Interleukin-1 Receptor Antagonist Synthesis by Peripheral Blood Mononuclear Cells

Proinflammatory cytokines have been implicated in the short- and long-term morbidity experienced by hemodialysis (HD) patients. The present study, which is based on long-term follow-up of a cohort of 37 patients, relates peripheral blood mononuclear cell (PBMC) interleukin-1 receptor antagonist (IL-1Ra) synthesis (a reliable marker of IL-1β synthesis in HD patients) and plasma levels of an acute phase reactant, lipopolysaccharide binding protein (LBP), to clinical outcomes. In July 1993, predialysis blood samples from these patients were collected and IL-1Ra synthesis by PBMC and plasma LBP was measured. Hospital records were reviewed and patient follow-up data were obtained until December 1997 (54 mo) or death, whichever occurred earlier. The effect of age, diabetes, endotoxin- and IgG-stimulated IL-1Ra synthesis, and plasma LBP levels on mortality was assessed using the Cox proportional hazard regression model. Poisson regression was used to determine potential relationships between the number of outcome events and each continuous risk factor. Twenty-two patients (59%) died during the follow-up period. Mortality was unrelated to IL-1Ra synthesis but did increase with age (relative risk, 1.05/yr; P = 0.01) and diabetes (relative risk, 3.00/yr; P = 0.03). Cardiovascular event rates were higher among older individuals and in those with higher endotoxin-stimulated PBMC IL-1Ra synthesis. Cardiovascular events increased with plasma LBP levels in the range of 9,000 to 12,000 pg/ml but then seemed to decrease. In contrast, older age and low IgG-stimulated IL-1Ra synthesis were associated with an increased risk of infectious events. The results of this study demonstrate an interesting link between stimulus-dependent variability in IL-1Ra synthesis by PBMC and clinical outcomes among patients on chronic HD and provide interesting targets for therapeutic interventions in this vulnerable patient population.