Interleukin-1 and tumor necrosis factor and their naturally occurring antagonists during hemodialysis

Cytokines are polypeptides which possess various biological properties affecting host defense function and response to disease. Two cytokines, interleukin-1 (IL-1) and tumor necrosis factor (TNF) induce fever, hypotension and inflammation when injected into animals or human subjects. In humans injected with either IL-1 or TNF, sleepiness, generalized myalgias and headache are commonly reported. Therefore, the production of IL-1 and TNF as a consequence of hemodialysis was hypothesized to explain, in part, the signs and symptoms of the dialysis patient. Laboratory studies confirmed that the activation of complement and the passage of microbial products from the dialysate into the blood compartment induces the synthesis of IL-1 and TNF. Although elevated production of IL-1 and TNF in the mononuclear cells and in the circulation of patients during and after hemodialysis have been reported, these levels have not been a consistent finding and are low compared to the amount of dialysis related symptoms. Recent studies, however, demonstrate that IL-1 and TNF have naturally occurring antagonists which specifically block the biological activities of these two cytokines. The IL-1 receptor antagonist blocks IL-1 binding to cells but has no IL-1 activity of itself. Soluble TNF receptors prevent TNF from binding to its cellular receptors and hence serve as anti-TNF mechanisms. These inhibitors are currently in clinical trials for sepsis where efficacy has been demonstrated; however, the IL-1 receptor antagonist (IL-1Ra) and soluble TNF receptors (sTNFR) are likely candidates for use in dialysis patients with symptomatic hypotension. Although levels of IL-1Ra and sTNFR are elevated in patients on HD, these levels reflect the host response to inflammation. It is unclear whether acute or chronic administration of IL-1Ra or sTNFR will be beneficial in treating some of the acute or chronic changes seen in dialysis patients.