Enhancing Immune Protection in Hemodialysis Patients: Role of the Polymethyl Methacrylate Membrane

Abstract

End-stage renal disease (ESRD) is characterized by deep disorders in both innate and adaptive immune systems that imply unbalance deactivation and immunosuppression. The central, widely recognized factors responsible for this immune dysregulation are uremia, uremic toxin retention, hemodialysis membrane biocompatibility, and related cardiovascular complications. Recently, several studies strengthened the concept that dialysis membranes are not considered as a simple diffusive/adsorptive device but as a platform to personalize a dialysis approach to improve the quality of life of ESRD patients. Therefore, understanding of the molecules associated with altered immune response is crucial and could lead to therapeutically intervention or adaptation of the dialysis procedure itself for the management of immunological dysfunction of ESRD patients. The polymethyl methacrylate (PMMA)-based membrane is characterized by a symmetrical structure with large-sized pores, providing a better hydrophobic and cationic adsorption capacity compared to the other synthetic membranes. Together with hydrophobic interactions, the high adsorption rate of cytokines (i.e., IL-6) can also be enhanced by the size of nano-pores placed on the membrane surface. PMMA membranes exhibit adsorptive properties for a large amount of uremic toxins including p-cresol and indoxyl sulfate, as well as β2-microglobulin characterized by higher molecular weight, maintaining the diffusive clearance of small molecules like urea with a great biocompatibility. Besides exerting a strong anti-inflammatory effects in line with the improvement of immune responses in patients undergoing dialysis, PMMA also plays a role in modulating adaptive immune response, i.e., can clear blood from soluble CD40, a natural antagonist of the CD40/CD40L signaling that acts inhibiting immunoglobulin production by B cells. This review provides an overview of the main concepts and current understanding of immune dysfunction in hemodialysis and summarizes the recent findings regarding PMMA-based dialysis as potential strategy to restore immune balance in ESRD patients.

Keywords: Complement System; Hemodialysis; Immune dysfunction; Inflammaging; NOD-like receptor P3 (NLRP3); Polymethyl methacrylate; Senescence; Toll-like receptor 4 (TLR4); Uremic toxins.

Fig. 1.

Molecular mechanisms of ESKD immunological dysfunction and role of the PMMA membrane in reducing immune impairment. CKD is associated with chronic inflammation, immune system dysfunction, and cellular senescence, leading to a condition called “inflammaging.” This particular phenotype is mainly induced by dysfunction of neutrophils, monocytes, and natural killer (NK) cells with signaling mediated by Toll-like receptor 4 (TLR4); activation of the complement system mediated by dialysis membrane surfaces; and from adaptive response, by the imbalance in the CD4+/CD8+ T-cell ratio, a reduction of Th2 and regulatory T cells, together with an altered interaction with B lymphocyte by CD40/CD40L. ESKD results in the expansion of pro-inflammatory CD4⁺CD28⁻ T-cell and CD14+CD16++ monocyte populations, which are considered to be novel, nontraditional cardiovascular risk factors. Furthermore, uremic monocyte-derived DCs showed reduced endocytosis and a decreased expression of costimulatory molecules (CD40, CD80, and CD86) and maturation markers (CD83) compared with those of normal monocyte-derived DCs. These findings indicated that the terminal differentiation of monocyte-derived DCs (i.e., the transition from an immature to a mature stage) in patients with ESKD on HD was impaired. PMMA membranes appear to be highly effective in reducing circulating amount of soluble molecule sCD40 and uremic toxins that represents the natural antagonist of CD40/CD40L signaling on DC surface. PMMA dialysis membranes are highly effective for the removal of pCS and IS compared to PS membranes enabling clearance of β2-microglobulin and small solutes. The PMMA membrane adsorbs several cytokines as IL-6, IL-1β, TNF-α, and IL-8, thereby modulating chronic inflammation in HD patients with higher efficiency compared to the PS membrane; the adsorption efficiency to the PMMA membrane depends on the molecular weight of the cytokines. pCS, p-cresyl sulfate; IS, indoxyl sulfate.