CLINICAL PATHOPHYSIOLOGY OF NEPHROLITHIASIS

肾结石的临床病理生理学

• 批准号: 6898580
• 负责人: FREDERIC L COE
• 金额: $ 14.64万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6898580
• 关键词: 1,25 dihydroxycholecalciferol; apatites; calcium; calcium binding protein; calcium metabolism; clinical research; crystallization; diet; family genetics; gender difference; hormone regulation /control mechanism; human subject; insulin; kidney function; nephrolithiasis; nutrition related tag; oxalates; parathyroid hormones; pathologic process; patient oriented research; receptor expression; stomach /intestine bypass; urine; urine acidity; vitamin D receptors

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.

该项目旨在定义肾脏产生间质磷灰石斑块和内部髓质收集管道塞的机制。由于磷灰石斑块被认为是草酸钙结石生长的锚定nidus，因此了解其生产机制对于石材研究的进展至关重要。同样，理解引起异常高尿液pH和促进钙磷酸钙结石的机制以及收集管道磷灰石塞的机制可能会揭示防止肾损伤磷灰石塞的临床方法。 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.间质斑块的丰度与尿钙排泄直接相关，与尿量逆，这表明与薄肢体流明或间质的钙浓度有联系。该项目在三分之二的日子里使用了对肾矿物排泄和分数重吸收的多次测量，以及血液激素水平，以量化高钙硫硫磺石的甲状旁腺激素对估计的薄环和尿液钙的贡献，并降低了甲状旁腺激素对甲状旁腺甲状腺激素的含量。 收集管道塞似乎与异常高的尿液pH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调节的影响。该项目的具体目的是：（1）估计两种替代斑块机制的相对幅度； （2）探讨胰岛素，PTH，骨化三醇和肾钙受体信号在调节具有遗传性高钙尿的石材形成器中促进后肾脏钙的重吸收中的作用； （3）确定遗传性高钙尿中维生素D受体和钙受体的人类肾脏组织水平； （4）探讨胰岛素和饮食在调节餐后尿液中的作用； （5）确定草酸盐和草酸根离子在内髓质收集管道磷灰石中的作用，并在肠道旁路的石材中塞在肥胖症中。