PATHOPHYSIOLOGIC ROLE OF CALCITRIOL IN ABSORPTIVE HYPERCALCIURIA

越来越多的证据表明，吸收性高钙尿症(AH)是一种 肾结石的常见原因是一种由以下因素组成的异质性疾病 维生素D依赖和非维生素D依赖两种形式。此外， 维生素D依赖可能是由于骨化三醇增加所致 合成，或导致骨化三醇受体的初级上调，导致 对正常循环骨化三醇水平的敏感度增加。整体而言 这个项目的目标是获得生理学数据来证实 以上三种类型的急性早幼粒细胞白血病，提供了生物和组织标本 生物化学和分子生物学试验在项目1，比较一， 并获取尿样以确认生理学和 缓释钾的物理化学效应(项目1，组份IV) 磷酸盐(UroPhos-k)治疗急性胰腺炎。对准L，底线 将在AH患者和匹配的患者中进行生理学研究， 正常对照受试者，同时进行持续代谢饮食。研究将会 包括部分肠道吸收、尿钙排泄、血清 骨化三醇水平、腹部X线片和骨密度测定。外围 将获得血液单个核细胞(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……里面 有明显骨量减少的患者，经髂骨活检将 用于组织形态计量学和成骨细胞VDR研究。目标2涉及 确诊为RFLP的先证者的家系研究 在VDR基因的3‘非编码区。来自受影响和 未受影响的家庭成员将被用来检验假设 VDR 3‘-非编码区的多态可能是 钙吸收增加与初级受体上调有关 一些急性胰腺炎患者。在目标3中，骨化三醇在急性肝炎中的致病作用 将通过测量钙吸收、尿钙的变化来评估 排泄量和PBMC VDR数对抑制2周的反应 酮康唑法测定血清骨化三醇水平。待检验的假说 目标4是UroPhos-K的3个月试验将降低L，25-(OH)2D 合成，完全或部分纠正上调的状态 骨化三醇受体，降低肠道钙吸收和尿钙，减少 促进骨吸收，促进骨形成。目标5：长期安全 疗效数据将在继续的开放标签试验中寻求 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.