{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T04:55:38Z","timestamp":1790916938604,"version":"4.1.0"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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\u2014including the 24-month results of the APPLAUSE-IgAN trial\u2014have recently emerged, necessitating an updated appraisal of complement-targeted therapies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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\u2014terminal-pathway inhibitors carrying the strictest REMS requirements. Methodological heterogeneity\u2014particularly regarding biopsy timing and fibrosis exclusion\u2014emerged as a major barrier to cross-trial comparisons. Beyond these RCTs, a dynamic pipeline of ASO, siRNA, and small-molecule inhibitors continues to evolve.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats: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\u2014terminal-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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic Review Registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/www.crd.york.ac.uk\/PROSPERO\/view\/CRD420261385690<\/jats:ext-link>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1933632","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T04:37:01Z","timestamp":1790915821000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Mapping the complement-targeted landscape in igA nephropathy: a systematic review with structured descriptive synthesis"],"prefix":"10.3389","volume":"13","author":[{"given":"Xin-Yu","family":"Li","sequence":"first","affiliation":[{"name":"Institute of Rehabilitation and Health Care, Hunan Traditional Chinese Medical College","place":["Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang-Ying","family":"Zhong","sequence":"additional","affiliation":[{"name":"Otolaryngology Department, Hunan Provincial Hospital of Integrated Traditional Chinese and Western Medicine","place":["Changsha, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Nan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Rehabilitation and Health Care, Hunan Traditional Chinese Medical College","place":["Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Rehabilitation and Health Care, Hunan Traditional Chinese Medical College","place":["Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"S1","DOI":"10.1016\/j.kint.2021.05.021","article-title":"KDIGO 2021 clinical practice guideline for the management of glomerular diseases","volume":"100","author":"Rovin","year":"2021","journal-title":"Kidney Int"},{"key":"B2","doi-asserted-by":"publisher","first-page":"151564","DOI":"10.1016\/j.semnephrol.2025.151564","article-title":"Iga nephropathy: epidemiology and disease risk across the world","volume":"44","author":"Ghaddar","year":"2024","journal-title":"Semin Nephrol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1630","DOI":"10.34067\/KID.0002382022","article-title":"The gut and kidney crosstalk in immunoglobulin A nephropathy","volume":"3","author":"Sanchez-Russo","year":"2022","journal-title":"Kidney360"},{"key":"B4","doi-asserted-by":"publisher","first-page":"3620","DOI":"10.1093\/ndt\/gfp441","article-title":"Immune complex formation in IgA nephropathy: a case of the \u2018right\u2019 Antibodies in the \u2018wrong\u2019 Place at the \u2018wrong\u2019 Time?","volume":"24","author":"Barratt","year":"2009","journal-title":"Nephrol Dial Transplant"},{"key":"B5","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1136\/bmj.3.5875.326","article-title":"Glomerular deposition of properdin in henoch-sch\u00f6nlein syndrome and idiopathic focal nephritis","volume":"3","author":"Evans","year":"1973","journal-title":"Br Med J"},{"key":"B6","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1007\/s00281-021-00882-9","article-title":"Complement activation in IgA nephropathy","volume":"43","author":"Medjeral-Thomas","year":"2021","journal-title":"Semin Immunopathol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.1007\/s00467-014-3024-z","article-title":"Relationship between serum IgA\/C3 ratio and severity of histological lesions using the Oxford classification in children with IgA nephropathy","volume":"30","author":"Mizerska-Wasiak","year":"2015","journal-title":"Pediatr Nephrol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1111\/ped.13461","article-title":"Serum IgA\/C3 and glomerular C3 staining predict severity of IgA nephropathy","volume":"60","author":"Kawasaki","year":"2018","journal-title":"Pediatr Int"},{"key":"B9","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1016\/j.kint.2024.05.015","article-title":"The role of complement in kidney disease: conclusions from a kidney disease: improving global outcomes (KDIGO) controversies conference","volume":"106","author":"Vivarelli","year":"2024","journal-title":". 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