Molecular Mechanisms of Premature Aging in Hemodialysis: The Complex Interplay Between Innate and Adaptive Immune Dysfunction

Abstract

Hemodialysis (HD) patient are known to be susceptible to a wide range of early and long-term complication such as chronic inflammation, infections, malnutrition, and cardiovascular disease that significantly affect the incidence of mortality. A large gap between the number of people with end-stage kidney disease (ESKD) and patients who received kidney transplantation has been identified. Therefore, there is a huge need to explore the underlying pathophysiology of HD complications in order to provide treatment guidelines. The immunological dysregulation, involving both the innate and adaptive response, plays a crucial role during the HD sessions and in chronic, maintenance treatments. Innate immune system mediators include the dysfunction of neutrophils, monocytes, and natural killer (NK) cells with signaling mediated by NOD-like receptor P3 (NLRP3) and Toll-like receptor 4 (TLR4); in addition, there is a significant activation of the complement system that is mediated by dialysis membrane-surfaces. These effectors induce a persistent, systemic, pro-inflammatory, and pro-coagulant milieu that has been described as inflammaging. The adaptive response, the imbalance in the CD4+/CD8+ T cell ratio, and the reduction of Th2 and regulatory T cells, together with an altered interaction with B lymphocyte by CD40/CD40L, have been mainly implicated in immune system dysfunction. Altogether, these observations suggest that intervention targeting the immune system in HD patients could improve morbidity and mortality. The purpose of this review is to expand our understanding on the role of immune dysfunction in both innate and adaptive response in patients undergoing hemodialysis treatment.

Keywords: complement; hemodialysis; kidney; premature aging.

Figure 1

Factors involved in hemodialysis-induced inflammaging divided into traditional risk factors (in blue) and non-traditional risk factors (in red). Inflammaging is defined as the systemic, low-grade inflammation associated with increased pro-inflammatory cytokines in blood and tissues and represents a frequent cause of disability in elderly subjects. Inflammaging can be induced by a wide range of conditions such as diabetes, uremic toxins, genetic factors, or dialyzer biocompatibility. However, from the other side, inflammaging also contributes to the development and amplification of oxidative stress, cellular senescence, and persistent immune activation (i.e., complement system). The dialysis catheter contamination and the filters’ biocompatibility are exogenous risk factors that are dependent on the type of material used and the sterilization methods. On the contrary, genetic susceptibility, chronic inflammation, and the establishment of cellular senescence are examples of endogenous, patient-dependent risk factors. NRLP3, NOD-like receptor P3.

Figure 2

Innate immune activation on hemodialysis membrane surfaces. Hemodialysis filters can adsorb several complement components. The adhesion of circulating IgG can induce the classical pathway activation by the binding of C1q. The adsorption of Ficolin-2 to the dialyzer can lead to the lectin pathway by the binding of circulating mannose binding lectin-associated serine proteases (MASPs). Furthermore, properdin, C3b, albumin, lipopolysaccharide (LPS), or other bacterial components in dialysis solutions or hemodialysis patient bloodstream can promote the alternative route activation after the stabilization mediated by circulating factor B. The adsorption by polysulfone membranes of regulatory components as factor H, a crucial inhibitor of C3 convertase and C3b, and clusterin, able to prevent terminal pathway activation, significantly enhances the alternative pathway activation. Complement activation will result in a higher serum increase of anaphylotoxins C3a and C5a, augmented levels of soluble C5b-9, and the induction of coagulation. IL, interleukin, TNF; Tumor Necrosis Factor. Complement effectors directly boost coagulation. For example, C3a anaphylatoxin activates platelets, enhancing their aggregation and adhesion, and C5a increases blood thrombogenicity, mainly through the upregulation of TF and PAI-1 expression on neutrophils and monocytes. From the other side, the coagulation component thrombin cleaves C3 to C3a and C3b, and C5 to C5a and C5b, thus amplifying the activation of complement. The interplay between complement and coagulation system has been mainly involved in cardiovascular complication (short-term) and inflammaging and senescence processes (in the long-term). In addition, the complement system results in the recruitment and activation of neutrophils and monocytes on dialyzer membranes, leading to a transient leukopenia. The further dysfunctional activation will lead to the release of pro-inflammatory cytokines and will promote the impairment in the Th1/Th2 ratio, and thus the alterations in the subsequent T-mediated adaptive response.