Prof of Medicine at University “Ss. Cyril and Methodius”, Medical Faculty, Skopje, North Macedonia
Hemodialysis (HD) is a renal replacement modality for treatment of end-stage kidney disease (ESKD). Given the shortage of donor organs, ESKD patients are forced to rely on HD. The systemic inflammation, caused by dialysis related factors, represent an issue known as bioincompatibility. In dialysis, complement activation is caused by the interaction of blood with the HD membrane. Regardless of the eﬀorts to improve biocompatibility, complement activation still occurs in HD, even with the modern membranes. The cleavage of C3 results in the formation of C3a and C3b, and ultimately in terminal pathway activation, with the formation of C5a and C5b-9. The generation of C3a and C5a activates the leukocytes, resulting in the release of cytokines and chemokines, such as interleukin (IL)-1β, IL-6, IL-8, TNF-α, monocyte chemoattractant protein-1, and interferon-γ, shifting HD patients to a pro-coagulative state. These events are thought to culminate in the activation of the cardiovascular endothelium, which gradually loses its antithrombotic and anti-inflammatory properties, leading to atherogenesis and arteriosclerosis. In the past decade, numerous complement inhibitors have been developed; two are currently used in the clinics: C1 esterase inhibitor (C1-INH) and Eculizumab, a C5 antibody. Administration of a single dose of C1-INH in an ex-vivo model of HD, resulted in attenuated C3 activation and decreased levels of key pro-inflammatory and prothrombotic markers implicated in cardiovascular disease predisposition. Recently, cynomolgus monkeys were subjected to HD and significant complement activation was observed after a single HD session. However, a single intravenous bolus injection of the compstatin analog Cp40 prior to HD, completely abrogated complement activation and led to elevated levels of the anti-inflammatory cytokine IL-10. The emerging correlation between C3 inhibition and a reciprocal increase in IL-10, offers a basis for considering C3-targeted intervention as an effective strategy for preventing complement-mediated proinflammatory activation in chronic HD patients.