Abstract
BACKGROUND: Although the medical determinants of mortality in patients with end-stage renal disease (ESRD) treated with hemodialysis (HD) are well appreciated, the contribution of immunologic parameters to survival in such patients is unclear, especially when variations in age, medical comorbidity and nutrition are controlled. In addition, although dysregulation of cytokine metabolism has been appreciated in patients with ESRD, the association of these parameters with outcomes has not been established. Recently, the type of dialyzer used in patients' treatment has been associated with survival, but the mechanisms underlying these findings, including their immune effects, have not been established. We conducted a prospective, cross-sectional, observational multicenter study of urban HD patients to determine the contribution of immunological factors to patient survival. We hypothesized increased proinflammatory cytokines would be associated with increased mortality, and that improved immune function would be associated with survival. METHODS: Patients were assessed using demographic and anthropometric indices, Kt/V, protein catabolic rate (PCR) and immunologic variables including circulating cytokine [interleukin (IL)-1, IL-2, IL-4, IL-5, IL-6, IL-12, IL-13 and tumor necrosis factor (TNF)-alpha] levels, total hemolytic complement activity (CH50), and T cell number and function. A severity index, previously demonstrated to be a mortality marker, was used to grade medical comorbidity. A Cox proportional hazards model, controlling for patients' age, severity index, level of serum albumin concentration, dialyzer type and dialysis site was used to asses relative survival risk. RESULTS: Two hundred and thirty patients entered the study. The mean (+/- SD) age of the population was 54.4 +/- 14.2 years, mean serum albumin concentration was 3.86 +/- 0.47 g/dl, mean PCR was 1.1 +/- 0.28 g/kg/day, and mean Kt/V 1.2 +/- 0.3. Patients' serum albumin concentration was correlated with levels of Kt/V and PCR, and their circulating IL-13 and TNF-alpha levels, but negatively with their circulating IL-2 levels, T-cell number and T-cell antigen recall function. T-cell antigen recall function correlated negatively with PCR, but not Kt/V. There was no correlation of any other immune parameter and medical or demographic factor. Immune parameters, were all highly intercorrelated. Mean level of circulating cytokines in HD patients were in all cases greater than those of a normal control group. There were few differences in medical risk factors or immune parameters between patients treated with different types of dialyzers. After an almost three-year mean follow-up period, increased IL-1, TNF-alpha, IL-6, and IL-13 levels were significantly associated with increased relative mortality risk, while higher levels of IL-2, IL-4, IL-5, IL-12, T-cell number and function, and CH50 were associated with improved survival. The difference in survival between patients treated with unmodified cellulose dialyzers and modified or synthetic dialyzers approached the level of statistical significance, but there were no differences in levels of circulating cytokines between these two groups. CONCLUSIONS: Higher levels of circulating proinflammatory cytokines are associated with mortality, while immune parameters reflecting improved T-cell function are associated with survival in ESRD patients treated with HD, independent of other medical risk factors. These factors may serve as markers for outcome. The mechanism underlying the relationship of immune function and survival, and the effect of interventions to normalize immune function in HD patients should be studied.