PMN ACTIVATION AND OXIDATIVE STRESS IN HEMODIALYSIS

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Cardiovascular disease and bacterial infections are the leading causes of death in patients with end-stage renal disease (ESRD) on hemodialysis (HD). Besides the high prevalence of well established risk factors, these patients are in a state of heightened oxidative stress, characterized by excessive free radical production and/or low antioxidant defenses. The principal hypothesis of this proposal is that exposure of polymorphonuclear cells to the extracorporeal circuit, triggers production of reactive oxygen species (ROS) leading to leukocyte dysfunction, as well as oxidative endothelial cell injury. Furthermore, the increasingly routine use of parenteral iron, a potent promoter of toxic free radical generation, in these patients may enhance oxidative stress-induced cell injury and dysfunction. This proposal will address these concerns using in vitro models to evaluate the impact of dialyzer biocompatibility and various iron preparations on indices of oxidative stress, and cell injury. These models will involve PMN (healthy vs uremic) activation by exposure to dialysis membrane fragments of varying composition t iron or ROS inhibitors, as well as during circulation through an in vitro dialysis circuit. In addition, a coculture model will be utilized to assess the effects of dialyzer membrane-activated PMN on reporter monolayers of cultured endothelial cells (t excess iron) grown under static and flow conditions. The results of this proposal are expected to enhance our understanding of the pathogenesis of ROS-induced cell injury and dysfunction and lay the foundation for the development of novel strategies to combat atherogenesis, vascular access and immune dysfunction in this vulnerable population.