The New York CKD Biomarker Discovery Program

描述(由申请人提供)： 慢性肾病(CKD)影响着十分之一以上的美国人。慢性肾脏病确实进展到终末期肾病(ESKD)的一些患者，但不是所有的患者，尽管是“最佳”的治疗。目前还没有生物标志物能够充分地预测单个CKD患者的风险和/或进展速度，以指导预防性干预。因此，发现CKD进展的“预测性”生物标记物是一个重要的未得到满足的需求，也是拟议的纽约CKD生物标记物发现计划的目标。该计划将汇集一个由肾病学家、实验室医学专家、病理学家和统计学家组成的跨学科团队，在NIDDK CKD生物标记物联盟的合作和指导下，实现这一目标。在我们团队的初步发现工作中，通过全基因组转录图谱和系统生物学分析，在一系列糖尿病、免疫介导性和肾小球疾病的小鼠模型的肾组织中鉴定了78个候选生物标记物，包括中性粒细胞明胶结合脂钙蛋白(Lcn2或NGAL)，这是急性肾损伤的尿液生物标记物。在目标1(资格鉴定阶段)，我们建议通过系统的Western blotting检测从78个候选CKD生物标记物中选择的多达20个最佳候选者的尿液排泄情况，并在少数选定的晚期CKD的金标准病例中包括NGAL，并通过系统的Western blotting进行对照。接下来，我们将为通过免疫印迹筛选的候选人建立并鉴定可用于商业用途的酶联免疫吸附试验。在AIM 2(验证阶段)，首选生物标志物 对进展性或非进展性慢性肾脏病患者的尿样进行酶联免疫吸附试验(EL ISA)检测，这些患者的尿样已经进行了特征良好的长期队列追踪，包括非裔美国人高血压肾病研究(AASK)、肾脏疾病饮食调整(MDRD)、糖尿病控制和并发症试验/糖尿病干预和并发症流行病学(DCCT/EDIC)，以及来自非慢性肾脏病患者的样本。统计分析将被应用于评估候选CKD生物标记物作为CKD进展的“预测因素”。在AIM 2中交付的高资质候选人(预期为2至4名)的肾内表达将通过哥伦比亚大学肾脏病理实验室的免疫组织化学进行评估。拟议的纽约CKD生物标记物计划的长期目标是与新兴的NIDDK CKD生物标记物联盟合作，发现和开发面向临床应用的有前途的“预测性”CKD生物标记物。 与公共卫生相关：目前还没有能够‘预测’单个CKD患者的风险和/或进展速度以充分指导预防性干预的生物标志物。因此，发现CKD进展的“预测性”生物标记物是一个重要的未得到满足的需求，也是拟议的纽约CKD生物标记物发现计划的目标。

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) affects more than one in ten Americans. CKD does progress to end stage kidney disease (ESKD) in some, but not all patients, despite 'optimal' management. Biomarkers that 'predict' the risk and/or rate of progression in individual CKD patients sufficiently to guide preventive interventions are currently not available. Thus, discovery of 'predictive' biomarkers for CKD progression is an important unmet need and the goal of the proposed New York CKD Biomarker Discovery Program. The Program will bring together an interdisciplinary team of nephrologists, laboratory medicine specialists, pathologists, and statisticians to achieve this goal, in collaboration and with guidance from the NIDDK CKD Biomarker Consortium. In preliminary discovery work by our groups, 78 candidate biomarkers, including neutrophil gelatinaseassociated lipocalin (LCN2 or NGAL), a urinary biomarker for acute kidney injury, were identified by genomewide transcriptional profiling and systems biology analysis in kidney tissue of a range of murine models with diabetic, immune-mediated, and glomemlar renal diseases. In Aim 1 (Qualification Phase) we propose to examine the urinary excretion profiles of up to 20 top candidates, selected from the 78 candidate CKD biomarkers, and including NGAL, in few selected 'gold standard' cases of advanced CKD, and controls by systematic western blotting. Next, we will establish and characterize commercially available ELISA for candidates that passed the western blot screen. In Aim 2 (Verification Phase), the top candidate biomarkers will be measured by ELISA in urine samples of patients with progressive or non-progressive CKD that have been followed in well-characterized, longterm cohorts, including the African-American Study of Kidney Disease in Hypertension (AASK), the Modification of Diet in Renal Disease (MDRD), and the Diabetes Control And Complications Trial/Epidemiology Of Diabetes Intervention And Complications (DCCT/EDIC), together with samples from patients without CKD. Statistical analysis will be applied to assess the candidate CKD biomarker as 'predictors' of progression of CKD. Intrarenal expression of highly credentialed candidates (anticipated 2 to 4) delivered in Aim 2, will be assessed by immunohistochemistry at the Renal Pathology Laboratory at Columbia University. The long-term goal of the proposed New York CKD Biomarker Program is to work collaboratively with the emerging NIDDK CKD Biomarker Consortium to discover and develop promising 'predictive' CKD biomarkers towards clinical application. PUBLIC HEALTH RELEVANCE: Biomarkers that 'predict' the risk and/or rate of progression in individual CKD patients sufficiently to guide preventive interventions are currently not available. Thus, discovery of 'predictive' biomarkers for CKD progression is an important unmet need and the goal of the proposed New York CKD Biomarker Discovery Program.