The Complement System in Dialysis: A Forgotten Story?

Abstract

Significant advances have lead to a greater understanding of the role of the complement system within nephrology. The success of the first clinically approved complement inhibitor has created renewed appreciation of complement-targeting therapeutics. Several clinical trials are currently underway to evaluate the therapeutic potential of complement inhibition in renal diseases and kidney transplantation. Although, complement has been known to be activated during dialysis for over four decades, this area of research has been neglected in recent years. Despite significant progress in biocompatibility of hemodialysis (HD) membranes and peritoneal dialysis (PD) fluids, complement activation remains an undesired effect and relevant issue. Short-term effects of complement activation include promoting inflammation and coagulation. In addition, long-term complications of dialysis, such as infection, fibrosis and cardiovascular events, are linked to the complement system. These results suggest that interventions targeting the complement system in dialysis could improve biocompatibility, dialysis efficacy, and long-term outcome. Combined with the clinical availability to safely target complement in patients, the question is not if we should inhibit complement in dialysis, but when and how. The purpose of this review is to summarize previous findings and provide a comprehensive overview of the role of the complement system in both HD and PD.

Keywords: complement; dialysis; hemodialysis; kidney; peritoneal dialysis.

Figure 1

The complement system. A schematic view of activation of the complement system and its regulation. The classical pathway (CP) is initiated by C1q binding to immune complexes or other molecules (e.g., CRP), thereby activating C1r and C1s resulting in the cleavage of C2 and C4 thereby forming the C3-convertase (C4b2b). The lectin pathway (LP) is initiated by mannose-binding lectin (MBL), ficolins, or collectin-11 binding to carbohydrates or other molecules (e.g., IgA), thereby activating MASP-1 and MASP-2, forming the same C3-convertase as the CP. Subsequently, the C3-convertase cleavages C3 into C3a and C3b. Activation of the alternative pathway (AP) occurs via properdin binding to certain cell surfaces (e.g., LPS) or by spontaneous hydrolysis of C3 into C3(H₂O). Next, binding of factor B creates the AP C3-convertase (C3bBb). Increased levels of C3b results in the formation of the C5-convertases, which cleaves C5 in C5a, a powerful anaphylatoxin, and C5b. Next, C5b binds to the surface and interactions with C6–C9, generating the membrane attack complexes (MAC/C5b-9). Several complement regulators (either soluble and membrane-bound) prevent or restrain complement activation. C1 esterase inhibitor (C1-INH) inhibits the activation of early pathway activation of all three pathways, while C4b-binding protein (C4BP) controls activation at the C4 level of the CP and LP. Factor I and factor H regulate the C3 and C5-convertase. Furthermore, the membrane-bound inhibitors include complement receptor 1 (CR1), membrane cofactor protein (MCP) that acts as an co-factors for factor I and decay accelerating factor (DAF) which accelerates the decay of C3-convertases. The membrane-bound regulator Clusterin and CD59 prevents the generation of the C5b-9.

Figure 2

Proposed model for complement activation in hemodialysis (HD). The principal mechanism leading to complement activation in HD is the binding of ficolin-2 to the membrane, resulting in lectin pathway activation. Simultaneously, properdin and/or C3b bind to the membrane resulting in alternative pathway activation. Complement activation will result in the formation of anaphylatoxins (C3a, C5a), opsonins (C3b, iC3b), and the membrane attack complex (C5b-9). First, complement activation leads to the upregulation of complement receptor 3 (CR3) allowing leukocytes to bind C3 fragments deposited on the membrane, leading to leukopenia. Second, CR3 on neutrophils is also important for the formation of platelet-neutrophil complexes, which contributes to thrombotic processes. Furthermore, C5a generation during HD leads to the expression of tissue factor and granulocyte colony-stimulating factor in neutrophils, shifting HD patients to a procoagulant state. Third, complement activation also promotes recruitment and activation of leukocytes resulting in the oxidative burst and the release of pro-inflammatory cytokines and chemokine’s. More specifically, the activation of neutrophils by C5a leads to the release of granule enzymes, e.g., myeloperoxidase (MPO).

Figure 3

Proposed model for complement activation in peritoneal dialysis (PD). In PD patients, mesothelial cells produce and secrete different complement factors. One of the proposed mechanisms of complement activation in PD patients is that PD therapy decreases the expression of complement regulators such as CD55 and CD59 on the peritoneal mesothelium, leading to local complement activation. In addition, cellular debris as a result of direct peritoneal damage by bioincompatible PD fluids as well as antibodies against microorganisms could contribute to local complement activation during PD. Complement activation will result in the formation of anaphylatoxins (C3a, C5a), opsonins (C3b, iC3b), and the membrane attack complex (C5b-9). First, complement activation leads to the influx of leukocytes, predominantly neutrophils. Second, complement activation increased the production of thrombin anti-thrombin complexes and fibrin exudation on the surface of the injured peritoneum. Altogether, these events indicate the activation of the coagulation system. Third, complement activation during PD leads to direct damage of the peritoneum. Moreover, recent evidence suggests that complement activation promotes the progression to fibrosis after tissue injury. In PD, complement activation could stimulate mesothelial cells to undergo epithelial-to-mesenchymal transition, resulting in the accumulation of myofibroblasts and consequently peritoneal fibrosis.