Table 1_Mapping the complement-targeted landscape in igA nephropathy: a systematic review with structured descriptive synthesis.docx

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.</p>Conclusion<p>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.</p>Systematic Review Registration<p>crd.york.ac.uk/PROSPERO/view/CRD420261385690</p>