PATHOPHYSIOLOGY AND HISTOPATHOLOGY OF NEPHROLITHIASIS

项目总结（见说明）： 我们在上一个资助期内进行的手术、代谢和解剖学研究表征了7组SF的组织病理学和矿物质组成：CaOx ICSF、因肥胖症行肠旁路手术导致结石的患者、CaP ICSF、dRTA伴磷酸盐结石、胱氨酸、PHT伴磷酸盐结石和回肠造口术，以检验间质斑块在独特的 肾脏的解剖区域，并且它们的形成由特定的SF病理生理学调节。 我们对这一发现感到惊讶，因为每组SF都有独特的晶体沉积组织病理学模式，所有间隙部位的晶体材料均由羟基磷灰石组成，小管内部位由HA与胱氨酸、CaOx或酸式尿酸钠和酸式尿酸铵的混合物组成。 目的1将确定矿物和超微结构特征的塞-增生-结石复杂的结石形成与管状堵塞。目标2概述了一组新的研究，将确定是否所有的肾结石连接到网站兰德尔的斑块有磷灰石过度生长。这些研究将推动 在本供资周期内已经完成的牙菌斑-组织界面研究。目的3概述了一系列新的研究，以确定是否正常肾小管相邻堵塞，害怕肾小管获得（场效应）细胞变化，包括透明质酸表达介导的细胞因子，可能导致酸化 缺损目的4将使用冷冻电子显微镜和X射线微量分析来量化CaOx ICSF患者乳头组织中的钙水平，这表明斑块形成的血管冲洗机制。目的5a和B将确定CaOx ICSF中CaSR、VDR和VDR激活的各种靶点的肾组织蛋白表达是否增加。最后，目标6将确定与CaP ICSF和非结石形成对照相比，CaOx ICSF餐后钙重吸收显著异常减少的那些CaOx ICSF中参与钙处理的转运蛋白的膜位置和/或丰度是否异常。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，这将有望转化为结石疾病更有效的临床治疗方法。

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.