Infection risk mitigation with complement inhibitors in kidney disease

Abstract Complement inhibitors are increasingly used in kidney diseases, ranging from complement-mediated thrombotic microangiopathies to glomerulonephritis. Because complement is central to host defence against encapsulated bacteria, therapeutic blockade creates a predictable infectious vulnerability requiring structured prevention strategies. This narrative review integrates complement biology with evidence from pivotal kidney trials, pharmacovigilance analyses, and national public health recommendations to propose a pragmatic framework for mitigating infection-risk in patients treated with complement inhibitors. Key complement functions (C3b-mediated opsonisation, C3a/C5a-driven inflammation, and membrane attack complex formation) underlie target-specific patterns of infectious risk. Terminal C5 inhibition (eculizumab, ravulizumab) confers a reproducible exposure-adjusted risk of invasive meningococcal disease, including rare but documented infection-related mortality, with breakthrough infections reported despite vaccination. In contrast, inhibition at the level of C3/C3b or the alternative pathway amplification loop has not, to date, demonstrated a consistent encapsulated-pathogen signal in phase 3 kidney trials, although follow-up remains limited and rare events cannot be excluded. Effective prevention relies on target-adapted vaccination against encapsulated bacteria, consideration of antimicrobial prophylaxis when therapy must begin before vaccine protection is established—and in selected higher-risk settings during sustained complement blockade—and structured patient education with rapid-access pathways for febrile illness. Chronic kidney disease, dialysis exposure, transplantation, and concomitant immunosuppression may further amplify infectious risk and attenuate vaccine responsiveness. Infection risk under complement inhibition is target-dependent and not eliminated by vaccination alone, particularly with terminal C5 blockade. Mechanism-informed, kidney-specific prevention strategies are essential as complement therapies expand into routine clinical practice.