urinary supersaturation with respect to CaOx and brushite (CaHPO4), we fed 36th and 37th generation genetic hypercalciuric rats a normal Ca diet (1.2% Ca) alone or with sodium oxalate added at 0.5%, 1.0%, or 2.0% for a total of 18 weeks. We measured urinary ion excretion and calculated supersaturation with respect to the CaOx and CaHPO4 solid phases and determined the type of stones formed. RESULTS: Increasing dietary oxalate from 0% to 2.0% significantly increased urinary oxalate and decreased urinary calcium excretion, the latter presumably due to increased dietary oxalate-binding intestinal calcium. Increasing dietary oxalate from 0% to 2.0% decreased CaOx supersaturation due to the decrease in urinary calcium offsetting the increase in urinary oxalate and the decreased CaHPO4 supersaturation. Each rat in each group formed stones. Scanning electron microscopy revealed discrete stones and not nephrocalcinosis. X-ray and electron diffraction and x-ray microanalysis revealed that the stones were composed of calcium and phosphate; there were no CaOx stones. CONCLUSION: Thus, increasing dietary oxalate led to a decrease in CaOx and CaHPO4 supersaturation and did not alter the universal stone formation found in these rats, nor the type of stones formed. These results suggest the necessity for human studies aimed at determining the role, if any, of limiting oxalate intake to prevent recurrence of CaOx nephrolithiasis.     

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.     

Two triterpene saponins from Arenaria filicaulis

Uropontin is the urinary form of osteopontin, an aspartic acid-rich phosphorylated glycoprotein. Uropontin has been previously shown to be a potent inhibitor of the nucleation, growth and aggregation of calcium oxalate crystals and the binding of these crystals to renal epithelial cells. Quantitative data defining the excretion of this protein are necessary to determine its role in urinary stone formation. In the present studies, we determined uropontin excretion rates of normal humans. Urine samples were obtained under conditions of known dietary intake from young adult human volunteers with no history, radiographic or laboratory evidence of renal disease. Urinary concentrations of uropontin were measured by a sensitive ELISA employing an affinity purified polyclonal antiserum to uropontin. Thirteen normal subjects ingested a constant diet providing 1 gram of calcium, 1 gram of phosphorus, 150 mEq of sodium and 1 gram of protein per kilogram of body wt per day during an eight day study period. The relationship of urinary volume to uropontin excretion was assessed by varying fluid intake on the last four days of the study to change the mean urine volume/24 hr by > 500 ml. Urine collected in six hour aliquots for eight days was analyzed for uropontin by ELISA, and for calcium, and creatinine. Daily uropontin excretion of 13 individual subjects was 3805 +/- 1805 micrograms/24 hr (mean +/- 1 SD). The mean urinary levels (1.9 micrograms/ml) detected in the present study are sufficient for inhibition of crystallization; our previous studies have demonstrated that the nucleation, growth and aggregation of calcium oxalate crystals and their binding to renal cells in vitro are inhibited by this concentration of purified uropontin. In contrast to the regular pattern of diurnal variation of calcium excretion seen in most subjects, uropontin excretion showed no regularity of diurnal variation and was not directly related to either calcium or creatinine excretion or changes in urinary volume. However, uropontin concentration varied inversely with urine volume (P < or = 0.001), so that the highest uropontin concentrations occurred when urine volume was the lowest. We conclude that the physiologic characteristic of an inverse relationship of uropontin concentration to urine volume favors protection from urinary crystallization of calcium oxalate by uropontin. Our quantitative definition of urinary uropontin excretion of normal adults provides the basis for the evaluation of uropontin excretion by individuals who have formed urinary stones.     

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.     

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.     

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.     

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.     

Cytokine and cytotoxic pathways of NK cell rejection of class I-deficient bone marrow grafts: influence of mouse colony environment

OBJECTIVE: To identify biochemical and dietary factors which may play a role in the low incidence of stone formation in the black South African population. SUBJECTS AND METHODS: The study included 31 semiurbanized black and 29 urbanized white subjects. The protocol and modern laboratory techniques used to assess recurrent stone formers were followed. Urinary sodium, potassium, creatinine, calcium, phosphate and urate levels were measured, and urinary citrate, oxalate and cystine assessed. RESULTS: Black subjects ate a diet significantly higher in sodium (P < 0.04); there was no difference in serum levels but urinary sodium was significantly higher (P < 0.001) in black than in white subjects. Urinary potassium, calcium, citrate, phosphate and cystine were all significantly lower in black than in white subjects (P < 0.001 for the first four and P < 0.03 for cystine). CONCLUSION: Certain intrinsic factors in South African black subjects may account for their lower frequency of stone formation than in white subjects. Of these, the very low urinary calcium, decreased urinary cystine and different interactions between sodium and calcium/cystine are probably important.     

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.     

Urolithiasis in clinical practice. Occurrence, etiology, investigation and preventive treatment

The author reviews the epidemiological, etiological aspects of stone disease of the urinary tract, and prophylactic treatment. The occurrence of urolithiasis has increased considerably since the second world war and now affects 10% of the adult male and 4% of the adult female population. In Norway the yearly incidence of patients presenting with urinary stone colic in general practice is two per 1,000 inhabitants. Urinary calculi form when the concentration of the crystal-forming substances such as calcium oxalate, calcium phosphate, uric acid and cystine exceed their solubility. Important risk factors for stone formation are low fluid intake and high consumption of animal protein. Etiological examination and stone prophylactic treatment should reflect the most prevalent types of stone disease. An examination programme that probably can reveal one or several causes of the stone disease in about 60-70% of the patients is described. The recommended examinations car be performed in general practice. Prophylactic treatment in terms of dietary advice and fluid intake is suggested. In patients with a high recurrence rate of stone formation prophylactic drug treatment with tiazid or alluopurinol should be considered. The beneficial effect of the treatment is well documented.     

