Biomarkers of Drug-induced Kidney Injury in HIV

HIV 药物性肾损伤的生物标志物

基本信息

批准号：
9270400
负责人：
Vasantha Kolavennu Jotwani
金额：
$ 19.98万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9270400
关键词：
AIDS prevention Acquired Immunodeficiency Syndrome Acute Renal Failure with Renal Papillary Necrosis Age Algorithms Anti-Retroviral Agents Applications Grants Biological Markers California Cardiolipins Chronic Chronic Kidney Failure Clinical Clinical Investigator Clinical Research Cohort Analysis Cohort Studies Collagen Type III Consequences of HIV Creatinine Cytochromes Detection Development Diagnosis Diagnostic tests Enrollment Epidemiologic Studies Fanconi Syndrome Fibrosis Fumarates Functional disorder Glomerular Filtration Rate Goals HIV HIV Infections Health Individual Injury Interleukin-18 International K-Series Research Career Programs Kidney Kidney Diseases Lead Measures Medicine Mentored Patient-Oriented Research Career Development Award Mentors Mentorship Metabolic Mitochondria Modeling Monitor Multicenter Studies N-terminal Nephrotoxic Participant Peptides Performance Persons Pharmaceutical Preparations Population Prevention Prevention strategy Prophylactic treatment Proteinuria Public Health Regimen Renal function Reporting Research Research Personnel Reverse Transcriptase Inhibitors Risk Safety San Francisco Sensitivity and Specificity Serum Staging Statistical Methods Tenofovir Time Toxic effect Toxin Tubular formation Universities Urine Woman alpha-1-microglobulin antiretroviral therapy authority base biomarker evaluation career clinical practice disease diagnosis disorder risk emtricitabine improved men multidisciplinary nephrotoxicity novel novel diagnostics novel marker novel therapeutics nucleoside analog patient oriented predictive modeling prognostic prospective rat KIM-1 protein research study skills specific biomarkers transgender

项目摘要

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.

项目概要这是为瓦桑塔·乔特瓦尼 (Vasantha Jotwani) 博士重新提交的 K23 申请，他是阿布扎比大学的肾病专家。加利福尼亚州、旧金山。 Jotwani 博士正在将自己打造成以患者为导向的临床领域的年轻研究者 HIV感染者和未感染者的生物标志物和药物性肾损伤的研究。她的目标是到成为利用新型肾脏生物标志物检测的领先临床研究者肾毒性。该 K23 奖项将为 Jotwani 博士提供完成以下目标所需的支持目标：1）成为以患者为导向的新型生物标志物和药物诱导临床研究的专家肾损伤； 2）获得用于队列分析的先进统计方法的专业知识； 3）变得熟练生物标志物性能评估； 4）在前瞻性临床中实施生物标志物测量学习; 5）发展独立的临床研究事业。为了实现这些目标，Jotwani 博士组建了一个多学科指导团队，由主要导师 Michael Shlipak 博士组成，一个肾脏疾病诊断和预测生物标志物的著名专家，以及以下附加内容导师和顾问： Phyllis Tien 博士，艾滋病毒感染长期后果方面的权威；奇拉格博士 Parikh，急性肾损伤生物标志物领域的国际领导者； Eric Vittinghoff 博士，应用统计学家流行病学和临床研究；以及在艾滋病毒实施方面拥有专业知识的Albert Liu博士预防策略。富马酸替诺福韦二吡呋酯 (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) 与急性肾病的发生有关损伤和慢性肾脏疾病。然而，目前的临床测量缺乏敏感性和特异性。检测 TDF 相关的肾毒性。 Jotwani 博士建议利用肾小管的新型尿液生物标志物和线粒体损伤，以识别和监测 HIV 感染者和未感染者的肾损伤接收TDF。在目标 1 中，她将在 TDF 启动后纵向测量新型尿液生物标志物描述女性艾滋病毒感染者肾脏损害的发生和进展机构间艾滋病毒研究（WIHS）和多中心艾滋病队列研究（MACS）；然后，她会比较这些具有现有的肾小管健康临床测量指标。在目标 2 中，她将评估是否整合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，Aim 3 将应用 Aims 1 中最有前途的生物标志物 2 在 PrEP-T 示范项目中调查 PrEP 对肾损伤的影响，这是一项前瞻性研究对未感染 HIV 的跨性别者进行的临床研究，他们将通过 TDF/恩曲他滨启动 PrEP 旧金山公共卫生部。这项研究将为实施基于生物标记的算法，用于检测和监测 HIV 感染者和未感染者的肾毒性人，将在本 K 奖结束时在 R01 拨款申请中提出。