RENAL MINERAL DELIVERY

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。本项目旨在确定肾脏产生间质磷灰石斑块和内髓集管堵塞的机制。由于磷灰石斑块被认为是草酸钙结石生长的锚定病灶，因此了解其产生机制对结石研究的进展至关重要。同样，了解导致异常高的尿液pH值、促进磷酸钙结石和收集管磷灰石堵塞的机制，可以揭示预防磷灰石堵塞似乎产生的肾损害的临床方法。在普通草酸钙结石形成患者中，发现肾间质磷灰石斑块起源于亨利氏袢细肢基底膜，以及刷状石结石形成者用磷灰石晶体堵塞髓内集管并发展肾单位退化的肾脏疾病，这使我们能够描述这两种结晶现象的病理生理基础。间质斑块丰度与尿钙排泄直接相关，与尿量相反，提示与细肢管腔或间质钙浓度有关。本项目在一日三餐的过程中，对肾脏矿物质排泄和部分重吸收以及血液激素水平进行多次测量，以量化骨化醇和胰岛素的增加以及甲状旁腺激素的减少对高钙血症结石患者瘦环和尿钙浓度的贡献。收集管堵塞似乎与异常高的尿液pH值有关。使用相同的基本方案，我们探索饮食和胰岛素对餐后尿液pH值调节的影响。该项目的具体目标是：(1)估计两种可选斑块机制的相对大小；(2)探讨胰岛素、甲状旁腺激素、骨化三醇和肾钙受体信号在遗传性高钙尿结石患者餐后肾钙重吸收中的作用；(3)测定遗传性高钙尿症患者肾组织中维生素D受体和钙受体水平；(4)探讨胰岛素和饮食在调节餐后尿液pH值中的作用；(5)确定草酸盐及草酸盐离子在肥胖症结石患者肠旁路治疗中髓内集管灰石堵塞中的作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project seeks to define mechanisms by which kidneys produce interstitial apatite plaque and inner medullary collecting duct plugging. Since apatite plaque is thought to be the anchored nidus on which calcium oxalate stones grow, understanding mechanisms of its production is essential for progress in stone research. Likewise, understanding mechanisms that cause abnormally high urine pH and foster calcium phosphate stones and collecting duct apatite plugging may disclose clinical approaches to preventing the renal damage apatite plugging appears to produce. The discovery of an origin of renal interstitial apatite plaque in basement membranes of thin limbs of Henle's loops in the common calcium oxalate stone forming patient, and that brushite stone formers plug inner medullary collecting ducts with apatite crystals and develop renal disease with nephron obsolescence has led us to delineate the pathophysiological basis for both crystallization phenomina. Interstitial plaque abundance is directly related to urine calcium excretion and inverse to urine volume, suggesting a link to calcium concentrations in the thin limb lumens or the interstitium. This project uses multiple measurements of renal mineral excretion and fractional reabsorption along with blood hormone levels during the course of a three meal day to quantify the contributions of increased calcitrol and insulin and reduced parathyroid hormone to estimated thin loop and urine calcium concentration in hypercalciuric stone formers. Collecting duct plugging appears related to abnormally high urine pH. Using the same basic protocol we explore effects of diet and insulin on postprandial urine pH regulation. The specific aims of the project seek to: (1) Estimate the relative magnitudes of two alternative plaque mechanisms; (2) Explore the role of insulin, PTH, calcitriol and renal calcium receptor signalling in regulating post prandial renal calcium reabsorption in stone formers with genetic hypercalciuria; (3) Determine human kidney tissue levels of the vitamin D receptor and calcium receptor in genetic hypercalciuria; (4) Explore the role of insulin and diet in regulating postprandial urine pH; (5) determine the role of oxalate and oxalate ion in inner medullary collecting duct apatite plugging in stone formers with intestinal bypass for obesity.