CLINICAL PATHOPHYSIOLOGY OF NEPHROLITHIASIS

该项目试图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固核，了解其产生的机制对于结石研究的进展至关重要。同样，了解导致尿液pH异常高并促进钙磷结石和集合管磷灰石堵塞的机制可能揭示防止磷灰石堵塞所产生的肾脏损害的临床方法。在常见的草酸钙结石形成患者Henle‘s环细肢基底膜上发现了肾间质磷灰石斑块的起源，刷石成石者用磷灰石晶体堵塞内髓集合管，并发展成肾脏疾病，伴肾单位消失，这两种结晶现象的病理生理基础使我们得以描述。间质斑块的丰度与尿钙排泄直接相关，与尿量成反比，提示与细小肢腔或间质中的钙浓度有关。该项目使用三餐期间肾脏矿物质排泄和重吸收分数以及血液激素水平的多项测量，以量化高钙尿石症结石患者增加的降钙素和胰岛素以及减少的甲状旁腺激素对估计的细环和尿钙浓度的贡献。 集合管堵塞似乎与异常高的尿液pH有关。使用相同的基本程序，我们探讨了饮食和胰岛素对餐后尿pH调节的影响。该项目的具体目标包括：(1)估计两种不同斑块机制的相对大小；(2)探讨胰岛素、甲状旁腺素、骨化三醇和肾脏钙受体信号通路在调控遗传性高钙尿石症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脏组织中维生素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)确定草酸和草酸离子在肥胖患者肠道旁路置入结石患者髓内集合管磷灰石中的作用。

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.