Mixed matrix membranes with incorporated glycosaminoglycans have good blood biocompatibility combined to high toxin removal

Abstract

Most patients in need of renal replacement therapy use peritoneal or hemodialysis (HD) therapy. Major drawbacks of HD are the incomplete removal of uremic solutes (especially middle-sized uremic solutes and protein-bound uremic solutes, PBUTs) as well as the non-continuous therapy (3 times per week for 4 h), causing large fluctuations in water balance and uremic waste, potassium, and phosphate. For achieving better patient outcomes, more continuous therapies are required including the application of home HD or portable HD. The latter require membranes with excellent long-term biocompatibility. Heparin-modified dialysis membranes can offer improved biocompatibility, but systemic anticoagulation is still needed, whereas potential heparin-induced thrombocytopenia (HIT) may occur.Glycosaminoglycans (GAGs) contribute to the kidney glomerular filtration barrier and provide natural anti-fouling properties. Here, we hypothesized that the incorporation of GAGs within polymeric membranes, either via membrane coating, post membrane fabrication, or via blending GAGs into the membrane forming polymer matrix, would provide membranes with improved hemocompatibility. We implemented these strategies to mixed matrix membranes (MMMs) which combine diffusion and adsorption for removing a broad range of uremic solutes. Firstly, we fabricated flat sheet MMMs with various GAG sources, including heparan sulphate from bovine kidney (HSBK), heparinase III-digested HSBK, HS isolated from cultured glomerular endothelial glycocalyx, GAGs from porcine intestinal mucosa (danaparoid, DA), or heparin. The flat sheet MMMs with DA blended within the membrane selective layer have excellent blood compatibility, based on a panel of anti-coagulation and immune activation assays, combined to high water transport and very low albumin leakage. Besides, these MMMs had low clot formation, did not activate immune cells or the complement system and had low platelet adhesion. Based on these findings, we also developed first hollow fiber MMMs with DA blended in the selective layer, which also had high water transport, no leakage of protein, and achieved very good removal of various uremic solutes, comparable to commercial HD membranes.