calcitriol and Kidney-Calculi

We will describe the pathophysiology of hypercalciuria and the mechanism of the resultant stone formation in a rat model and draw parallels to human hypercalciuria and stone formation.. Through inbreeding we have established a strain of rats that excrete 8-10 times more urinary calcium than control rats. These genetic hypercalciuric rats absorb more dietary calcium at lower 1,25-dihydroxyvitamin D3 levels. Elevated urinary calcium excretion on a low-calcium diet indicated a defect in renal calcium reabsorption and/or an increase in bone resorption. Bone from hypercalciuric rats released more calcium when exposed to 1,25-dihydroxyvitamin D3. Bisphosphonate significantly reduced urinary calcium excretion in rats fed a low-calcium diet. Clearance studies showed a primary defect in renal calcium reabsorption. The intestine, bone and kidneys of the hypercalciuric rats had increased numbers of vitamin D receptors. When hydroxyproline is added to their diet they form calcium oxalate stones, the most common stone type in humans. Increased numbers of vitamin D receptors may cause hypercalciuria in these rats and humans.. Understanding the mechanism of hypercalciuria and stone formation in this animal model will help clinicians devise effective treatment strategies for preventing recurrent stone formation in humans.

Topics: Adsorption; Animals; Calcium Oxalate; Calcium, Dietary; Disease Models, Animal; Humans; Kidney; Kidney Calculi; Rats; Rats, Mutant Strains; Receptors, Calcitriol; Vitamin D

Calcium and phosphorus regulatory hormones may contribute to the pathogenesis of calcium nephrolithiasis. However, there has been no prospective study to date of plasma hormone levels and risk of kidney stones. This study aimed to examine independent associations between plasma levels of 1,25-dihydroxyvitamin D (1,25[OH]2D), 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, fibroblast growth factor 23 (FGF23), parathyroid hormone, calcium, phosphate, and creatinine and the subsequent risk of incident kidney stones.. This study was a prospective, nested case-control study of men in the Health Professionals Follow-Up Study who were free of diagnosed nephrolithiasis at blood draw. During 12 years of follow-up, 356 men developed an incident symptomatic kidney stone. Using risk set sampling, controls were selected in a 2:1 ratio (n=712 controls) and matched for age, race, and year, month, and time of day of blood collection.. Baseline plasma levels of 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, parathyroid hormone, calcium, phosphate, and creatinine were similar in cases and controls. Mean 1,25(OH)2D and median FGF23 levels were higher in cases than controls but differences were small and statistically nonsignificant (45.7 versus 44.2 pg/ml, P=0.07 for 1,25[OH]2D; 47.6 versus 45.1 pg/ml, P=0.08 for FGF23). However, after adjusting for body mass index, diet, plasma factors, and other covariates, the odds ratios of incident symptomatic kidney stones in the highest compared with lowest quartiles were 1.73 (95% confidence interval, 1.11 to 2.71; P for trend 0.01) for 1,25(OH)2D and 1.45 (95% confidence interval, 0.96 to 2.19; P for trend 0.03) for FGF23. There were no significant associations between other plasma factors and kidney stone risk.. Higher plasma 1,25(OH)2D, even in ranges considered normal, is independently associated with higher risk of symptomatic kidney stones. Although of borderline statistical significance, these findings also suggest that higher FGF23 may be associated with risk.

Topics: Adult; Aged; Biomarkers; Calcium; Case-Control Studies; Chi-Square Distribution; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Hormones; Humans; Incidence; Kidney Calculi; Logistic Models; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Phosphorus; Prospective Studies; Risk Assessment; Risk Factors; Time Factors; United States; Vitamin D

To find out the possible role of 1,25(OH)₂ vitamin D₃ [1,25(OH)₂D₃] and parathyroid hormone (PTH) as intrinsic factors in urinary calcium stone formers (SFs), we investigated their relationship with serum and urinary biochemical parameters.. A total of 326 calcium SFs (male: 204, female: 122) were enrolled and underwent outpatient metabolic evaluations including 1,25(OH)₂D₃ and PTH as well as serum and 24-hour urinary biochemical parameters. As control, 163 age- and sex-matched (2:1) individuals (non-SFs) who have never urinary stone episode were included.. 1,25(OH)₂D₃ level was positively correlated with urinary calcium excretion (r=0.347, p<0.001). The hypercalciuric group and recurrent SFs had higher serum 1,25(OH)₂D₃ levels than the normocalciuric group (p<0.001) and first SFs (p=0.050). In the adjusted multiple linear regression analysis, serum 1,25(OH)₂D₃ level (β=0.259, p<0.001) and serum PTH level (β=-0.160, p<0.001) were significantly correlated with urinary calcium excretion. The patients in highest tertile of 1,25(OH)₂D₃ had a more than 3.1 fold risk of hypercalciuria than those in the lowest tertile (odds ratio=3.14, 95% confidence interval: 1.431-6.888, p=0.004). No correlation was observed between PTH and 1,25(OH)₂D₃ (R=0.005, p=0.929) in calcium SFs, while a negative correlation was found in controls (R=-0.269, p=0.001).. 1,25(OH)₂D₃ was closely correlated with urinary calcium excretion, and high 1,25(OH)₂D₃ levels were detected in the hypercalciuric group and in recurrent SFs. However, 1,25(OH)₂D₃ was not correlated with PTH in calcium SFs. These findings suggest that 1,25(OH)₂D₃ might be important intrinsic factor for altered calcium regulation in SFs.

