Role of lymphocyte co-stimulation pathways and extracellular vesicles in cardiovascular damage of chronic uremic patients and new therapeutic strategies

Introduction: Chronic kidney disease (CKD) is characterized by high cardiovascular (CV) risk and the RISCAVID study identified a correlation between CV risk and blood levels of sCD40L in uremia. Moreover, sCD40L correlates with osteoblastic differentiation of vascular smooth muscle cells (VSMC) and endothelial cells (EC) inflammation. In addition, CKD-related extracellular vesicles (EVs) express CD40L and polymethylmethacrylate (PMMA) dialyzer could reduce not only uremic toxins as indoxyl sulfate (IS), but also sCD40L and EVs by adsorption. Aim of the study: 1) identify a sCD40L predictive value for major cardiovascular events (MACE) in uremia, 2) assess the sCD40L role, 3) compare the efficacy of PMMA vs polysulfone (PS) in sCD40L and other molecule removal, and 4) perform CKD-EV characterization and analysis of their role CKD vascular damage. Patients and methods: In 201 dialysis patients from 6 Italian dialysis Centers, we assessed sCD40L and MACE during the follow-up. 48 high CV risk patients started 9 months randomized doublecrossover study (treatment with PMMA or PS). We assessed SCD40L and biochemical parameters every 3 months. We evaluated sCD40L/IS mass removal and sCD40L effects on EC and VSMC in vitro. We characterized CKD-EVs and evaluate their role incubating EC and VSMC in vitro. Results: sCD40L cut-off of 7,8 ng/mL was the best predictor of MACE and PMMA was more efficient in reducing hepcidin, sCD40L and IS. PMMA decreased ROS production, monocyte adhesion and osteoblastic differentiation. CKD-EVs expressed CD40L and other inflammation markers, were internalized by EC and VSMC and modulated osteoblastic differentiation. Conclusions: sCD40L predicts MACE in CKD patients and PMMA is able to remove this molecule. sCD40L is not only a marker of CKD-CV damage, but also a mediator of progression. sCD40L and IS reduction could therefore have an impact on CKD-CV risk and CKD-EVs could also be considered true uremic toxins and effective mediators of damage.