Mechanisms of Increased Ambulatory Blood Pressure in Intradialytic Hypertension

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DESCRIPTION (provided by applicant): This NIH Mentored Patient-Oriented Research Career Development Award proposal describes a 5 year training program with the long-term goal of the candidate developing into an independent academic investigator with a research focus in hypertension in patients with chronic and end-stage kidney disease. The candidate will build on a background in clinical research developed during a comprehensive research fellowship spent studying ambulatory blood pressure and endothelial cell dysfunction in patients with intradialytic hypertension. The career development objectives are to obtain skills in designing and conducting prospective clinical research studies, learn statistical models to analyze ambulatory blood pressure in hemodialysis patients, gain experience in measuring and interpreting cardiovascular physiologic parameters including extracellular water and vascular resistance utilizing bioimpedance analysis, and participate in scholarly activities to facilitate te transition into an independent investigator. These will be applied immediately to investigating how extracellular volume and mediators of vascular resistance affect ambulatory blood pressure in patients with intradialytic hypertension and hemodialysis controls. Aim 1 will use a case control design to compare differences in extracellular water in patients with intradialytic hypertension and hemodialysis controls. Aim 2 will determine how extracellular volume, vasoconstrictor mediators of vascular resistance, and vascular resistance itself modify ambulatory blood pressure and the ambulatory blood pressure slope in these two groups. In aim 3, the candidate will gain experience in designing and conducting a randomized trial by comparing the effects of carvedilol vs. prazosin on ambulatory blood pressure, vascular resistance, and mediators of vascular resistance in patients with intradialytic hypertension. The candidate will develop these skills with the support a primary mentor, 3 co-mentors (including one translational research cardiologist and one biostatistician), and a research advisory committee with extensive experience in multiple research disciplines. The candidate and his advisors are located at the University of Texas Southwestern Medical Center, a leading academic medical center with substantial physical and intellectual resources necessary for the career development of young investigators and the performance of cutting-edge research. The candidate will take advantage of numerous courses and research activities as a Clinical Research Scholar in the Department of Clinical Sciences that will promote the overall development of his career. Consistent with the candidate's long term career goals, the findings from this study can be broadened to studying hypertension in hemodialysis patients in general. Understanding the relationship between extracellular volume, vascular resistance, and ambulatory blood pressure will provide the opportunity to investigate how pharmacologic therapies affect each component and how this can improve cardiovascular outcomes in hemodialysis patients.