Biomarkers of Drug-induced Kidney Injury in HIV

项目摘要 这是一个K23申请的重新提交博士Vasantha Jotwani，一个肾病学家在大学 加州，旧金山弗朗西斯科。Jotwani博士正在建立自己作为一个年轻的研究人员在以病人为导向的临床 研究HIV感染者和未感染者的生物标志物和药物性肾损伤。她的目标是 到 成为利用新型肾脏生物标志物检测 肾毒性 该K23奖项将为Jotwani博士提供必要的支持，以完成以下工作 目标：1）成为以患者为导向的新型生物标志物和药物诱导的临床研究专家 肾损伤; 2） 获得先进的队列分析统计方法的专业知识; 3）精通 在生物标志物性能的评价中; 4）在前瞻性临床研究中实施生物标志物测量 研究;和5）发展独立的临床研究生涯。 为了实现这些目标，Jotwani博士 组建了一个多学科导师团队，由主要导师Michael Shlipak博士组成， 一 肾脏疾病诊断和鉴别生物标志物的著名专家，以及以下额外的 导师和顾问：Phyllis Tien博士，艾滋病毒感染长期后果的权威; Chirag博士 Parikh，急性肾损伤生物标志物的国际领导者; Eric Vittinghoff博士，应用统计学家， 流行病学和临床研究;以及Albert Liu博士，他在实施艾滋病毒 预防战略。替诺福韦酯富马酸盐（TDF），一种广泛用于治疗HIV的抗逆转录病毒药物 治疗和暴露前预防（PrEP）与急性肾功能衰竭的发生有关。 损伤和慢性肾病。然而，目前的临床措施缺乏敏感性和特异性， 检测TDF-associated肾毒性。Jotwani博士建议利用新的尿生物标志物， 和线粒体损伤，以确定和监测肾损伤的艾滋病毒感染者和未感染者谁是 接收TDF。在目标1中，她将在TDF开始后纵向测量新的尿液生物标志物， 描述妇女艾滋病毒感染者肾损害的发病和进展， 机构间艾滋病研究（WIHS）和多中心艾滋病队列研究（MACS）;然后，她将比较这些研究结果。 标记物与现有的肾小管健康的临床测量。在目标2中，她将评估 具有临床因素的生物标志物可以改善HIV感染者肾脏疾病风险的长期预测。 WIHS和MACS中受感染的TDF用户。最后，目标3将应用目标1中最有前途的生物标志物 和2调查PrEP对PrEP-T示范项目中肾损伤的影响， 对未感染HIV的变性人进行的临床研究，这些人将通过TDF/恩曲他滨启动PrEP， 旧金山弗朗西斯科公共卫生部。这项研究将为实施一项 基于生物标志物的算法用于检测和监测HIV感染者和未感染者的肾毒性 人，将在R 01补助金申请中提出对这个K奖结束。

PROJECT SUMMARY This is a resubmission of a K23 application for Dr. Vasantha Jotwani, a nephrologist at the University of California, San Francisco. Dr. Jotwani is establishing herself as a young investigator in patient-oriented clinical research of biomarkers and drug-induced kidney injury in HIV-infected and uninfected individuals. Her goal is to become a leading clinical investigator in the utilization of novel kidney biomarkers for the detection of nephrotoxicity. This K23 award will provide Dr. Jotwani with the support necessary to accomplish the following goals: 1) to become an expert at patient-oriented clinical research on novel biomarkers and drug-induced kidney injury; 2) to gain expertise in advanced statistical methods for cohort analyses; 3) to become proficient in the evaluation of biomarker performance; 4) to implement biomarker measures in a prospective clinical study; and 5) to develop an independent clinical research career. To achieve these goals, Dr. Jotwani has assembled a multidisciplinary mentorship team comprised of a primary mentor, Dr. Michael Shlipak, a renowned expert on biomarkers for kidney disease diagnosis and prognostication, and the following additional mentors and advisors: Dr. Phyllis Tien, an authority on the long-term consequences of HIV infection; Dr. Chirag Parikh, an international leader in biomarkers of acute kidney injury; Dr. Eric Vittinghoff, an applied statistician in epidemiologic and clinical research studies; and Dr. Albert Liu, who has expertise in the implementation of HIV prevention strategies. Tenofovir disoproxil fumarate (TDF), a widely prescribed antiretroviral medication for HIV treatment and pre-exposure prophylaxis (PrEP), has been associated with the development of acute kidney injury and chronic kidney disease. However, current clinical measures lack sensitivity and specificity for the detection of TDF-associated nephrotoxicity. Dr. Jotwani proposes to utilize novel urine biomarkers of tubular and mitochondrial damage to identify and monitor kidney injury in HIV-infected and uninfected persons who are receiving TDF. In Aim 1, she will measure the novel urine biomarkers longitudinally following TDF initiation to characterize the onset and progression of kidney damage in HIV-infected participants of the Women's Interagency HIV Study (WIHS) and the Multicenter AIDS Cohort Study (MACS); then, she will compare these markers with existing clinical measures of tubular health. In Aim 2, she will evaluate whether the integration of biomarkers with clinical factors can improve long-term prognostication of kidney disease risk among HIV- infected TDF users in WIHS and MACS. Finally, Aim 3 will apply the most promising biomarkers from Aims 1 and 2 to investigate the impact of PrEP on kidney injury in the PrEP-T Demonstration Project, a prospective clinical study of HIV-uninfected transgender persons who will initiate PrEP with TDF/emtricitabine through the San Francisco Department of Public Health. This research will lay the groundwork for the implementation of a biomarker-based algorithm for the detection and monitoring of nephrotoxicity in HIV-infected and uninfected persons, to be proposed in an R01 grant application towards the end of this K award.