Classical and mannose-binding-lectin complement pathway activation in patients with ANCA associated vasculitis

Abstract Introduction While the complement system's role in ANCA-associated vasculitis (AAV) pathogenesis is well-established, the interplay between its activation pathways remains enigmatic. Specifically, evidence regarding the classical and mannose-binding lectin (MBL) pathways is inconsistent, contrasting with the well-documented involvement of the alternative pathway. This study delves into this crucial area. Material and Methods We conducted a retrospective analysis of 163 AAV patients (129 with complete renal biopsy data). We investigated the association between baseline levels of key complement activation markers - specifically, C3 and C4, representing the alternative and classical/MBL pathways, respectively - and clinically significant outcomes: end-stage kidney disease (ESKD) and mortality. Results Baseline demographics, clinical characteristics, histopathological findings, prognostic scores, and treatment regimens were comparable between patients with C4 levels above and below the median (0.27 g/dL). Although ESKD and mortality rates were similar within the first year, long-term follow-up revealed that patients with isolated low C4 levels had a survival advantage. This group exhibited improved survival compared to those with isolated low C3 or combined low/high C3 and C4 levels (p=0.073 for mortality; p=0.026 for the composite endpoint of death or ESKD). No significant differences were observed in the overall incidence of ESKD (p=0.163). Conclusion Our findings reinforce the primacy of the alternative complement pathway in AAV pathogenesis. While the classical and MBL pathways appear to play a less prominent role overall, a distinct subset of patients with isolated C4 consumption demonstrates a surprising survival benefit. This suggests a potentially protective, yet currently undefined, modulatory role for these pathways in a subgroup of AAV patients. Further research is warranted to elucidate the precise mechanisms underlying this unexpected observation.