Urinary Biomarkers of Chronic Kidney Disease Pathology and Progression

描述(由申请人提供)： 慢性肾病(CKD)是一种常见的、有害的、可治疗的疾病。治疗慢性肾脏病的主要障碍之一是缺乏敏感和特异的生物标记物来衡量疾病的发病、进展、预后和治疗反应。我们建议加入CKD生物标记物联盟作为CKD尿液生物标记物的验证站点，这源于我们在临床前和临床环境中发现和验证新型肾小管损伤生物标记物的经验，以及与食品和药物管理局等监管机构的互动。我们建议为CKD Biomarker Consortium带来四个具有可用尿样的队列，以验证尿液生物标记物：1)来自布里格姆妇女医院的肾活检生物标本库(N=121例本地人和78例同种异体移植物；每周登记1至3例)。2)与北京大学中国第一医院合作建立的肾脏活检生物检验库，包括IgA肾病、狼疮性肾炎、肾血管炎和中草药肾病(N=430人，每月招生7人)；3)萨格勒布大学医学院的地方性(巴尔干)肾病流行病学研究(N=1074人；2010年新增500至700人)；4)布里格汉姆妇产科医院狼疮中心的狼疮患者观察队列(迄今为40人，登记人数预计为~300人，24个月)。我们能够接触到大量不同的慢性肾脏病患者和风险人群，将为研究下列尿液生物标志物的临床应用提供充足的统计能力：肾损伤分子-1(KIM-1)；N-乙酰-β-D-氨基葡萄糖苷酶(NAG)；嗜网织红细胞明胶酶相关脂蛋白(NGAL)；尿L脂肪酸结合蛋白(L-FABP)；白细胞介素18(1L-18)；尿胱抑素C；白蛋白；肝细胞生长因子(HGF)；干扰素诱导蛋白(IP-10)；以及结缔组织生长因子(CTGF)。我们假设尿液生物标记物可以无创地预测肾活检的组织病理学结果，而肾活检组织病理学结果反过来又能预测CKD的进展；作为CKD进展的预测指标，尿液生物标志物优于传统的标志物(血肌酐和蛋白尿)。

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) is common, harmful, and treatable. One of the major obstacles to the care of individuals with and at risk for CKD is the lack of sensitive and specific biomarkers to measure disease onset, progression, prognosis, and response to treatment. Our proposal to join the CKD Biomarker Consortium as a validation site for urinary biomarkers of CKD draws from our experience with discovery and validation of novel tubular injury biomarkers in preclinical and clinical settings as well as interactions with regulatory agencies such as the Food and Drug Administration. We propose bringing to the CKD Biomarker Consortium four cohorts with available urine samples to validate urinary biomarkers: 1) A kidney biopsy biospecimens bank from Brigham and Women's Hospital (N = 121 native and 78 allograft to date; enrollment 1 to 3 per week). 2) A kidney biopsy biospecimens bank of IgA nephropathy, lupus nephritis, renal vasculitis, and Chinese herbal nephropathy from our established collaboration with Peking University First Hospital (PUFH) in Beijing, China (N = 430; enrollment 7 per month); 3) An epidemiological study on endemic (Balkan) nephropathy from the University of Zagreb School of Medicine (N = 1074; additional 500 to 700 in 2010); 4) An observational cohort of lupus patients seen at the Brigham and Woman's Hospital Lupus Center (N=40 to date; enrollment expected to be ~300 withing 24 months). Our access to large and diverse cohorts of individuals with and at risk for CKD will provide ample statistical power to investigate the clinical utility of the following urinary biomarkers: kidney injury molecule-1 (KIM-1); N-acetyl-beta-D-glucosaminidase (NAG); neturophil gelatinase-associated lipocalin (NGAL); urinary L-type fatty acid binding protein (L-FABP); interleukin-18 (1L-18); urinary cystatin C; albumin; hepatocyte growth facmr (HGF); interferon-inducible protein (IP-10); and connective tissue growth factor (CTGF). We hypothesize that urinary biomarkers noninvasively predict histopathological findings on kidney biopsy, which are in turn predictive of CKD progression; and that urinary biornarkers are superior to conventional markers (serum creatinine and albuminuria) as predictors of CKD progression.