Hemodialysis, peritoneal dialysis or renal transplantation are lifesaving therapies for patients with end-stage renal disease (ESRD). Despite many technical advances, these patients still confront substantial short and long-term dialysis-related morbidity which interfere with their ability to function productively in society. inflammatory cytokines (IL-1beta and TNFalpha) stimulated by the dialysis procedure have been postulated to mediate a portion of these complications. Recently, naturally occurring specific inhibitors of IL-1beta and TNFalpha have been identified. We hypothesize that the balance of pro- and anti-inflammatory cytokines is an important determinant of morbidity in this patient population. The initial experiments will address the effect of artificial membranes on the transcription and translation of both IL-1beta and TNFalpha, and their respective inhibitors IL-1 receptor antagonist (IL-lra) and TNFalpha binding protein (TNF BP). Subsequently, the onset, duration, and magnitude of inhibitory cytokine production will be assessed using an in vitro model of dialysis. The impact of different membranes and reuse of membranes will be examined. we will also develop a new model of in vitro dialysis which will evaluate the role of the endothelium in cytokine production, by incorporating an endothelial cell-lined cartridge into the dialysis circuit. Further, clinical studies will attempt to correlate the balance of pro- and anti-inflammatory cytokines with dialysis-related symptoms and adequacy of dialysis. These studies will form the basis of trials of IL-lra infusion in patients. Phase 1 will determine the safety of IL-lra infusion in this patient population. Phase 2 will assess the effect of IL-lra on cytokine profiles and other clinical effects. Phase 3 will evaluate the efficacy of IL-lra in reducing the frequency and severity of dialysis-induced hypotension. In summary, the role of inhibitory cytokines in dialysis related symptoms and their potential therapeutic role will be the focus of these studies.
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