Discovery & Validation of Biomarkers of Kidney Pathology

发现

• 批准号: 8734905
• 负责人: BRAD H ROVIN
• 金额: $ 39.76万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8734905
• 关键词: Area; Biological Markers; Biopsy; Cardiovascular system; Chronic Kidney Failure; Cicatrix; Clinical; Clinical Data; Country; Development; Diabetes Mellitus; Diabetic Nephropathy; Diagnosis; Diagnostic; Discriminant Analysis; Disease; Early Diagnosis; Early Intervention; End stage renal failure; Fibrosis; Glomerulonephritis; Goals; Healed; Healthcare Systems; Hematuria; Histologic; Histology; Immunosuppression; Immunosuppressive Agents; Immunotherapy; Individual; Inflammation; Injury; Kidney; Kidney Glomerulus; Lasers; Lead; Lesion; Literature; Measures; Methods; Microarray Analysis; Microdissection; Monitor; Morbidity - disease rate; Nature; Necrosis; Outcome; Pathogenesis; Pathologic; Pathology; Patients; Pattern; Pharmaceutical Preparations; Physicians; Population; Procedures; Proteins; Proteinuria; Proteome; Proteomics; Renal function; Renal glomerular disease; Risk; Safety; Sample Size; Sampling; Sclerosis; Series; Testing; Time; Tissues; Toxic effect; Treatment Effectiveness; Treatment Efficacy; Treatment outcome; United States; Urine; Validation; Work; base; burden of illness; clinical Diagnosis; glomerular basement membrane; healing; improved; interstitial; mortality; non-diabetic; novel; prevent; protein expression; public health relevance; response; time use

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.

描述（由申请人提供）：肾小球疾病对美国终末期肾病负担有显著影响。虽然有许多针对肾小球疾病的特定疗法，而且还有更多的疗法正在开发中，但有几个因素会降低这些治疗的有效性。大多数肾小球疾病需要通过肾活检来诊断，而这种手术的侵入性通常会导致它被推迟，直到肾损伤的临床体征显着。这段等待期可能导致慢性、不可逆转的损害的累积，而这些损害本可以通过早期诊断和干预来预防。此外，用于肾小球疾病的疗法通常涉及免疫抑制药物及其相关毒性。因为天然肾活检不是连续进行的，所以这些毒性治疗是临床监测的。然而，如果真实的时间监测肾脏病理学并用于滴定治疗，则可以提高治疗效果。因此，我们建议使用新的尿液和传统的临床生物标志物（如蛋白尿）的组合，以获得准确反映肾脏病理的复合生物标志物。与先前使用非靶向总尿蛋白质组学方法或基于文献的候选方法进行的尿生物标志物研究不同，本研究的个体尿生物标志物将通过从定义的肾小球疾病和肾小球疾病谱中重要的特定病理病变中收集的激光捕获显微切割肾小球和肾小管的蛋白质组学分析来获得信息。差异表达的组织蛋白将被视为候选生物标志物。将验证尿液中这些候选生物标志物的存在，然后将对尿液中存在的候选物进行定量。将对排泄的候选生物标志物和临床数据的组合进行数学测试，以确定每种类型的肾小球疾病或病理性病变的生物标志物的最佳组成。这些复合生物标志物将在从接受诊断性肾活检的患者中前瞻性采集的独立尿液样本中进行验证。预计这项工作将产生一组复合生物标志物，可用于非侵入性诊断肾小球疾病，并在治疗期间跟踪肾脏组织学变化，以改善肾小球疾病的管理。