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.     

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.     

Metabolic risk factors in patients with first-time and recurrent stone formations as determined by comprehensive metabolic evaluation

OBJECTIVES: To determine whether patients with recurrent calcium stone formation have more significant metabolic abnormalities compared with patients with first-time stone formation as determined by a comprehensive metabolic evaluation. METHODS: We investigated metabolic abnormalities in 37 patients (14 men, 23 women) with first-time and 136 patients (83 men, 53 women) with recurrent calcium stones, stratified according to sex. Calcium oxalate supersaturation indexes of Tiselius (1991) and Ogawa (1996) were also compared between the groups. In addition to the specific metabolic abnormalities, we analyzed the total number of such defects for each group. RESULTS: In men, the average number of metabolic abnormalities in each patient was greater in patients with recurrent stones (2.20+/-0.86) than in those with first-time stones (1.46+/-1.27). Such a difference could only be demonstrated for women if low urine volume was excluded as a specific abnormality. Although the frequency of each abnormality was higher in patients with recurrent stones, a statistically significant difference was only noted in the frequency of hypocitraturia between women with first-time and recurrent stone formation (11.1% versus 37.8%, P < 0.05). There were no significant differences in the calcium oxalate supersaturation indexes between first-time and recurrent stone formation in either men or women. CONCLUSIONS: Women with recurrent stones have a higher prevalence of hypocitraturia than women with first-time stones. Potassium citrate therapy for prevention of urolithiasis may be especially useful for this patient population.     

Current information on the composition and breed distribution of urinary stones in dogs

5706 canine urinary stones were analyzed by means of infrared spectroscopy from 1984-1996. The stones were sent in together with epidemiologic data (breed, age, sex, localisation of the stones, type of stone removal, stone frequency etc.) by more than 800 veterinarians from Germany, the Netherlands, Austria, and Switzerland. Irrespective of stone type, urinary stones were observed in almost all breeds, but small breeds like dachshound, poodle, terrier, schnauzer, and pekingese have a higher tendency to form stones. With 59.5% struvite is the most frequent stone type, followed by cystine with 15.5%. Cystine stones are becoming less frequent during the observation time, whereas the share of calcium oxalate (14.2%) and ammonium urate (6.0%) stones remains unchanged. The latter stone types are found predominantly in specific breeds. The stone formation appears predominantly at the age of 7. Male dogs form stones twice as often as female dogs. 98% of the stones were located in the lower urinary tract. About 90% of the urinary stones required surgical treatment.     

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.     

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.     

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.     

Acute toxic effects of fragrance products

To estimate the prevalence of urinary stone disease in Koreans, and to determine the inter-relationships between urinary stone disease and various epidemiological factors, 1,521 controls and 1,177 cases with urinary stones were evaluated. Of special interest in this study were: 1) proportion of past urinary stone history among controls; 1.9% 2) the point prevalence rate of urinary stones among controls; 0.2% 3) the recurrence rate of urinary stones (the proportion of past history of urinary stone) among cases; 56.8% 4) high incidences (76.3%) in the thirties to the fifties among cases 5) the risk factors for urolithogenesis; obesity [higher than 25 of BMI (body mass index, weight/height2)], more than 10 year-experience as a production worker, past stone history, familial stone history, low physical activity (< 2,000 Kcal/day), and low intake of fruit. However, the well-known risk factors for urinary stones; over intake of meat or fish and milk or dairy products, perspiration, amount and kind of drinking water, and stress unexpectedly were not significantly different between the controls and the cases.     

Nephrolithiasis: acute management and prevention

The primary care physician has a responsibility not only to recognize and treat acute stone passage but to ensure that the patient with recurrent stones has metabolic evaluation and appropriate preventive care. Renal colic is typically severe, radiates to the groin, is associated with hematuria, and may cause ileus. About 90% of stones that cause renal colic pass spontaneously. The patient with acute renal colic should be treated with fluids and analgesics and should strain the urine to recover stone for analysis. Highgrade obstruction or failure of oral analgesics to relieve pain may require hospitalization; a urinary tract infection in the setting of an obstruction is a urologic emergency requiring immediate drainage, usually with a ureteral stent. Several approaches are available when stones do not pass spontaneously, including extracorporeal shock wave lithotripsy, percutaneous lithotripsy, and ureteroscopic laser lithotripsy. Calcium stone disease has a lifetime prevalence of 10% in men and causes significant morbidity. Renal failure is unusual. Stone types include calcium oxalate, uric acid, struvite, and cystine. Stone analysis is particularly important when a noncalcareous constituent is identified. The majority of patients with nephrolithiasis will have recurrence, so prevention is a high priority. High fluid intake is a mainstay of prevention. Metabolic evaluation will indicate other appropriate preventive measures, which may include dietary salt and protein restriction, and use of thiazide diuretics, neutral phosphate, potassium citrate, allopurinol, and magnesium salts. Dietary calcium restriction may worsen oxaluria and negative calcium balance (osteoporosis).     

Chemolysis of calcium containing urinary calculi. A review

A review of current literature and research on chemolysis of calcium containing urinary stones is made. The type of chemolytic solution is dependent upon the composition of the stone. Calcium phosphates can be desolved with Suby or Renadecin solution although it is often tedious and time consuming procedure. Calcium oxalate, the major urinary stone component, can not be dissolved by these solutions. EDTA and other strong calcium chelators cannot be used because of their local toxicity. Certain enzymes can digest the organic matrix of the stone. The indication to chemolysis of stones are rather restricted.