Determinants of chronic kidney disease in African-American live kidney donors

 简介(申请人提供)：Allan B.Massie，博士，约翰霍普金斯大学外科和流行病学助理教授。他寻求获得导师研究科学家发展奖，以获得肾病学、遗传流行病学和队列研究的培训和经验，并过渡到独立研究。在美国，每年有6000名健康的人接受活体供肾切除，以造福于患有终末期肾病(ESRD)的亲戚、朋友或陌生人。迄今为止对肾脏捐赠者进行的最大规模的队列研究--“活体肾脏捐赠是安全的”这一传统智慧的基础--涉及99%的高加索人。然而，与高加索人相比，非裔美国人(AA)捐赠者捐赠后ESRD和死亡的风险更高。不幸的是，在这一至关重要的人群中，风险预测能力很差，这阻碍了捐赠者的筛选和知情同意，剥夺了AA肾脏捐赠者在肾脏捐赠后关于其个人风险的准确信息，并限制了降低这一人群长期风险的机会。这项拟议的研究嵌套在一项正在进行的、由NIH资助的针对AA捐赠者的多中心队列研究中。该项目的目的是：1)确定AA活体肾脏捐赠者捐赠后APOL1基因的高危变异与CKD之间的联系；2)确定AA肾脏捐赠者长期EGFR下降的危险因素；3)比较AA捐赠者和AA非捐赠者捐献后的EGFR轨迹。AIM 1将在母研究中实施嵌套病例队列研究；AIM 2将利用通过母研究获得的捐赠者医疗记录；AIM 3将比较从父研究的医疗记录计算的EGFR与ARIC和CARDIA队列的数据。拟议的研究利用了大量AA捐赠者，但在研究设计上与母公司研究不同，新的生物学标本收集来了解遗传决定因素，以及新的纵向数据收集来研究EGFR的轨迹。这项研究提案概述了一项详细的建议，即在导师Dorry Segev博士和Josef Coresh博士的领导下，向Massie博士提供完成研究所需的培训，该建议借鉴了包括肾病学、遗传流行病学、研究设计和生物统计学专家在内的顾问小组的建议。赛格夫博士是一名移植外科医生，是约翰·霍普金斯大学移植部门的临床研究主任，也是这项拟议研究的母公司研究的PI。科雷什博士是流行病学家、约翰·霍普金斯大学心血管流行病学项目主任和慢性肾脏疾病联盟的负责人。马西博士希望最终能领导独立的研究项目，调查移植受者和活体器官捐赠者的长期结果。拟议目标的完成将改善AA活体肾脏捐赠者和潜在捐赠者的风险预测，帮助医疗决策，增强知情同意，并提供与居住在美国的14,000名AA活体肾脏捐赠者的长期健康结果相关的重要信息。

 DESCRIPTION (provided by applicant): Allan B. Massie, PhD, is an Assistant Professor of Surgery and Epidemiology at Johns Hopkins. He seeks a Mentored Research Scientist Development Award in order to gain training and experience in nephrology, genetic epidemiology, and the conduct of cohort studies and to transition to independent research. Every year, 6000 healthy individuals undergo live donor nephrectomy in the United States to benefit a relative, friend, or stranger with end-stage renal disease (ESRD). The largest cohort study of kidney donors to date - the foundation of the conventional wisdom that "live kidney donation is safe" - involved a > 99% Caucasian population. However, African-American (AA) donors are at elevated risk of post-donation ESRD and death compared to Caucasians. Unfortunately, risk prediction in this critically important population is poor, hampering donor screening and informed consent, depriving AA kidney donors of accurate information about their personal risk after kidney donation, and limiting opportunities to mitigate long-term risk in this population. The proposed research is nested within an ongoing, NIH-funded multicenter cohort study of AA donors. The aims of the project are: 1) to identify the association between high-risk variants of the APOL1 gene and CKD following donation in AA live kidney donors; 2) to identify risk factors for long-term eGFR decline in AA kidney donors; and 3) to compare post-donation eGFR trajectories in AA donors to those in AA nondonors. Aim 1 will implement a nested case-cohort study within the parent study; Aim 2 will draw on donor medical records obtained via the parent study; and Aim 3 will compare eGFR calculated from medical records of the parent study to data from the ARIC and CARDIA cohorts. The proposed research leverages a large cohort of AA donors, but is distinct from the parent study in its study design, novel collection of biologica specimens to understand genetic determinants, and novel collection of longitudinal data to study eGFR trajectories. The research proposal outlines a detailed proposal to give Dr. Massie the training required to complete the research, under the leadership of mentor Dr. Dorry Segev MD PhD and Dr. Josef Coresh MD PhD, drawing from the advice of an advisory team that includes experts in nephrology, genetic epidemiology, study design, and biostatistics. Dr. Segev is a transplant surgeon, Director of Clinical Research in the Division of Transplantation at Johns Hopkins, and PI of the parent study for the proposed research. Dr. Coresh is an epidemiologist, Director of the Cardiovascular Epidemiology Program at Johns Hopkins and leader of the Chronic Kidney Disease Consortium. Dr. Massie hopes eventually to lead independent research programs investigating long-term outcomes of transplant recipients and live organ donors. Completion of the proposed aims will improve risk prediction for AA live kidney donors and prospective donors, aid in medical decision-making, enhance informed consent, and provide vital information relevant to the long-term health outcomes of the 14,000 AA live kidney donors living in the United States.