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

老年人的肾小管分泌、肾脏疾病进展和药物剂量

• 批准号: 9926239
• 负责人: Pranav Garimella
• 金额: $ 20.07万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926239
• 关键词: Acids; Adverse drug effect; Adverse effects; Age; Albumins; Biological Markers; Biometry; Biopsy; Biopsy Specimen; Blood; California; Case-Control Studies; Chronic Kidney Failure; Cisplatin; Clinical; Clinical Pharmacology; Cohort Studies; Comb animal structure; Communities; Creatinine; Creatinine clearance measurement; Data; Development; Diagnosis; Disease Progression; Dose; Drug Interactions; Drug Kinetics; Elderly; Equation; Fibrosis; Future; Glomerular Filtration Rate; Goals; Health; Hippuric acid; Histology; Homeostasis; Hormones; Impairment; Individual; Injury; International; Kidney; Kidney Diseases; Kidney Failure; Learning; Measurement; Measures; Mentors; Mentorship; Metabolism; Methodology; Minerals; Morbidity - disease rate; Non-Invasive Cancer Detection; Older Population; Outcome; Pathologic; Patients; Penicillins; Persons; Pharmaceutical Preparations; Pilot Projects; Polypharmacy; Production; Recommendation; Renal clearance function; Renal function; Renal tubule structure; Research; Research Design; Research Personnel; Risk; Risk Estimate; Risk Factors; Serum; Severities; Staging; Statistical Methods; Study models; Therapeutic; Therapeutic Index; Toxic effect; Toxin; Training; Translations; Tubular formation; Universities; Urine; Work; appropriate dose; authority; base; career development; cohort; design; disease diagnosis; drug clearance; experience; glomerular function; high risk; hormone resistance; improved; kidney biopsy; kidney dysfunction; mortality; mortality risk; multidisciplinary; novel; novel marker; patient oriented research; pharmacometrics; predictive marker; preservation; prevent; prognostic; programs; skills; tool

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.

项目摘要 这是Pranav Garimella，医学博士，公共卫生硕士第二次提交K23申请，他是一名肾脏病学家， 加州圣地亚哥大学（UCSD）。该提案将使加里梅拉博士成为一名独立的 肾小管分泌研究者。该项目将严格评估肾小管分泌的标志物 与肾脏组织学、肾功能下降和药物清除相关。 候选人：本申请的目的是支持加里梅拉博士的职业发展成为一个 独立研究者和肾小管分泌的国际领导者。Garimella博士的培训目标 通过K23是; 1）学习药代动力学（PK）研究的设计和实施; 2）成为 精通新的生物标志物方法学和翻译以患者为导向的研究; 3）获得专业知识， 生物标志物分析的先进统计方法;）评估生物标志物如何与 组织学和临床结果;和5）开发一个独立的研究计划。他已经召集了一个 多学科指导小组由一位主要导师Joachim IX博士组成，他是一位著名的 肾脏疾病诊断和诊断的管状方面，以及以下额外的共同导师和 顾问：Mark Sarnak博士，老年人非肾小球肾功能的权威，Edmund博士 Capparelli是PK研究和建模的领导者; Florin Vaida博士是一位应用统计学家， UCSD CREST生物统计学课程，并在生物标志物，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，可预测肾衰竭，通常存在于 老年人，尽管肌酐值看似正常。TIF可能导致重要的肾小管功能丧失， 功能，如分泌，这是消除许多药物的主要方式。加里梅拉医生的 总的假设是，新的内源性分泌标志物的测量可以改善我们的研究。 了解TIF，目前仅通过活检评估，提高我们识别那些有风险的人的能力， 肾脏疾病进展，并提高我们更适当地服用分泌药物的能力。在Aim中 1，他将在200例TIF患者中鉴定与TIF密切相关的肾小管分泌的内源性标志物。 接受过自体肾活检的患者。在目标2中，他将进行病例对照研究， 确定内源性分泌标志物是否可预测社区居住老年人的肾功能丧失 成年人了目标3将提供一个重要的概念验证研究，与他计划的培训广泛地相一致 在PK/PD和临床药理学中，Garimella博士将进行PK研究，以确定 在目的1和2中鉴定的相同分泌标志物也预测青霉素（一种高度分泌的药物）的清除。 本研究将为临床药理学的进一步研究（将在R 01中提出）奠定基础 在K23的末端）具有窄治疗指数的分泌药物（例如，顺铂、利伐沙班）与 总体目标是改善药物剂量，降低老年人的发病率和死亡率。