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The biology underlying it varies between patients, which may explain why treatments have not succeeded. Here we show, using an ensemble method that groups patients by patterns across hundreds of blood proteins in three independent groups of patients, that sepsis-associated acute kidney injury comprises two reproducible subphenotypes. One subphenotype shows widespread activation of inflammation, metabolism, and oxidative stress; the other shows a quieter profile. Patients in the inflammatory subtype have higher mortality, more complications, and fewer days alive and out of the intensive care unit. A simple seven-protein test reproduces these groupings and identifies them accurately in separate cohorts. In a randomized trial, the drug ilofotase alfa appears to benefit the inflammatory subtype but not the other, suggesting that this classification could guide future treatment.<\/jats:p>","DOI":"10.1038\/s41467-026-76889-3","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:45:00Z","timestamp":1787161500000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Plasma proteomics defines two reproducible subphenotypes of sepsis-associated acute kidney injury with distinct outcomes"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9788-5316","authenticated-orcid":false,"given":"Matthieu","family":"Legrand","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanh","family":"Nguyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn S.","family":"Calfee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7187-1511","authenticated-orcid":false,"given":"Yingying","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0553-674X","authenticated-orcid":false,"given":"Michael","family":"Harhay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9413-8152","authenticated-orcid":false,"given":"David","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliane","family":"Bernholz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3039-8155","authenticated-orcid":false,"given":"Michael","family":"Matthay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8715-7753","authenticated-orcid":false,"given":"Alexandre","family":"Mebazaa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Pickkers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6837-7678","authenticated-orcid":false,"given":"Ernesto","family":"Rojas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3238-4643","authenticated-orcid":false,"given":"Alexendar R.","family":"Perez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"76889_CR1","doi-asserted-by":"publisher","DOI":"10.1186\/s13054-024-04877-4","volume":"28","author":"M Legrand","year":"2024","unstructured":"Legrand, M. et al. Sepsis-associated acute kidney injury: recent advances in enrichment strategies, sub-phenotyping and clinical trials. Crit. Care 28, 92 (2024).","journal-title":"Crit. Care"},{"key":"76889_CR2","doi-asserted-by":"publisher","DOI":"10.1186\/s13054-024-05167-9","volume":"28","author":"MJ Song","year":"2024","unstructured":"Song, M. J. et al. Epidemiology of sepsis-associated acute kidney injury in critically ill patients: a multicenter, prospective, observational cohort study in South Korea. Crit. Care 28, 383 (2024).","journal-title":"Crit. Care"},{"key":"76889_CR3","doi-asserted-by":"publisher","unstructured":"Zarbock, A. et al. Sepsis-associated acute kidney injury: consensus report of the 28th Acute Disease Quality Initiative workgroup. Nat. Rev. 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NEJM Evid. 2, EVIDoa2200196 https:\/\/doi.org\/10.1056\/EVIDoa2200196 (2023).","DOI":"10.1056\/EVIDoa2200196"}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-026-76889-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-026-76889-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-026-76889-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T22:32:24Z","timestamp":1791412344000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-026-76889-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,19]]},"references-count":32,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["76889"],"URL":"https:\/\/doi.org\/10.1038\/s41467-026-76889-3","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,19]]},"assertion":[{"value":"29 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 August 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 August 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"M.L. reports receiving consulting fees from Pharmazz Inc, OceaneX, Idorsia, Estor and is co-founder of Augura Inc. All outside the submitted work. C.S.C. reports grants to her institution from the NIH, Roche-Genentech, the Department of Defence, and the Quantum Leap Healthcare Collaborative, consulting fees from Vasomune, Gen1e Life Sciences, EnliTISA, Novartis, Merck, Healios, Matisse, Ocean Dx, Aurobac, Iris Kinetics, and Boehringer, payment from Fisher-Paykel and is a co-recipient of a patent on metagenomic sequencing for sepsis diagnosis. K.L. reports ongoing funding from NIH. She has ongoing consultancy relationships with SeaStar Biomedical and prior consultancy relationships with Lightning Health, Atom, InflaRX, and Guard Pharmaceuticals. She serves on DSMB for Regeneron, Novartis and Direct Biologics. She holds publicly traded stock in Amgen, 3M, and Procter and Gamble. She has royalties with UpToDate.M.O.H received consulting fees from the American Thoracic Society, American Medical Association, and Elsevier for statistical editorial work, all unrelated to this paper. J.B. is an employee of AM-Pharma B.V., the sponsor of the REVIVAL trial. PP received travel and consultancy reimbursements from AM-Pharma, Ebi, 4Teen4, and Bayer. AM received research contracts from 4TEEN4, Roche, Windtree; consultation fee from Roche, Corteria, Adrenomed, Fire, Johnson&Johnson; honorarium for lecture from Merck, Novartis, Roche, Bayer; is co-inventor of patent on combined therapies to treat dyspnea, owned by S-Form Pharma; member of Committee of trials for Secret-HF, sponsored by the French Government, for S-Form Pharma, for 4TEEN4, Echosens, and Implicity. The remaining authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"10575"}}