The complement cascade and renal disease

Abstract

Serum complement cascade, a part of innate immunity required for host protection against invading pathogens, is also a mediator of various forms of disease and injury. It is activated by classical, lectin, and alternative pathways that lead to activation of C3 component by C3 convertases, release of C3b opsonin, C5 conversion and eventually membrane attack complex formation. The tightly regulated activation process yields also C3a and C5a anaphylatoxins, which target a broad spectrum of immune and non-immune cells. The review discusses the involvement of the complement cascade in kidney disease pathogenesis and injury. The role of the complement pathways in autoantibody-mediated forms of glomerulonephritis (lupus nephritis, anti-glomerular basement membrane disease, anti-neutrophil cytoplasmic autoantibody-induced or membranoproliferative glomerulonephritis, membranous nephropathy), C3 glomerulopathy, atypical forms of hemolytic uremic syndrome, ischemic-reperfusion injury of transplanted kidney, and antibody-mediated renal allograft rejection are discussed. The disturbances in complement activation and regulation with underlying genetics are presented and related to observed pathology. Also promising strategies targeting the complement system in complement-related disorders are mentioned.

Fig. 1

Complement activation pathways. Classical pathway is activated by C1 assembled on antigen-bound antibodies or in an antibody-independent manner by some viruses or Gram-negative bacteria, and the lectin pathway by mannose-binding lectin (MBL) attached to carbohydrates on the surface of microorganisms. Both pathways converge to release the common C3 convertase (C4bC2b). The alternative pathway is constantly activated at a tightly controlled level and generates C3 convertase (C3(H₂O)Bb/C3bBb) that release C3b at low level, which can readily initiate amplification. The assembled convertases cleave C3 to anaphylactic and antimicrobial C3a and C3b, an opsonin that is deposited on nearby surfaces and serves to amplify the activation signals. C3b also serves to generate the next generation C5 convertases, which further activate the cascade, leading to terminal membrane attack complex and target cell lysis