Estimating the association between systemic Interleukin-6 and mortality in the dialysis population. Re-analysis of the global fluid study, systematic review and meta-analysis

Background: Systemic inflammation, measured as circulating Interleukin-6 (IL-6) levels, is associated with cardiovascular and all-cause mortality in chronic kidney disease. However, this has not been convincingly demonstrated in a systematic review or a meta-analysis in the dialysis population. We provide such evidence, including a re-analysis of the GLOBAL Fluid Study.

Methods: Mortality in the GLOBAL fluid study was re-analysed using Cox proportional hazards regression with IL-6 levels as a covariate using a continuous non-logarithmic scale. Literature searches of the association of IL-6 levels with mortality were conducted on MEDLINE, EMBASE, PyschINFO and CENTRAL. All studies were assessed for risk of bias using the QUIPS tool. To calculate a pooled effect size, studies were grouped by use of IL-6 scale and included in the meta-analysis if IL-6 was analysed as a continuous linear covariate, either per unit or per 10 pg/ml, in both unadjusted or adjusted for other patient characteristics (e.g. age, comorbidity) models. Funnel plot was used to identify potential publication bias.

Results: Of 1886 citations identified from the electronic search, 60 were included in the qualitative analyses, and 12 had sufficient information to proceed to meta-analysis after full paper screening. Random effects meta-analysis of 11 articles yielded a pooled hazard ratio (HR) per pg/ml of 1.03, (95% CI 1.01, 1.03), [Formula: see text]= 81%. When the analysis was confined to seven articles reporting a non-adjusted HR the result was similar: 1.03, per pg/ml (95% CI: 1.03, 1.06), [Formula: see text]=92%. Most of the heterogeneity could be attributed to three of the included studies. Publication bias could not be determined due to the limited number of studies.

Conclusion: This systematic review confirms the adverse association between systemic IL-6 levels and survival in people treated with dialysis. The heterogeneity that we observed may reflect differences in study case mix.

Systematic review registration: PROSPERO - CRD42020214198.