PATHOPHYSIOLOGIC ROLE OF CALCITRIOL IN ABSORPTIVE HYPERCALCIURIA

有证据表明，吸收性高钙尿症（AH）， 肾结石的常见原因，是一种异质性的条件，包括 维生素D依赖型和维生素D非依赖型。 此外，委员会认为， 维生素D依赖可能是由于骨化三醇的增加率 合成，或与骨化三醇受体的初级上调有关， 对正常循环骨化三醇水平的敏感性增加。整体 该项目的目标是获得证实 上述三种类型的AH，提供生物和组织样本， 项目1，Comp I， 并获得尿液样本，以确认生理和 缓释钾的物理化学（Proj 1，Comp IV）有效性 磷酸盐（UroPhos-k）治疗AH。在目标1中，基线 将在AH患者中进行生理学研究， 正常对照受试者，而在恒定的代谢饮食。 研究将 包括肠47 Ca吸收分数、尿Ca排泄、血清 骨化三醇水平腹部X光片和骨密度测定 外围 将获得血液单核细胞（PBMC）和皮肤成纤维细胞， 测定骨化三醇受体（VDR）的数量、功能和调节。在 对于明显骨质减少的患者，将进行经髂骨活检， 用于组织形态计量学和成骨细胞VDR研究。目标2涉及 对显示有RFLP的AH索引患者进行的家族研究 在VDR mRNA的3 '端非编码区。淋巴细胞从受影响的和 未受影响的家庭成员将被用来测试假设， VDR的3 '-非编码区的多态性可以表征 主要受体上调负责增加钙的吸收， 一些AH患者。在目的3中，骨化三醇在AH中的发病作用 将通过测量钙吸收、尿钙 排泄和PBMC VDR数量对2周抑制的响应 酮康唑测定的血清骨化三醇水平。待检验的假设 目的4是使用UroPhos-K的3个月试验将减少1，25-（OH）2D 合成，完全或部分地纠正上调的状态， 骨化三醇受体，降低肠道钙吸收和尿钙，减少 骨吸收和刺激骨形成。目标5：长期安全 将在一项持续的开放标签试验中寻求疗效数据。 UroPhos-K治疗24个月。

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.