Topics: Adult; Calcium; Female; Humans; Kidney Calculi; Linear Models; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Parathyroid Hormone; Vitamin D

Data regarding the prevalence of 25-hydroxyvitamin D (25(OH)D) insufficiency in patients with nephrolithiasis, and the effects of vitamin D supplementation on parathyroid hormone (PTH) are few and conflicting. In this article, we examined the prevalence of vitamin D insufficiency and deficiency in 236 recurrent kidney stone formers and the correlation of vitamin D levels with other parameters of stone formation. The prevalent stone composition was calcium oxalate (80.4%) and uric acid (16.45%). One third of stone formers had vitamin D insufficiency and a quarter of them high PTH levels (PTH >7.5 pmol/l) with normal serum (total and ionized) calcium values. Predictor of high PTH was low 25(OH)D level (r = 0.989, r(2) = 0.977, p < 0.001). Stone formers with hypercalciuria had higher 25(OH)D values (72.26 ± 4.21 vs. 59.29 ± 1.76, p = 0.0013) compared to stone formers with urine calcium within normal ranges. Further studies are needed in order to better define the consequences of vitamin D insufficiency and to evaluate the impact of the therapeutic interventions in this cohort.

Topics: Biomarkers; Comorbidity; Female; Humans; Kidney Calculi; Male; Middle Aged; Ontario; Prevalence; Recurrence; Risk Factors; Vitamin D; Vitamin D Deficiency

This retrospective data analysis was undertaken to examine the biochemical differences between renal stone formers with normocalcemic hyperparathyroidism (NHPT) and those with normal parathyroid hormone (PTH) levels. Our goal was to ascertain whether 25-hydroxyvitamin D (25(OH)D) status related to PTH levels in this patient cohort. Our findings among 74 patients with NHPT indicate that stone formers with NHPT had significantly lower 25(OH)D levels compared to 192 controls (p = 0.0001) and that 25(OH)D is positively correlated with 1,25-dihydroxyvitamin D values (R = 0.736, p = 0.015). Sequential measurements (after 3 - 5 years), among 11 patients with NHPT who did not receive vitamin D (VitD) preparations, showed a significant increase in urinary calcium (3.43 ± 1.96 vs. 5.72 ± 3.95, p = 0.0426) without a significant change in PTH levels. VitD supplementation, to 3 patients resulted in significant PTH decrease (11.8 ± 1.8 vs. 9.8 ± 1.3, p = 0.003). Prospective studies are needed to confirm the role of vitamin supplementation in renal stone formers with NHPT.

Topics: Biomarkers; Calcium; Chi-Square Distribution; Dietary Supplements; Female; Humans; Hyperparathyroidism; Kidney Calculi; Male; Middle Aged; Ontario; Parathyroid Hormone; Recurrence; Retrospective Studies; Time Factors; Vitamin D; Vitamin D Deficiency; Vitamins

Hypercalciuria and hyperoxaluria are important risk factors in the pathogenesis of kidney stones. Urinary glycolate has also been reported to be elevated in patients with renal stones. 1,25-Dihydroxyvitamin D(3), the active metabolite of vitamin D, has been reported to induce hyperoxaluria after either oral or intravenous administration. 1-alpha-D(3), a synthetic derivative of vitamin D, together with ethylene glycol, has been reported to induce renal stones in experimental rats. We have examined the effect of 1-alpha-vitamin D(3) on urinary oxalate and glycolate excretion. Our results indicate that 1-alpha-D(3), together with ethylene glycol, caused a significant increase in urinary glycolate, without a parallel rise in urinary oxalate excretion, in ethylene glycol-fed rats. This increase in urinary glycolate was due to the synergistic effect of both drugs.

