Kidney Week Educational Symposia-Targeting Complement in ANCA-Associated Vasculitis

Video Transcription

Video Summary

The session reviews how complement drives ANCA‑associated vasculitis (AAV) and how this pathway is being targeted therapeutically. After outlining the complement cascade, the moderator emphasizes persistent unmet need: despite major survival gains with cyclophosphamide/rituximab plus high‑dose glucocorticoids, mortality remains elevated and many deaths relate to treatment toxicity (especially infections), with ongoing fatigue, relapse risk, and progression to kidney failure.<br /><br />Mechanistic data show alternative pathway activation in AAV: circulating Bb and C5a rise in active disease and normalize in remission, while factor H (an alternative pathway “brake”) is reduced during flares. In mouse models, C5 and factor B are required for necrotizing crescentic glomerulonephritis, whereas C4 is not, implicating the alternative rather than classical/lectin pathway. C5a–C5a receptor signaling on myeloid cells amplifies neutrophil activation (including via NETs), links to coagulation, and also influences adaptive immunity. A complement-related protein, FHR1, may worsen inflammation via monocyte inflammasome activation independent of complement.<br /><br />Clinically, complement activation products and renal deposition (C3d, factor B, MAC) correlate with worse renal outcomes. Trials of the oral C5a receptor inhibitor avacopan (CLEAR, CLASSIC, phase 3 ADVOCATE) show it can replace prednisone for induction, achieving noninferior remission at 26 weeks and superior sustained remission at 52 weeks, with better kidney function, quality of life, and less steroid toxicity. Anti‑C5a antibody trials are ongoing.

Asset Subtitle

A. Richard Kitching, Ralph Kettritz, Duvuru Geetha
Support is provided by an educational grant from ChemoCentryx, Inc.

Keywords

ANCA-associated vasculitis (AAV)

complement cascade

alternative complement pathway

C5a–C5a receptor signaling

avacopan (C5aR inhibitor)

necrotizing crescentic glomerulonephritis

neutrophil activation and NETs

renal complement deposition (C3d, factor B, MAC)

glucocorticoid-sparing therapy