Currently, over 280,000 patients in the U.S. undergo chronic HD for the treatment of end-stage renal disease (ESRD). Technical advances have improved the procedure, yet dialysis- related blood pressure alterations remains a common complication and may contribute to increased morbidity and mortality in HD. Intradialytic hypotension (IH) occurs in up to 48% of HD treatments, contributes to inadequate dialysis and reduces patient comfort and compliance. IH results from a complex interaction between the patient's volume status and the cardiovascular and hemodynamic responses to fluid and solute removal. Several mediators have been incriminated for their likely contribution to IH including inflammatory cytokines [interleukin 1(IL-1) and tumor necrosis factor alpha (TNFa)], complement, and recently NO. NO, a potent vasodilator formed by nitric oxide synthase (NOS), is released from the vascular endothelium. NO levels are elevated in ESRD, and recent studies have reported a strong association between NO and IH with increased NO being associated with more IH. Although NO may have a significant effect on the hemodynamic response to HD, the mechanisms contributing to elevated NO levels, including the effect of HD have yet to be clearly defined. The applicant proposes to test the hypothesis that NO is an important mediator of the hemodynamic response to HD, and that reducing NO would allow for prevention and treatment of dialysis-related events. The project will provide an evaluation of the prevalence of elevated NO in hemodialysis patients, as well as explore the relationship of these levels to hemodynamic profiles including an assessment of blood volume changes and distribution of fluid in various compartments during dialysis. Additionally, mechanisms that may elevate NO levels will be explored through systematic study of the effect of HD and dialysis-related factors on NO levels. Finally, the effect of reducing NO levels, via NO scavengers or NOS inhibitors, on blood pressure changes will be studied. The proposed work will add to the knowledge and understanding of the pathophysiology of blood pressure changes in the HD patient population, and permit development of better strategies to prevent and treat the occurrence of IH in the HD population.
