PATHOPHYSIOLOGY AND HISTOPATHOLOGY OF NEPHROLITHIASIS

项目总结(见说明)： 我们在上一次资助期间进行的外科、代谢和解剖学研究已经表征了七组SF的组织病理学和矿物成分：CaOx ICSF、肥胖的肠道旁路手术导致的结石患者、CAP ICSF、DRTA与磷酸盐结石、胱氨酸、PHT与磷酸盐结石、以及回肠造口以测试间质斑块出现在独特的 肾脏的解剖区域，它们的形成受特定的SF病理生理条件的影响。 令我们惊讶的是，每组SF都有独特的晶体沉积组织病理学模式，晶体材料的所有间质部位由羟基磷灰石组成，管内部位由HA与半胱氨酸、CaOx或酸性尿酸钠和酸性尿酸铵的混合物组成。 目标1将确定管状堵塞的结石形成中的堵塞-过度生长-结石复合体的矿物和超微结构特征。目标2概述了一组新的研究，该研究将确定是否所有附着在兰德尔斑块部位的肾结石都有磷灰石过度生长。这些研究将推动 关于斑块-组织界面的研究已经在这个资金周期中完成。Aim 3概述了一系列新的研究，以确定与堵塞的、受阻的小管相邻的正常小管是否获得(场效应)细胞变化，包括由可能导致酸化的细胞因子介导的透明质酸的表达 叛逃。目的4将使用冷冻电子显微镜结合X射线显微分析来量化CaOx ICSF患者乳头组织中的钙水平，提示血管冲洗是斑块形成的机制。目的5a和b将确定CaOx ICSF肾组织CaSR、VDR和各种VDR激活靶点的蛋白表达是否增加。最后，AIM 6将确定参与钙处理的转运体的膜位置和/或丰度是否异常，这些患者的CaOx ICSF与CAP ICSF和非结石形成对照组相比，餐后钙重吸收明显异常减少。这些新的目标将极大地促进我们对结石形成和生长的精确机制的理解，这将有望转化为更有效的结石疾病的临床治疗。

PROJECT SUMMARY (See instructions): The surgical, metabolic and anatomical studies we performed during the last funding period have characterized the histopathological and mineral composition in seven groups of SF: CaOx ICSF, patients with Stones due to intestinal bypass surgery for obesity, CaP ICSF, dRTA with phosphate stones, cystine, PHT with phosphate stones, and ileostomy to test the hypothesis that interstitial plaque, arise in unique anatomical regions of the kidney, and that their formation is conditioned by specific SF pathophysiologies. We were amazed at the finding, in that, each group of SF had a unique histopathologic pattern of crystal deposition with all interstitial sites of crystalline material composed of hydroxyapatite, and intratubular sites composed of HA with a mixture of cystine, CaOx or a mixture of Na acid urate and ammonium acid urate. Aim 1 will determine mineral and ultrastructural characteristics of the plug-overgrowth-stone complex in stone formers with tuubular plugging. Aim 2 outlines a new set of studies that will determine if all kidney stones attached to sites of Randall's plaque have apatite overgrowths. These studies will advance the studies on the plaque-tissue interface already accomplished in this funding cycle. Aim 3 outlines a new series of studies to determine if normal tubules adjacent to plugged, scared tubules acquire (the field effect) cellular changes including hyaluronan expression mediated by cytokines that could lead to an acidification defect. Aim 4 will use cryo-electron microscopy with X-ray microanalysis to quantify the calcium levels in papillary tissue from CaOx ICSF patients suggesting a vas wash down mechanism for plaque formation. Aim 5a and b will determine if renal tissue protein expression of CaSR, VDR and various targets of VDR activation are increased in CaOx ICSF. Lastly, Aim 6 will determine if membrane location and/or abundance is abnormal for transporters involved in calcium handling, in those CaOx ICSF with documented markedly abnormal reduction of post-prandial calcium reabsorption compared to CaP ICSF and non-stone forming controls. These new Aims will greatly advance our understanding of the precise mechanisms of stone formation and growth, which will hopefully translate into more effective clinical treatments for stone disease.