Vascular Stiffness and Endothelial Cell Function in Intradialytic Hypertension

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DESCRIPTION (provided by applicant): Patients with end stage renal disease (ESRD) carry a higher risk for cardiovascular morbidity and mortality than the general population. Hemodialysis (HD) patients whose blood pressure increases during a HD session represent a subpopulation with even greater risk for adverse outcomes. When defined as an increase in systolic blood pressure greater than 10 mmHg from pre to post HD treatment, intradialytic hypertension (IH) is an additional independent risk factor for hospitalization and cardiovascular and all cause mortality in HD patients. Endothelial cell dysfunction (ECD) and increased arterial stiffness both are prevalent in HD patients and may be involved in the pathophysiology of IH. The specific aims of the project are to: 1) establish an association with arterial stiffness and IH; 2) demonstrate an association with ECD and IH using more than one variable to asses for ECD; 3) investigate the effects of carvedilol in abolishing IH. For specific aim 1: Pulse wave velocity (PWV) will be obtained from 25 subjects with IH and 25 control HD subjects without IH. Ambulatory blood pressure (ABP) will also be measured in these subjects as a possible confounding variable for PWV. For specific aim 2: Pre and post HD levels of endothelin-1 and asymmetric dimethyl arginine will be measured in addition to mid week non-HD day flow mediated dilation and endothelium independent vasodilation. For specific aim 3: Subjects with IH will be started on carvedilol after all baseline measurements are taken. After 8 weeks of carvedilol therapy, including 4 weeks after titration up to 50 mg twice daily, all measurements from Aims 1 and 2 will be repeated. Establishing an association of IH with ECD and arterial stiffness can prompt efforts to explore the possible causal relationships. Additionally, results from the effects of carvedilol on IH may propagate randomized, controlled trials to determine if improvements in endpoints such as CV or all cause mortality are attainable. The relevance of this information could eventually be extended to more general populations such as pre-HD chronic kidney disease patients or patients without kidney disease, but with elevated arterial stiffness or ECD. The applicant will be supervised by a sponsor and co-sponsor during the program. The applicant will be involved in every step of the project from recruitment to manuscript writing. In addition to gaining clinical research skills, the applicant will be learning the techniques of measuring ABP, PWV, and FMD. Additionally, the applicant will be enrolled in courses in pursuit of a Masters Degree in Clinical Sciences. All activities are aimed towards the applicant gaining knowledge and experience in clinical research to pursue a more independent level of involvement in a research career. PUBLIC HEALTH RELEVANCE: End stage renal disease patients on hemodialysis are at higher risk for cardiovascular disease and death than the general population. Among hemodialysis patients, those whose blood pressure increases during hemodialysis carry a higher risk for poor outcomes. The present study investigates if poor blood vessel health is related to blood pressure increases during dialysis and whether treatment with a specific blood pressure lowering medication helps prevent these blood pressure elevations.