Over the last decade, the mortality rate for U.S. dialysis patients has increased. In addition diabetic dialysis patients have more severe co- existing illnesses, and an accelerated mortality. The high morbidity and mortality of both hemodialysis (HD) and peritoneal dialysis (PD) cannot be fully explained by adequacy of dialysis (KT/V) and protein catabolic rate. Abnormalities in plasma cytokine levels and stimulated monocyte responses have been associated with both forms of dialysis. Based on our preliminary data, we hypothesize that dialysis patients experience chronic stimulation of monocytes, resulting in increased activation to produce cytokines. Sources of this stimulation include low-grade endotoxin exposure, dialyzer induced activation of complement products, and possibly the increased production of advanced glycosylation end products (in diabetics and patients on PD). These factors result in the development of a state of further immune suppression through depressed Il-1 and TNF production and increased Il-1 antagonists and Il-6, analogous to models of chronic endotoxin exposure. We postulate that tolerance contributes to the immune depression associated with dialysis, with resultant increased morbidity and mortality. Abnormalities in the expression of Il-6 and other cytokines are likely to be complementary predictors with KT/V or serum albumin of dialysis outcome. Patterns of cytokine response which are similar to those of normal non-uremic individuals are anticipated in patients who are doing well on dialysis. We propose to confirm and further define defects in lymphocyte and monocyte/macrophage function in peripheral blood mononuclear cells (PBMC) from 150 diabetic and nondiabetic dialysis patients compared to 20 normal volunteers. In this group we will correlate selected immunologic parameters with prospective indicators of dialysis outcome. Our in vivo results will guide the development of rigorous in vitro models which focus on specific mechanisms of cytokine effects in altering immunity and homeostasis on dialysis. We propose to determine whether exogenous Il-1 can reconstitute the defective T cell Il-2 production seen in renal failure patients. We will also study in vitro aspects of the role of the dialysis system (HD vs. PD) and membrane biocompatibility which result in defective immunologic function and vascular events in dialysis patients. In our model of endothelial cell function we will assess the toxic and metabolic effects of clinically and experimentally derived serum and supernatants from a variety of dynamic and static cell- membrane incubations. Finally we will define in a large (N approximately 400) prospective study specific determinants of well being on dialysis. Circulating Il-6 and other factors identified as important in our initial cohort and in vitro experiments will be prospectively assessed. We will determine if these parameters correlate with a variety of measures of dialysis outcome maintained in our comprehensive dialysis unit-based computer system.
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