1,25(OH)₂D₃-enhanced hypercalciuria in genetic hypercalciuric stone-forming rats fed a low-calcium diet

Abstract

(1,25D) increases urine (U) Ca to a greater extent in GHS than in controls [Sprague-Dawley (SD)]. The additional UCa may result from an increase in intestinal Ca absorption and/or bone resorption. To determine the source, we asked whether 1,25D would increase UCa in GHS fed a low-Ca (0.02%) diet (LCD). With 1,25D, UCa in SD increased from 1.2 Ϯ 0.1 to 9.3 Ϯ 0.9 mg/day and increased more in GHS from 4.7 Ϯ 0.3 to 21.5 Ϯ 0.9 mg/day (P Ͻ 0.001). In GHS rats on LCD with or without 1,25D, UCa far exceeded daily Ca intake (2.6 mg/day). While the greater excess in UCa in GHS rats must be derived from bone mineral, there may also be a 1,25D-mediated decrease in renal tubular Ca reabsorption. RNA expression of the components of renal Ca transport indicated that 1,25D administration results in a suppression of klotho, an activator of the renal Ca reabsorption channel TRPV5, in both SD and GHS rats. This fall in klotho would decrease tubular reabsorption of the 1,25D-induced bone Ca release. Thus, the greater increase in UCa with 1,25D in GHS fed LCD strongly suggests that the additional UCa results from an increase in bone resorption, likely due to the increased number of VDR in the GHS rat bone cells, with a possible component of decreased renal tubular calcium reabsorption. vitamin D; calcium; kidney stones; intestinal absorption THE MOST COMMON METABOLIC abnormality in patients who form calcium-based kidney stones is hypercalciuria (14, 50). The increased urine (U) calcium (Ca) excretion enhances nucleation and growth of calcium hydrogen phosphate (CaHPO 4 ; brushite) and/or calcium oxalate (CaOx) crystals into stones (14). Idiopathic hypercalciuria (IH) typically manifests as hypercalciuria with normal serum (S) Ca, normal or elevated S1,25(OH) 2 D 3 (1,25D), normal or elevated S parathyroid hormone (PTH), normal or low S phosphate (P), and low bone mass (14,48,55) and is polygenic (48,49,55).To study the pathophysiology of hypercalciuria and stone formation, we established a strain of hypercalciuric rats by selectively inbreeding Sprague-Dawley (SD) rats for increased UCa excretion (3-5, 11-13, 15-19, 21-24, 27, 32, 35, 36, 40, 41, 43, 45, 52, 57, 61, 62). After more than 80 generations, each rat consistently excretes ϳ8-to 10-fold more UCa than SD controls (3-5, 11-13, 15-19, 21-24, 27, 32, 35, 36, 40, 41, 43, 45, 52, 57, 61, 62) and forms kidney stones (3,17,18,22); these animals are termed genetic hypercalciuric stone-forming (GHS) rats (3-5, 11-13, 15-19, 21, 23, 24, 27, 32, 35, 36, 40, 41, 43, 45, 52, 57, 61, 62).GHS rats exhibit many features of human IH including normal SCa (15), increased intestinal Ca absorption (45) and bone resorption (43), decreased renal tubule Ca reabsorption (57), and normal S1,25D levels in addition to decreased bone mineral density (24, 32) and have a polygenic mode of inheritance (35). GHS rats have elevated levels of vitamin D receptor (VDR) protein in Ca-transporting organs including the kidney, intestine, and bone (30,43,45,57).In humans, the changes in intestine, kidney, and ...

Expression of Fibroblast Growth Factor 23, Vitamin D Receptor, and Sclerostin in Bone Tissue from Hypercalciuric Stone Formers

“…In the present series, serum 1,25(OH) 2 D 3 correlated with VDR immunostaining in osteoblasts from IH patients. These findings agree well with experimental data showing a 4-fold increase in the level of VDR in GHS calvarias versus controls and a greater sensitivity to 1,25(OH) 2 D 3 compared with bone from control rats (17,35). The direct correlation that we have found between VDR and Tb.N in osteoblasts in IH further reinforces the contribution of VDR to increase bone resorption.…”

“…In our study, there were no significant correlations between FGF-23 bone immunostaining and serum phosphate or between PTH and vitamin D. The small number of hypophosphatemic patients in the current series might have accounted for the lack of such correlation. Among the presumed mechanisms responsible for impaired bone formation in IH patients, elevated serum 1,25 (OH) 2 D 3 levels may play a role (11-14,33,34) through decreasing bone collagen synthesis (31) or increasing bone resorption (35). A greater increase in urinary calcium with 1,25D in GHS rats fed a low calcium diet has suggested that the additional urinary calcium must result from increased bone resorption because of the increased number of VDR in their bone cells (35).…”

“…Among the presumed mechanisms responsible for impaired bone formation in IH patients, elevated serum 1,25 (OH) 2 D 3 levels may play a role (11-14,33,34) through decreasing bone collagen synthesis (31) or increasing bone resorption (35). A greater increase in urinary calcium with 1,25D in GHS rats fed a low calcium diet has suggested that the additional urinary calcium must result from increased bone resorption because of the increased number of VDR in their bone cells (35). With a few exceptions (27,28), most of the previous histomorphometric studies have shown increased bone resorption among hypercalciuric patients (3,5,7,8).…”

Effect of Potassium Citrate on Calcium Phosphate Stones in a Model of Hypercalciuria

“…28,29,33,34,37,40,43,48,[67][68][69] Ratios of 1 denote a urine at equilibrium, those .1 denote supersaturation, and those ,1 denote undersaturation. We have found excellent correspondence between calculated and experimentally measured saturation in urine and blood and in bone culture medium.…”

Persistence of 1,25D-induced hypercalciuria in alendronate-treated genetic hypercalciuric stone-forming rats fed a low-calcium diet

“…To identify the source(s) of the increased uCa, a low-Ca diet (LCD) was utilized to remove the contribution of increased intestinal Ca absorption to the hypercalciuria. The hypercalciuria persisted in GHS either with or without additional 1,25D (30), suggesting that the increased uCa was derived from increased bone resorption. In this study we tested the hypothesis that in rats fed LCD, inhibition of bone resorption with a maximal dose of the bisphosphonate alendronate (alen) would result in equalization of uCa between GHS and SD rats.…”