HISTOPATHOLOGIC DETERMINANTS OF HUMAN NEPHROLITHIASIS

我们在前一次赠款期间进行的组织病理学研究表明， 对三组结石形成者的组织病理学和矿物成分进行了研究：常见的特发性草酸钙结石成石者、因肥胖而行肠道搭桥手术的结石患者和刷状结石患者(以及非结石成石者)，以验证兰德尔斑块(钙质肾结石患者肾脏中的磷酸钙沉积)存在于肾脏独特的解剖区域的假说，其形成受到特定的成石病理生理条件的制约。我们对这一发现感到惊讶，因为每组结石形成者都有不同和独特的晶体沉积组织病理学模式，而晶体材料的所有实质内和间质位置都是羟基磷灰石，这是另一个令人惊讶的地方。因为我们在上一个资助期非常成功地确定了一套明确的外科/ 我们将利用组织病理学、MU CT和MU FTIR技术，研究这三组不同的人体结石形成物(CaOx、肥胖肠道搭桥术和刷石)的形态/代谢特征，并将这些分析扩展到新的结石组：磷灰石(包括RTAS)结石、原发性甲状旁腺功能亢进症合并肾结石、肾结石回肠吻合术、胱氨酸结石、尿酸结石、肥胖患者以及尿液pH高(&GT；PH6.3)的CaOx结石患者。此外，我们还将尝试测试一组关于结石形成机制的新假说。首先，我们将检验这一假设 HA的积累沿着Henle循环的特定节段进行，Henle是一条细长的降支。其次，将通过定量的透射电子显微镜和四环素研究来确定普通CaOx患者的晶体颗粒形成和聚集的机制。第三，测试假设，在乳头状间质或管腔内存在促进或抑制晶体成核和生长的候选蛋白质。这将使用免疫组织化学分析来确定骨桥蛋白、凝血酶原片段1、胎球蛋白-A和Bikunin在间质和斑块-结石界面上的相互作用。第四，我们将使用RT-PCR技术来检测成骨细胞样活性的转录本。最后，我们将探讨SWL损伤导致内髓集合管失去液体pH控制可能导致大量尿液碱化的观点，从而深入了解刷石结石病的结石形成机制。

Our histopathologic studies performed during the previous grant period have characterized the histopathological and mineral composition in three groups of stone formers: common idiopathic calcium oxalate stone formers, patients with stones due to intestinal bypass surgery for obesity and brushite stone formers (as well as non-stone formers) to test the hypothesis that Randall's plaque, calcium phosphate deposits in kidneys of patients with calcium renal stones, arise in unique anatomical regions of the kidney, their formation conditioned by specific stone-forming pathophysiologies. We were amazed at the finding, in that, each group of stone formers had a different and unique histopathologic pattern of crystal desposition while all intraparenchymal and interstitial sites of crystalline material were hydroxyapatite, yet another surprise. Because we were so highly successful in the last funding period in identifying a clear set of surgical/ morphological/metabolic characteristics in these three different groups of human stone formers (CaOx, intestinal bypass for obesity and brushite) and will extend these analyses to new groups of stone formers: apatite (including RTAs) stone formers, primary hyperparathyroidism with kidney stones, ileostomy with kidney stones, cystine stone formers, uric acid stones, bariatric patients with stones and CaOx stone formers with high urine pH (> pH 6.3) using histopathology,mu CT, and mu FTIR. In addition, we will seek to test a new set of hypotheses concerning the mechanisms of stone formation. First, we will test the hypothesis that the progression of HA accumulation occurs along a specific segment of the loops of Henle, the thin descending limb. Second, the mechanism of crystal particle formation and coalescence in the common CaOx patients will be determined by quantitative TEM and tetracycline studies. Third, test the hypothesis that there are candidate proteins that either promote or inhibit crystal nucleation and growth within the papillary interstitium or tubular lumens. This will be done using TEM immunohistochemical analysis to define the interaction of osteopontin, prothrombin fragment 1,fetuin-A and bikunin on interstitial and the plaque-stone interface. Fourth, we will use RT-PCR techniques to detect transcripts for the presence of osteoblast-like activity. Lastly, we will examine the idea that a loss of fluid pH control in the inner medullary collecting ducts due to SWL injury may result in an alkalization of the bulk urine and, therefore, give insights into the mechanisms of stone formation in brushite stone disease.