Despite significant advances in technology, the mortality among patients with end-stage renal disease and acute renal failure on dialysis is 26% and 42-75%, respectively. Although a) inadequate dose of dialysis, b) malnutrition, c) bioincompatibility of the dialysis membrane and d) reuse of dialyzers have been associated with the high mortality, the mechanisms behind these associations have not been completely elucidated. The studies in this proposal will prospectively evaluate: 1) The long-term effects of dialyzer flux and dose of dialysis on cytokine production by peripheral blood mononuclear cells (PBMC) and polymorphonuclear leukocytes (PMN) function, 2)PBMC and PMN functions as predictors of morbidity and mortality in patients on chronic hemodialysis, 3) The effect of dialyzer biocompatibility on PBMC and PMN function and clinical outcomes in patients with acute renal failure (ARF), 4) PBMC and PMN function as predictors of clinical outcomes in patients with ARF, 5) The impact of severity of ARF on plasma levels of inflammatory mediators, cytokine production by mononuclear cells and PMN function, 6) Cytokine production by mononuclear cells and tests of PMN function at the onset of acute renal failure as predictors of morbidity and mortality in patients on HD, 7) The effect of pre-existing chronic renal failure on plasma levels of inflammatory mediators, cytokine production by mononuclear cells and PMN function in patients with ARF. These studies will utilize the resources already committed by the National Institutes of Health to the HEMO Study at institutions in Boston. The PBMC and PMN function that will be studied include, 1) Gene expression and production of pro-inflammatory cytokines (interleukin-1a, interleukin-1b, tumor necrosis factor a) and specific inhibitory proteins (interleukin-1 receptor antagonist, soluble TNF receptors) by PBMC. 2) PMN degranulation, oxidative burst and phagocytosis. 3) Proportion of cells undergoing apoptosis and expression of apoptotic and survival genes. 4) Plasma levels of cytokines and acute phase reactants. The results of these studies are expected to shed light on the cause for the high morbidity and mortality in ESRD and ARF, and mechanisms behind the interventions to improve clinical outcomes.
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