The
complement cascade, traditionally considered an effector arm of innate immunity required for host defense against pathogens, is now recognized as a crucial pathogenic mediator of various
kidney diseases.
Complement components produced by the liver and circulating in the plasma undergo activation through the classical and/or
mannose-binding lectin pathways to mediate anti-HLA antibody-initiated kidney transplant rejection and
autoantibody-initiated GN, the latter including
membranous glomerulopathy, antiglomerular basement membrane disease, and
lupus nephritis. Inherited and/or acquired abnormalities of
complement regulators, which requisitely limit restraint on alternative pathway complement activation, contribute to the pathogenesis of the C3 nephropathies and
atypical hemolytic uremic syndrome. Increasing evidence links
complement produced by endothelial cells and/or tubular cells to the pathogenesis of kidney
ischemia-reperfusion injury and progressive kidney
fibrosis. Data emerging since the mid-2000s additionally show that immune cells, including T cells and antigen-presenting cells, produce alternative pathway
complement components during cognate interactions. The subsequent local complement activation yields production of the
anaphylatoxins C3a and C5a, which bind to their respective receptors (C3aR and C5aR) on both partners to augment effector T-cell proliferation and survival, while simultaneously inhibiting regulatory T-cell induction and function. This immune cell-derived
complement enhances pathogenic alloreactive T-cell immunity that results in transplant rejection and likely contributes to the pathogenesis of other T cell-mediated
kidney diseases. C5a/C5aR
ligations on neutrophils have additionally been shown to contribute to vascular
inflammation in models of
ANCA-mediated renal
vasculitis. New translational immunology efforts along with the development of pharmacologic agents that block human
complement components and receptors now permit testing of the intriguing concept that targeting
complement in patients with an assortment of
kidney diseases has the potential to abrogate
disease progression and improve patient health.