Spectrum of Anti-Factor B-Associated Glomerular Diseases in Adults.

RATIONALE & OBJECTIVE: Autoantibodies targeting complement factor B (anti-FB) are among the most recently described alternative pathway anomalies. Although they have been strongly associated with post-infectious glomerulonephritis in children, the clinical phenotypes associated with such antibodies, along with their effects on the alternative pathway in adults, remain elusive and require further characterization, which was the goal of this study. STUDY DESIGN: Retrospective case series. SETTING & PARTICIPANTS: Patients for whom anti-FB IgG was systematically detected by the French reference center for complement abnormalities between October 2017 and June 2020 and who underwent concurrent kidney biopsy confirming kidney disease were included as cases. FINDINGS: Seventy-one patients tested positive for anti-FB antibodies using ELISA and single-bead antigen assays in the setting of newly diagnosed biopsy-proven kidney disease. Detection of both anti-FB and anti-C3b autoantibodies occurred for 36/71 (51%) patients. In vitro, total purified IgG from these patients enhanced alternative pathway activity, with anti-FB titers being correlated with C3bB proconvertase formation (R2 = 0.40, p < 0.001) and anti-C3b titers being correlated with C3bBb convertase stabilization (R2 = 0.46, p < 0.001), suggesting distinct and potentially synergistic functional effects. Clinically, the most frequent diagnosis associated with anti-FB detection was infection-related glomerulonephritis (IR-GN) (46/71 - 65%), with higher anti-FB titers in patients with IR-GN compared to those with other diagnoses (median 791 [IQR 287-2000] vs. 326 [173-790] AU/mL; Hodges-Lehmann difference 354 AU/mL [95% CI: 58-1020]; p = 0.01). No difference was detected in anti-C3b titers between IR-GN and other diagnoses. Anti-FB antibodies became undetectable in 21 of 36 retested patients (58%); among the 10 patients with persistent detection beyond 3 months, 8 (80%) had uncontrolled infection. After a median follow-up of 12.5 (5-24) months, 18/67 (27%) patients experienced a major adverse kidney event (kidney failure or a sustained >50 decline in eGFR below the baseline value). LIMITATIONS: Retrospective design, the series was enriched in alternative pathway anomalies due to reference center recruitment. CONCLUSIONS: Detection of anti-FB antibodies is strongly associated with infection-related glomerulonephritis in adult patients, highlighting an important mechanism of alternative pathway deregulation in such diseases. PLAIN LANGUAGE SUMMARY: Antibodies targeting factor B, a key protein of the complement cascade, have been shown to activate the complement system and promote kidney inflammation. However, the clinical characteristics and outcomes of patients with such autoantibodies remain largely understudied, particularly in adults. This study systematically screened over 700 adults referred for complement investigation and identified 71 patients with anti-factor B antibodies and concurrent biopsy-proven kidney disease. These antibodies were predominantly associated with infection-related glomerulonephritis, activated the alternative complement pathway, and tended to disappear once the underlying infection was controlled. These findings highlight the importance of screening for anti-factor B antibodies in patients with complement-mediated kidney disease, as their detection may prompt the search for an underlying infection and guide therapeutic decisions.