Investigating strategies to reduce fluid-related complications among hemodialysis patients

PROJECT SUMMARY/ ABSTRACT The purpose of this K23 Mentored Career Development Award proposal is to provide Jennifer E. Flythe, MD, MPH with the protected time and resources to allow her to pursue the additional training needed to reach her long-term goal of becoming an independent patient-oriented investigator. Dr. Flythe is a board-certified nephrologist at the University of North Carolina (UNC) at Chapel Hill. Her research focuses on fluid management among maintenance hemodialysis (HD) patients. Dialysis patients experience exceedingly high rates of cardiovascular complications that contribute to both poor health-related quality of life and high healthcare costs. Fluid-related factors are critical contributors to these adverse outcomes. Greater fluid gain between treatments obligates faster fluid removal (ultrafiltration, UF) during dialysis. Rapid UF rates are associated with intradialytic hypotension, chronic volume expansion due to reactive fluid boluses and failure to achieve target weight, and other adverse clinical outcomes. Innovative and patient-acceptable approaches to reducing UF-related harm are needed to improve outcomes. The support of the K23 Award will allow Dr Flythe to achieve the following objectives: 1) investigate the comparative cardiovascular risks of diuretic cessation (versus continuation) among patients initiating HD; 2) investigate the comparative effectiveness of UF profiling vs. conventional dialysis in reducing cardiovascular- related HD complications; 3) gain new epidemiology and clinical trials research skills; and 4) acquire expertise in cardiovascular outcomes. To accomplish these objectives, Dr. Flythe will investigate the comparative risks of diuretic cessation (vs. continuation) after HD initiation in a cohort of incident HD patients with histories of pre- dialysis diuretic use (Aim 1). Second, she will perform a crossover study of 30 maintenance HD patients with histories of elevated UF rates to investigate whether UF profiling vs. conventional HD reduces hypotension and cardiac ischemia (Aim 2). Additionally, she will complete formal coursework in advanced epidemiology and clinical trials and participate in targeted workshops and seminar series to broaden her comparative effectiveness research skillset. She will leverage a unique dialysis cohort of merged large dialysis organization and Medicare administrative claims data as well as UNC-owned outpatient dialysis facilities to accomplish these aims. The proposed work has high potential to make a significant clinical impact, as completion of the project aims will not only advance the current understanding of strategies to reduce UF-related harm but also provide preliminary data on strategies to target in future, larger trials. Importantly, the proposed work is realistic and feasible within the award period and will allow Dr. Flythe to build research skills, generate preliminary data, create collaborative relationships, and compete for R01 funding. Dr. Flythe will be closely guided by her co-primary mentors, M. Alan Brookhart, PhD, Professor of Epidemiology at the UNC Gillings School of Global Public Health, and Ronald J. Falk, MD, Professor of Medicine at the UNC School of Medicine. Doctors Brookhart and Falk?s complementary strengths in epidemiology and biostatistics (Brookhart) and national nephrology leadership (Falk) will be augmented by Dr. Flythe?s scientific advisory committee: 1) Alan Hinderliter, MD, Associate Professor of Medicine at UNC, cardiologist and echocardiography and cardiovascular outcomes expert; 2) Steven M. Brunelli, MD, MSCE, Vice President and Medical Director of Health Economics and Outcomes Research at DaVita Clinical Research and expert in dialysis outcomes research and HD hemodynamics; and 3) Laura Dember, MD, Professor of Medicine at the University of Pennsylvania Perelman School of Medicine and dialysis clinical trial expert. Dr. Flythe will also draw upon the wealth of resources available in UNC?s research environment that include the UNC Schools of Medicine and Public Health, UNC Kidney Center, NC TraCS (home to UNC?s Clinical and Translational Science Award), Cecil G. Sheps Center for Health Services Research, and the UNC- owned Carolina dialysis units. Dr. Flythe?s proposed K23 research aims, mentorship team, career development plan, and collaborative research environment will catalyze her scientific productivity and provide her with the necessary skills and experience in epidemiology and clinical trials to become an independent investigator and future leader in dialysis research.