Urinary Biomarkers of Chronic Kidney Disease Pathology and Progression

描述（由申请人提供）： 慢性肾脏病（CKD）是常见的，有害的，可治疗的。护理CKD患者和有CKD风险的患者的主要障碍之一是缺乏敏感和特异性的生物标志物来测量疾病的发作、进展、预后和对治疗的反应。我们建议加入CKD生物标志物联盟作为CKD尿液生物标志物的验证中心，这得益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志物的经验，以及与食品药品监督管理局等监管机构的互动。我们建议向CKD生物标志物联盟引入四个具有可用尿液样本的队列以验证尿液生物标志物：1）来自Brigham and Women's Hospital的肾活检生物标本库（迄今为止N = 121个本地和78个同种异体移植物;每周招募1至3人）。2)我们与北京大学第一医院（PUFH）合作建立的伊加肾病、狼疮性肾炎、肾血管炎和中草药肾病的肾活检生物标本库（N = 430;每月入组7例）; 3）萨格勒布大学医学院关于地方性（巴尔干半岛的）肾病的流行病学研究（N = 1074; 2010年增加500至700）; 4）在布里格姆妇女医院狼疮中心观察的狼疮患者的观察性队列（迄今为止N=40;预计在24个月内招募约300人）。我们获得了大量不同的CKD患者和有CKD风险的人群，这将为研究以下尿生物标志物的临床应用提供充分的统计学依据：肾损伤分子-1（KIM-1）、N-乙酰-β-D-氨基葡萄糖苷酶（NAG）、嗜中性粒细胞明胶酶相关脂质运载蛋白（NGAL）、尿L-型脂肪酸结合蛋白（L-FABP）、白细胞介素-18（1 L-18）、尿胱抑素C（cystatin C）、尿蛋白酶抑制剂（L-FABP）、白蛋白;肝细胞生长因子（HGF）;干扰素诱导蛋白（IP-10）;和结缔组织生长因子（CTGF）。我们假设尿生物标志物非侵入性地预测肾活检的组织病理学结果，这反过来又预测CKD进展;尿生物标志物作为CKD进展的预测因子上级传统标志物（血清肌酐和白蛋白尿）。 公共卫生相关性：慢性肾脏疾病困扰着超过11%的美国人口，是心血管疾病和全因死亡率最有效的预测因子之一。临床上有用的CKD生物标志物的鉴定将改善患有CKD和有CKD风险的个体的护理。

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. PUBLIC HEALTH RELEVANCE: Chronic kidney disease afflicts more than 11% of the United States population and is one of the most potent predictors of cardiovascular disease and all-cause mortality. The identification of clinically useful CKD biomarkers will improve the care of individuals with and at risk for CKD.