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

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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.