The Clinical Applications of the Difference in Estimated Glomerular Filtration Rate by Cystatin C vs. Creatinine (eGFRDiff)

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PROJECT SUMMARY This is an initial submission of a K23 application by Dr. Alison Potok, under the mentorship of Dr. Dena Rifkin, at the University of California San Diego (UCSD). This proposal will establish Dr. Potok as an independent investigator, and will evaluate the clinical applications of the difference in estimated glomerular filtration rate by cystatin C (eGFRCys) vs. creatinine (eGFRCr), for prognosis in the long-term and drug dosing in the short-term. Candidate: Dr. Potok’s training objectives and career goals through this proposal include: 1) to become an expert in geriatric nephrology and proficient in pharmacology and drug dosing in the elderly; 2) to develop skills in advanced statistical methods, epidemiology, manuscript and grant writing; 3) to learn the necessary skills to design and conduct a clinical study and develop a research team. She has assembled a multidisciplinary mentorship team comprised of a primary mentor, Dr. Rifkin, an established leader in geriatric nephrology, and the following additional co-mentors and collaborators: Dr. Ix, an expert in nephrology clinical trials; Dr. Moore, an authority in geriatric medicine and aging research, Dr. Gutierrez, an expert in kidney disease with extensive experience and insight to the REasons for Geographic and Racial Differences in Stroke (REGARDS) study utilized for Aim 2; Dr. Katz, the Director of Biostatistics at the University of Washington, who has worked extensively with Drs. Rifkin, Ix, and Potok; Dr. Hallan, Professor of Medicine with expertise in decision curve analysis and extensive experience in the Norwegian Nord-Trondelag Health Study (HUNT) utilized for Aim 1. Research: Most patients with chronic kidney disease (CKD) will not progress to end stage kidney disease (ESKD) due to the competing risk of death. Frailty may increase the risk of death vs. the risk of ESKD. The current kidney failure risk equation (KFRE) and mortality risk equation in kidney disease (MREK) do not account for frailty. In preliminary work, Dr. Potok has showed that the difference in eGFR by cystatin C vs. creatinine (eGFRDiff defined as eGFRCys – eGFRCr) is associated with risk of incident frailty and death. Moreover, Dr. Potok’s preliminary results show heterogeneity across the spectrum of eGFRDiff regarding which marker between cystatin C vs. creatinine is the best surrogate for true kidney function. The overall hypothesis is that eGFRDiff can be used to guide clinicians on whether to start preparing patients for renal replacement therapy and with medication dosing. In Aim 1, she will determine whether the inclusion of eGFRDiff, as a marker of frailty within the KFRE and MREK will improve assessment of the competing risk of ESKD vs. death in older adults. This Aim will be conducted in participants aged >65years with CKD of the HUNT study, an exclusively White European population. In Aim 2, she will explore the competing risk of ESKD vs. death in a biracial American population in REGARDS. In Aim 3, Dr. Potok will examine whether eGFRDiff could be used to determine those in whom eGFRCr should not be trusted for drug dosing, and eGFRCys should be used instead, with vancomycin as the prototype medication.