High-flux hemodialysis with polymethylmethacrylate membranes reduces soluble CD40L, a mediator of cardiovascular disease in uremia

Background and hypothesis: Major Adverse Cardiovascular Events (MACE) are the main cause of mortality in hemodialysis (HD). Soluble CD40Ligand (sCD40L) binds to CD40 on endothelial cells (EC) and vascular smooth muscle cells (VSMC), playing a potential role in MACE. HD Registries showed a reduced mortality for MACE using the polymethylmethacrylate (PMMA) membrane. Study objectives: (1) to confirm the role of sCD40 L as independent predictor and mediator of MACE; (2) to evaluate the effect of PMMA on sCD40L-mediated vascular aging. Methods: In 201 patients treated by high-flux HD, sCD40 L levels were measured and correlated with MACE; 54/201 patients with sCD40L ≥ median value were randomized for 9 months in 2 cross-over groups alternatively treated with PMMA or polysulfone (PS): sCD40 L and dialytic parameters were recorded. In vitro, the role of sCD40 L was studied on EC dysfunction and VSMC calcification after incubation with patients' sera: cells engineered to knock down CD40 by siRNA were also used to confirm the role of CD40-CD40 L pathway activation. Results: At study admission, the sCD40 L median level of 8.4 ng/ml (IQR 2.9-12.7) showed the best statistical performance to identify MACE, that occurred in 51/201 (25.4%) patients. Indoxyl sulfate (IS) and p-Cresyl Sulfate (pCS) directly correlated with sCD40L levels and induced its release by platelets. In comparison to PS, PMMA treatment significantly reduced sCD40 L levels, in accordance with its enhanced mass removal by adsorption. In vitro, sera collected after PMMA treatment reduced EC dysfunction and VSMC osteoblastic differentiation through a mechanism involving the CD40-CD40 L pathway. Conclusion: sCD40 L is an independent predictor and mediator of MACE in chronic HD patients. PMMA membrane stably reduced sCD40 L under the high-risk cut-off of 8.4 ng/ml. In vitro studies confirmed the role of PMMA in the reduction of EC dysfunction and VSMC calcification in association with sCD40 L modulation.