Topics: Administration, Oral; Animals; Carbon Radioisotopes; Drug Synergism; Ethylene Glycol; Glycolates; Injections, Intraperitoneal; Kidney Calculi; Male; Oxalates; Rats; Rats, Wistar; Vitamin D

To analyze the pathophysiology of hypophosphatemia in calcium nephrolithiasis, we investigated the relation between serum phosphorus, 1,25-dihydroxyvitamin D, and parathyroid hormone (PTH) levels in 63 consecutive patients with calcium nephrolithiasis, comparing them with 26 age-matched control subjects.. Serum phosphorus concentrations in normocalciuric and absorptive hypercalciuric stone formers were significantly decreased compared with control subjects (P<0.001 and P<0.01, respectively). The fractional excretion (TRP) and renal threshold (TmP/GFR) of phosphorus were significantly decreased in the subjects with nephrolithiasis (P<0.01 and P<0.001, respectively). Serum phosphorus concentrations were inversely correlated with serum 1, 25-dihydroxyvitamin D in control subjects and in absorptive hypercalciuric stone formers (P<0.01 and P <0.05, respectively), suggesting that the physiologic relation between phosphorus and 1, 25-dihydroxyvitamin D is maintained in these patients. Serum phosphorus concentrations in absorptive hypercalciuric patients, although related to 1,25-dihydroxyvitamin D, were not related to PTH even though PTH and 1,25-dihydroxyvitamin D concentrations were directly related (P<0.05). The lack of a relation between PTH and serum phosphorus concentrations in absorptive hypercalciuric stone formers was similar to that in controls. In normocalciuric stone formers, there was no relation between serum 1,25-dihydroxyvitamin D and serum phosphorus, but PTH and 1,25-dihydroxyvitamin D were inversely correlated (P<0.05).. Abnormal renal tubular function with a depressed rate of renal phosphorus transport and an abnormal 1,25-dihydroxyvitamin D concentration is common in nephrolithiasis. Differences in the relations between phosphorus and 1,25-dihydroxyvitamin D observed in hypercalciuric v normocalciuric subjects suggest that the pathogenesis of proximal tubulopathy differs among patients with nephrolithiasis.

Topics: Adult; Aged; Calcium; Case-Control Studies; Female; Humans; Hypophosphatemia; Kidney Calculi; Male; Middle Aged; Models, Biological; Parathyroid Hormone; Phosphorus; Vitamin D

To determine whether an "atherogenic" diet (excess of cholesterol and neutral fat) induces pathological calcification in various organs, including the kidney, and abnormal oxalate metabolism, 24 male Sprague-Dawley rats were fed either normal lab chow (controls, n = 12) or the cholesterol- and fat-rich experimental diet (CH-F, n = 12) for 111 +/- 3 days. CH-F rats developed dyslipidemia [high blood levels of triglycerides, total, low-density lipoprotein (LDL)-, very low-density lipoprotein (VLDL)-, high-density lipoprotein (HDL)-bound cholesterol, total phospholipids], elevated serum total alkaline phosphatase and lactate dehydrogenase (LDH) levels, in the absence of changes in overall renal function, extracellular mineral homeostasis [serum protein-corrected total calcium, magnesium, parathyroid hormone (PTH), 1,25-dihydroxyvitamin D (1,25(OH)2D)], plasma glycolate and oxalate levels. There was a redistribution of bone calcium and enhanced exchange of this within the extraosseous space, which was accompanied by significant bone calcium loss, but normal bone histomorphometry. Liver oxalate levels, if expressed per unit of defatted (DF) dry liver, were three times higher than in the controls. Urinary glycolate, oxalate, calcium and total protein excretion levels were elevated, the latter showing an excess of proteins > 100 kD and a deficit of proteins > 30-50 kD. Urinary calcium oxalate supersaturation was increased, and calcium phosphate supersaturation was unchanged. There were dramatically increased (by number, circumference, and area) renal calcium phosphate calcifications in the cortico-medullary region, but calcium oxalate deposits were not detectable. Electron microscopy (EM) and elemental analysis revealed intratubular calcium phosphate, apparently needle-like hydroxyapatite. Immunohistochemistry of renal tissue calcifications revealed co-localization of phospholipids and calcium phosphate. It is concluded that rats fed the CH-F diet exhibited: (1) a spectrum of metabolic abnormalities, the more prominent being dyslipidemia, hyperoxaluria, hypercalciuria, dysproteinuria, loss of bone calcium, and calcium phosphate nephrocalcinosis (NC); and (2) an interaction between calcium phosphate and phospholipids at the kidney level. The biological significance of these findings for the etiology of idiopathic calcium urolithiasis in humans is uncertain, but the presented animal model may be helpful when designing clinical studies.

Topics: Absorptiometry, Photon; Animals; Aorta; Body Weight; Bone and Bones; Calcium; Calcium Oxalate; Calcium Phosphates; Cholesterol, Dietary; Diet, Atherogenic; Dietary Fats; Glycolates; Hyperlipidemias; Hyperoxaluria; Immunohistochemistry; Kidney; Kidney Calculi; Liver; Male; Microscopy, Electron; Minerals; Nephrocalcinosis; Parathyroid Hormone; Phospholipids; Proteinuria; Rats; Rats, Sprague-Dawley; Vitamin D