PATHOPHYSIOLOGIC ROLE OF CALCITRIOL IN ABSORPTIVE HYPERCALCIURIA

点击翻译按钮获取中文摘要

Evidence is beginning to emerge that absorptive hypercalciuria (AH), a common cause of kidney stones, is a heterogeneous condition comprised of both vitamin D-dependent and vitamin D-independent forms. Moreover, vitamin D-dependence may be due to an increased rate of calcitriol synthesis, or to a primary upregulation of calcitriol receptors causing increased sensitivity to normal circulating calcitriol levels. The overall goals of this project are to obtain physiologic data corroborating the above three types of AH, to provide biological and tissue samples for the biochemical and molecular biological tests described under Proj 1, Comp I, and to obtain urinary samples confirming the physiologic and physicochemical (Proj 1, Comp IV) effectiveness of slow-release potassium phosphate (UroPhos-k) in the treatment of AH. In Aim l, baseline physiologic studies will be performed in patients with AH and matched, normal control subjects, while on constant metabolic diets. Studies will include fractional intestinal 47Ca absorption, urinary Ca excretion, serum calcitriol levels, abdominal films and bone densitometry. Peripheral blood mononuclear cells (PBMC) and skin fibroblasts will be obtained to determine calcitriol receptor (VDR) number, function and regulation. In patients with significant osteopenia, trans-iliac bone biopsies will be obtained for histomorphometry and osteoblast VDR studies. Aim 2 involves family studies of the index patients with AH who were shown to have RFLP's in the 3'-noncoding region of VDR mRNA. Lymphocytes from affected and unaffected family members will be used to test the hypothesis that polymorphism in the 3'-noncoding region of the VDR may characterize primary receptor upregulation responsible for increased Ca absorption in some patients with AH. In Aim 3, the pathogenetic role of calcitriol in AH will be assessed by measuring the change in Ca absorption, urinary Ca excretion, and PBMC VDR number in response to a 2-week suppression of serum calcitriol levels by ketoconazole. The hypothesis to be tested in Aim 4 is that a 3 month trial with UroPhos-K would reduce l ,25-(OH)2D synthesis, completely or partially correct the upregulated state of the calcitriol receptor, lower intestinal Ca absorption and urinary Ca, reduce bone resorption and stimulate bone formation. In Aim 5, long-term safety and efficacy data will be sought in an open-label trial of continued treatment with UroPhos-K for 24 months.