Tubular secretion, kidney disease progression, and drug dosing in older adults

项目总结 这是Pranav Garimella医学博士第二次提交K23申请，她是 加州大学圣地亚哥分校(UCSD)。该提案将使加里梅拉博士成为一名独立的 肾小管分泌物的研究者。该项目将严格评估肾小管分泌物的标志物 与肾脏组织学、肾功能下降和药物清除有关。 应聘者：这份申请的目的是为了支持加里梅拉博士的职业发展 独立研究人员和国际领先的肾小管分泌物。加里梅拉博士的培训目标 通过K23；1)学习药代动力学(PK)研究的设计和实施；2)成为 精通新的生物标记物方法学和转化为以患者为中心的研究；3)获得专业知识 用于生物标记物分析的高级统计方法；)评估生物标记物与 组织学和临床结果；以及5)开发独立的研究计划。他已经组建了一支 多学科导师团队由一位主要导师约阿希姆九世博士组成，他是一位著名的 肾脏疾病诊断和预测的肾小管方面，以及以下其他辅导者和 顾问：老年非肾小球肾功能权威Mark Sarnak博士，Edmund博士 卡帕雷利是PK研究和建模领域的领先者；弗洛林·瓦伊达博士是应用统计学家，他指导 UCSD CREST生物统计学计划，在生物标记物、队列研究和药物计量学方面拥有专业知识。 研究：肾小管间质纤维化(TIF)在活检中很常见，预示着肾功能衰竭，通常出现在 尽管肌酸值看似正常，但年龄较大的人。TIF可能导致重要肾小管的丢失 功能，如分泌，这是消除一些药物的主要方式。加里梅拉医生的 总体假设是，测量新的内源性分泌物标记物可能会改善我们的 了解TIF目前仅通过活检进行评估，提高我们识别TIF风险的能力 肾脏疾病的进展，并提高我们的能力，以更适当的剂量分泌药物。在AIM 1，他将在200个TIF中确定与TIF密切相关的肾小管分泌物的内源性标记 接受过肾活组织检查的患者。在目标2中，他将进行病例对照研究，以 确定内源性分泌标志物是否能预测社区老年人肾功能的丧失 成年人。目标3将提供一项重要的概念验证研究，与他计划的训练广泛吻合 在PK/PD和临床药理学中，加里梅拉博士将进行PK研究，以确定 在AIMS 1和AIMS 2中发现的相同的分泌标志物也可以预测青霉素的清除；青霉素是一种高度分泌的药物。 这项研究将为临床药理学的进一步研究(将在R01中提出)奠定基础 在K23末尾)具有狭窄治疗指数的分泌药物(例如。顺铂、利伐沙班)联合 总体目标是改善药物剂量，减少老年人的发病率和死亡率。

PROJECT SUMMARY This is a second submission of a K23 application by Pranav Garimella, MD, MPH a nephrologist at the University of California San Diego (UCSD). The proposal will establish Dr. Garimella as an independent investigator in kidney tubule secretion. This project will rigorously evaluate how markers of tubular secretion are associated with kidney histology, kidney function decline and drug clearance. Candidate: The objective of this application is to support Dr. Garimella's career development into an independent investigator and international leader in tubular secretion. Dr. Garimella's training objectives through the K23 are; 1) to learn the design and implementation of pharmacokinetic (PK) studies; 2) to become proficient at novel biomarkers methodology and translation to patient oriented research; 3) to gain expertise in advanced statistical methods for biomarker analyses;) to evaluate how biomarkers are associated with histology and clinical outcomes; and 5) to develop an independent research program. He has assembled a multidisciplinary mentorship team comprised of a primary mentor, Dr. Joachim Ix, a renowned expert on tubular aspects of kidney disease diagnosis and prognostication, and the following additional co-mentors and advisors: Dr. Mark Sarnak, an authority on the non-glomerular kidney function in the elderly, Dr. Edmund Capparelli a leader in PK studies and modelling; and Dr. Florin Vaida, an applied statistician who directs the UCSD CREST biostatistics program and has expertise in biomarkers, cohort studies and pharmacometrics. Research: Tubulointerstitial fibrosis (TIF) is common on biopsy, predicts kidney failure and is often present in older adults despite seemingly normal creatinine values. TIF may result in the loss of important tubular functions such as secretion which is the predominant mode of elimination of a number of drugs. Dr. Garimella's overall hypothesis is that measurement of novel endogenous markers of secretion may improve our understanding of TIF which is currently only assessed on biopsy, improve our ability to identify those at risk of kidney disease progression, and improve our ability to more appropriately dose secreted medications. In Aim 1, he will identify endogenous markers of tubular secretion which are strongly associated TIF among 200 patients who have undergone native kidney biopsies. In Aim 2, he will perform a case control study to determine whether endogenous secretion markers predict loss of kidney function in community-dwelling older adults. Aim 3 will provide an important proof-of-concept study, dovetailing extensively with his planned training in PK/PD and clinical pharmacology, in which Dr. Garimella will perform a PK study to determine whether the same secretion markers identified in Aims 1 and 2 also predict clearance of penicillin; a highly secreted drug. This research will lay the groundwork for the further studies in clinical pharmacology (to be proposed in an R01 at the end of the K23) of secreted drugs with a narrow therapeutic index (ex. Cisplatin, Rivaroxaban) with the overall aim of improving drug dosing, and reducing morbidity and mortality of older persons.