The New York CKD Biomarker Discovery Program

描述（由申请人提供）： 慢性肾脏疾病（CKD）影响超过十分之一的美国人。尽管进行了“最佳”治疗，但在一些但不是所有患者中，CKD确实进展为终末期肾病（ESKD）。目前还没有生物标志物能够“预测”个体CKD患者的风险和/或进展速度，足以指导预防性干预。因此，发现CKD进展的“预测性”生物标志物是一个重要的未满足的需求，也是所提出的纽约CKD生物标志物发现计划的目标。该计划将汇集一个由肾脏病学家，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生物标志物联盟的合作和指导下实现这一目标。在我们小组的初步发现工作中，通过全基因组转录谱分析和系统生物学分析，在一系列糖尿病、免疫介导和肾小球肾病小鼠模型的肾组织中鉴定了78种候选生物标志物，包括中性粒细胞明胶酶相关脂质运载蛋白（LCN 2或NGAL），这是一种急性肾损伤的尿液生物标志物。在目标1（鉴定阶段）中，我们建议通过系统性蛋白质印迹法检查从78种候选CKD生物标志物中选出的多达20种最佳候选物（包括NGAL）的尿排泄谱，以及少数选定的晚期CKD“金标准”病例和对照。接下来，我们将为通过蛋白质印迹筛选的候选物建立并表征市售ELISA。在目标2（验证阶段）中， 将通过ELISA在进行性或非进行性CKD患者的尿液样本中进行测量，这些患者已在充分表征的长期队列中进行随访，包括非裔美国人高血压肾病研究（AASK）、肾病饮食改良（MDRD）和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），以及来自无CKD患者的样品。将应用统计分析评估候选CKD生物标志物作为CKD进展的“预测因子”。将在哥伦比亚大学肾脏病理学实验室通过免疫组织化学评估目标2中交付的高度合格候选物（预期2至4）的肾内表达。拟议的纽约CKD生物标志物项目的长期目标是与新兴的NIDDK CKD生物标志物联盟合作，发现和开发有前景的“预测性”CKD生物标志物，以供临床应用。 公共卫生相关性：目前还没有生物标志物能够“预测”个体CKD患者的风险和/或进展速度，足以指导预防性干预。因此，发现CKD进展的“预测性”生物标志物是一个重要的未满足的需求，也是所提出的纽约CKD生物标志物发现计划的目标。

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.