Mapping the complement-targeted landscape in igA nephropathy: a systematic review with structured descriptive synthesis
TL;DR
Complement inhibitors show promising but heterogeneous signals across individual trials, but marked differences in molecular targets, trial design, and eligibility preclude any inference of a uniform class effect, and underscore the need for mechanism-specific phase III programmes with hard renal endpoints and individual patient-level meta-analyses to advance precision complement therapeutics in IgAN.
Abstract
Background Complement activation is a key driver of disease progression in IgA nephropathy (IgAN). While previous syntheses were limited to phase II evidence, pivotal phase III data—including the 24-month results of the APPLAUSE-IgAN trial—have recently emerged, necessitating an updated appraisal of complement-targeted therapies. Methods We conducted a systematic literature search in PubMed, Web of Science, Embase, and Cochrane up to April 24, 2026, for randomized controlled trials of complement inhibitors in adults with biopsy-proven IgA nephropathy. Due to marked mechanistic heterogeneity across agents targeting distinct complement nodes, a quantitative meta-analysis was not performed. Instead, we performed a structured descriptive synthesis, a predefined, domain-based comparative method, focusing on efficacy signals, safety profiles, and methodological disparities across trials. Results Four RCTs comprising 584 patients were included, representing factor B and C5 inhibition. The phase III iptacopan trial demonstrated robust proteinuria reduction, eGFR slope attenuation, and a decreased risk of kidney failure, but a higher serious-infection rate and confirmed pneumococcal infections highlighted that alternative-pathway inhibition attenuates rather than abolishes encapsulated-bacteria risk. Phase II trials of ravulizumab, iptacopan, and cemdisiran provided early efficacy signals with no encapsulated-bacterial events reported, though small size and short follow-up limit safety inference. All trials required prophylactic vaccination, and infection-risk obligations differed by target—terminal-pathway inhibitors carrying the strictest REMS requirements. Methodological heterogeneity—particularly regarding biopsy timing and fibrosis exclusion—emerged as a major barrier to cross-trial comparisons. Beyond these RCTs, a dynamic pipeline of ASO, siRNA, and small-molecule inhibitors continues to evolve. Conclusion Complement inhibitors show promising but heterogeneous signals across individual trials; however, marked differences in molecular targets, trial design, and eligibility preclude any inference of a uniform class effect. Infection risk mitigation differs by complement target—terminal-pathway inhibitors carry the highest encapsulated-bacterial burden and strictest regulatory constraints, whereas alternative-pathway inhibitors preserve partial vaccine-mediated defence but still require comprehensive vaccination and surveillance. These observations are hypothesis-generating and underscore the need for mechanism-specific phase III programmes with hard renal endpoints and individual patient-level meta-analyses to advance precision complement therapeutics in IgAN. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/view/CRD420261385690
