Cytokine Production in Patients on Dialysis

Abstract

The close similarities between the biological effects of proinflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF), and the clinical symptoms observed in patients on HD have promoted the concept that cytokine production induced during dialysis could have a role in dialysis-related symptoms. However, over the last decade the discovery of cytokine-specific inhibitory proteins such as IL-1 receptor antagonist (IL-1Ra) and soluble TNF receptors (sTNFR), has raised new questions concerning the role of cytokines in dialysis-related morbidity. In HD patients, the molar ratios of plasma IL-1Ra:IL-1 beta range from 3:1 to 4:1 and the molar ratios of plasma sTNFR:TNF range from 13:1 to 38:1. Likewise, in patients on chronic HD with cuprophan membranes, peripheral blood mononuclear cell (PBMC) content of IL-1Ra in freshly obtained PBMC as well as the production of IL-1Ra by endotoxin-stimulated PBMC from these HD patients was several-fold higher than that in undialyzed patients with CRF, CAPD patients or healthy controls. In fact, endotoxin-stimulated PBMC from all three groups of patients with renal failure produced significantly more IL-1Ra than IL-1 beta. These findings raise the issue whether the production of cytokine-specific inhibitors observed in patients on HD are of functional significance or serve as markers of inflammation. In vivo studies have shown that a 1,000-fold excess of IL-1Ra is required to block the hemodynamic effects of IL-1. Therefore, it is unlikely that the levels of IL-1Ra and sTNFR observed in patients on HD are sufficient to block the systemic effects of IL-1 and TNF produced during dialysis. Therefore, elevated plasma levels of inhibitory proteins such as IL-1Ra and sTNRF are more likely to be 'footprints' of IL-1 and TNF, respectively, produced during dialysis.