Biomarkers of Drug-induced Kidney Injury in HIV

项目总结 这是哈佛大学肾病学家Vasantha Jotwani博士的K23申请的重新提交 加利福尼亚州，旧金山。乔特瓦尼博士在以病人为中心的临床领域确立了自己的年轻研究员的地位。 HIV感染者和非感染者生物标志物与药物肾损害的研究。她的目标是 至 成为利用新的肾脏生物标记物检测肾脏疾病的领先临床研究人员 肾毒性。 这项K23奖项将为Jotwani博士提供必要的支持，以实现以下目标 目标：1)成为以患者为中心的新型生物标志物和药物诱导临床研究的专家 肾损伤；2) 掌握用于队列分析的高级统计方法的专业知识；3)熟练掌握 在生物标记物性能评估中；4)在前瞻性临床中实施生物标记物措施 研究；5)发展独立的临床研究事业。 为了实现这些目标，约特瓦尼博士 组建了一个由主要导师Michael Shlipak博士组成的多学科导师团队， 一个 肾脏疾病诊断和预测生物标记物方面的知名专家，以及以下其他 导师和顾问：菲利斯·田博士，艾滋病毒感染长期后果方面的权威；希拉克博士 Parikh，急性肾损伤生物标志物的国际领先者；Eric Vittinghoff博士，应用统计学家 流行病学和临床研究；以及在实施艾滋病毒方面具有专业知识的艾伯特·刘博士 预防策略。富马酸替诺福韦(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)与急性肾脏的发展有关 损伤和慢性肾脏疾病。然而，目前的临床方法缺乏敏感性和特异性。 TDF相关肾毒性的检测。Jotwani博士建议利用新的尿小管生物标志物 和线粒体损伤，以识别和监测艾滋病毒感染者和未感染者的肾脏损伤 正在接收TDF。在目标1中，她将在TDF启动后纵向测量新的尿液生物标记物 女性HIV感染者肾脏损害的发生和发展特征 机构间艾滋病毒研究(WIHS)和多中心艾滋病队列研究(MACS)；然后，她将比较这些 与现有的肾小管健康临床指标相一致。在目标2中，她将评估是否整合了 具有临床因素的生物标志物可以改善对HIV-1患者肾脏疾病风险的长期预测 WIHS和Mac中受感染的TDF用户。最后，AIM 3将应用AIMS 1中最有前途的生物标志物 2在PrEP-T示范项目中，研究PrEP对肾脏损伤的影响 未感染HIV的变性人将通过TDF/恩曲他滨启动PrEP的临床研究 旧金山公共卫生局。这项研究将为实施 基于生物标记物的HIV感染和未感染患者肾毒性检测与监测 个人，将在本K奖结束时的R01拨款申请中提出。

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.