P1176DECLINING PERITONEAL HOST DEFENCES REVEALED BY EX-VIVO CYTOKINE RELEASE ASSAY OF PERITONEAL DIALYSIS EFFLUENT CELLS

Abstract

Abstract Background and Aims Infectious complications occur in a significant proportion of patients treated with peritoneal dialysis (PD), limiting its long-term applicability. Reduced peritoneal immune-competence, caused by the continuous exposure to PD-fluids, has been described as a therapy-related pathomechanisms, prompting the need for a tool to assess the functional peritoneal immune status. We established an ex-vivo stimulation assay to test host defence mechanisms in only 9ml of crude PD-effluent. The assay was used in two randomized clinical trials investigating immune-modulatory effects of a novel additive (alanyl-glutamine) to PD-fluid. Here we aimed to evaluate the assay as a method to assess peritoneal immune-competence in the general PD-population and linking it to PD vintage and outcome parameters. Method 462 PD-effluent samples, originating from 148 adult and paediatric PD patients, were stimulated ex-vivo (24h, 37°C) with toll-like receptor (TLR)-agonists lipopolysaccharide (LPS) and Pam3Cys. Unstimulated samples of each effluent were used as controls. Interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) concentrations and the predictive value of the assay for clinical outcome parameters were analyzed using Wilcoxon matched-pairs signed rank test and a mixed model logistic regression analysis. Results Ex-vivo stimulation of peritoneal cells resulted in a dwell-time dependent increase of cytokine release, with a significant lower cytokine released at the 1h PET time point (normalized to unstimulated controls). Ratios between stimulated PDE-samples and unstimulated controls, accounting for a potential increase in basal inflammation, significantly declined with PD therapy duration. Correlation of the cytokine levels with the predefined clinical parameters revealed predictive potential of the assay for the occurrence of infectious complications, as well as of ultrafiltration and technique failure. Conclusion In summary, the current study provides evidence of a correlation of declining local host defence and duration of PD-therapy. These data support the hypothesis of PD-duration dependent progressive impairment of the ability of the peritoneal immune cells to secrete cytokines in response to a pathogenic stimulus and thereby dampening the global peritoneal immuno-competence. The results suggest the utility of this clinically feasible ex-vivo induced cytokine-release assay in crude peritoneal effluent as a surrogate of the functional peritoneal immune competence. Future analyses will have to evaluate the assay as a tool to predict common clinical outcomes and define reference values to facilitate stratification of patient populations, clinical staging and to guide novel therapeutic interventions.