Discovery & Validation of Biomarkers of Kidney Pathology

描述(由申请人提供)：在美国，肾小球疾病对终末期肾脏疾病的负担有很大贡献。虽然有许多治疗肾小球疾病的特殊疗法，还有更多正在开发中，但有几个因素削弱了这些治疗的有效性。大多数肾小球疾病需要通过肾活检来诊断，而这一过程的侵袭性往往导致诊断被推迟，直到肾脏损伤的临床迹象明显。这段等待期可能会导致慢性不可逆转的损害，而如果及早诊断和干预，这种损害是可以预防的。此外，用于肾小球疾病的治疗方法通常涉及免疫抑制药物及其相关毒性。因为天然肾脏活检不是连续进行的，所以这些毒性疗法受到临床监测。然而，如果实时监测肾脏病理并用于滴定治疗，治疗效果可能会得到改善。因此，我们建议使用新的尿液和传统的临床生物标记物(如蛋白尿)的组合来获得准确反映肾脏病理的复合生物标记物。与以前使用非靶向总尿蛋白组学方法或基于文献的候选方法对尿液生物标记物进行研究不同，本研究的单个尿液生物标记物将通过对激光捕获的微解剖肾小球和肾小管间质进行蛋白质组学分析来了解，这些肾小球和肾小管间质收集自明确的肾小球疾病和重要的特定病理损害。差异表达的组织蛋白将被认为是候选生物标记物。这些候选生物标志物在尿液中的存在将得到验证，然后将对尿液中存在的候选生物标志物进行量化。排泄的候选生物标记物和临床数据的组合将进行数学测试，以确定每种类型的肾小球疾病或病理损害的生物标记物的最佳组成。这些复合生物标志物将在独立的尿样中得到验证，这些尿样是从接受诊断性肾活检的患者那里收集的。预计这项工作将产生一组复合生物标志物，可用于无创性诊断肾小球疾病，并在治疗过程中跟踪肾组织学变化，从而改善对肾小球疾病的管理。

DESCRIPTION (provided by applicant): Glomerular diseases contribute significantly to the End Stage Kidney Disease burden in the United States. Although there are a number of specific therapies for glomerular diseases, and many more under development, several factors mitigate the effectiveness of these treatments. Most glomerular diseases need to be diagnosed by kidney biopsy, and the invasive nature of this procedure often causes it to be put off until the clinical signs of kidney injury are significant. This waiting period may result in accrual of chronc, irreversible damage that could have been prevented with earlier diagnosis and intervention. Furthermore, the therapies used for glomerular diseases often involve immunosuppressive drugs with their associated toxicities. Because native kidney biopsies are not done serially, these toxic therapies are monitored clinically. However, treatment efficacy could be improved if renal pathology was monitored in real time and used to titrate therapy. We therefore propose using combinations of novel urine and traditional clinical biomarkers (e.g. proteinuria) to derive composite biomarkers that accurately reflect kidney pathology. Unlike previous studies of urine biomarkers using a non-targeted total urine proteomics approach, or a candidate approach based on the literature, the individual urine biomarkers for this study will be informed by proteomic analysis of laser-captured microdissected glomeruli and tubulointerstitium collected from defined glomerular diseases and specific pathologic lesions important across a spectrum of glomerular diseases. Differentially-expressed tissue proteins will be considered candidate biomarkers. The presence of these candidate biomarkers in urine will be verified and then candidates present in the urine will be quantified. Combinations of the excreted candidate biomarkers and clinical data will be tested mathematically to determine the optimal composition of a biomarker for each type of glomerular disease or pathologic lesion. These composite biomarkers will be validated in independent urine samples collected prospectively from patients undergoing diagnostic kidney biopsy. It is expected that this work will result in a panel of composite biomarkers that can be used to non-invasively diagnose glomerular diseases and follow changes in kidney histology during therapy so as to improve management of glomerular diseases.