CLINICAL PATHOPHYSIOLOGY OF NEPHROLITHIASIS

该项目旨在确定肾脏产生间质磷灰石斑块和内髓集合管堵塞的机制。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于结石研究的进展至关重要。同样地，了解导致尿液pH值异常高和促进磷酸钙结石和集合管磷灰石堵塞的机制可能会揭示预防磷灰石堵塞似乎产生的肾损伤的临床方法。在常见的草酸钙结石形成患者中，肾间质性磷灰石斑块起源于亨利氏袢薄肢的基底膜，透钙磷石结石形成者用磷灰石晶体堵塞内髓集合管，并发展为肾单位陈旧性肾病，这一发现使我们描绘了两种结晶现象的病理生理学基础。间质斑块的丰度与尿钙排泄直接相关，与尿量成反比，这表明与薄肢体管腔或回肠中的钙浓度有关。该项目使用多次测量肾矿物质排泄和部分重吸收沿着血液激素水平在一个三餐的过程中，以量化增加的骨化三醇和胰岛素和减少的甲状旁腺激素估计细环和尿钙浓度的高钙尿结石形成者的贡献。 集合管堵塞出现异常高的尿液pH值。使用相同的基本协议，我们探讨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）估计两种不同斑块机制的相对程度;（2）探索胰岛素、甲状旁腺素、骨化三醇和肾钙受体信号在调节遗传性高钙尿症结石患者餐后肾钙重吸收中的作用;（3）确定遗传性高钙尿症患者人体肾组织中维生素D受体和钙受体的水平;（4）探讨胰岛素和饮食在调节餐后尿pH中的作用;（5）探讨草酸盐和草酸根离子在肥胖肠旁路结石患者髓内集合管磷灰石封堵中的作用。

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 calciumoxalate 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.