{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T16:50:53Z","timestamp":1792601453594,"version":"4.5.0"},"reference-count":19,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T00:00:00Z","timestamp":1774310400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"content-version":"vor","delay-in-days":16,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Crit Care"],"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n Proenkephalin A 119\u2013159 (penKid) is a functional kidney biomarker inversely correlating with the glomerular filtration rate. We conducted a patient-level meta-analysis to evaluate whether penKid provides additional value to serum creatinine (sCr) for assessing kidney function and outcome in patients with sepsis or septic shock.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n To identify eligible studies, the database PubMed and internal resources have been searched in March 2025. Randomized controlled trials or observational trials enrolling patients with sepsis or septic shock admitted to ICU (>\u2009100 patients per study) were included. The primary endpoint was worsening renal function (WRF) defined as a further increase of sCr equal or greater 0.3\u00a0mg\/dL within 48\u00a0h from ICU admission value (baseline), or need for renal replacement therapy (RRT) or death within 48\u00a0h. Secondary endpoint was 28d-mortality. Subgroups were created applying upper normal reference values for penKid and sCr.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Individual data from 2,203 patients with sepsis or septic shock enrolled in four studies were included. penKid was independently associated with WRF (OR 3.4, 95% CI 2.7\u20134.3,\n p<\/jats:italic>\n \u2009<\u20090.0001) and 28d-mortality (OR 1.6, 95% CI 1.4\u20131.9,\n p<\/jats:italic>\n \u2009<\u20090.0001). Among patients with normal sCr at admission, those with elevated penKid had a higher incidence of WRF compared to patients with normal penKid (27.1% vs. 11.1%,\n p<\/jats:italic>\n \u2009<\u20090.0001) and the highest 28d-mortality (38.6% vs. 15.3%,\n p<\/jats:italic>\n \u2009<\u20090.0001).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n penKid adds predictive value beyond sCr for identifying patients at risk for WRF and 28d-mortality. Importantly, elevated penKid identifies at-risk patients even when sCr is normal. Combining both biomarkers may therefore offer a valuable tool for risk stratification in patients with sepsis or septic shock.<\/jats:p>\n <\/jats:sec>\n \n Trial registration<\/jats:title>\n This meta-analysis has been retrospectively registered at PROSPERO, CRD420251153702. Registered 23 September 2025.<\/jats:p>\n <\/jats:sec>","DOI":"10.1186\/s13054-026-05947-5","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T20:35:39Z","timestamp":1774384539000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Clinical utility of proenkephalin A 119-159 for prediction of worsening renal function and prognosis in patients with sepsis \u2013results of a patient-level meta-analysis"],"prefix":"10.1186","volume":"30","author":[{"given":"Birte","family":"Arlt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pietro","family":"Caironi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Meessen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Hartmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Mebazaa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthieu","family":"Legrand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etienne","family":"Gayat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Nusshag","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thorsten","family":"Brenner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre Fran\u00e7ois","family":"Laterre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ornella","family":"Tinelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Latini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Uhle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,24]]},"reference":[{"issue":"1","key":"5947_CR1","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1080\/10408363.2023.2242481","volume":"61","author":"A Rossiter","year":"2024","unstructured":"Rossiter A, La A, Koyner JL, Forni LG. New biomarkers in acute kidney injury. Crit Rev Clin Lab Sci. 2024;61(1):23\u201344.","journal-title":"Crit Rev Clin Lab Sci"},{"issue":"6","key":"5947_CR2","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1038\/s41581-023-00683-3","volume":"19","author":"A Zarbock","year":"2023","unstructured":"Zarbock A, Nadim MK, Pickkers P, Gomez H, Bell S, Joannidis M, et al. Sepsis-associated acute kidney injury: consensus report of the 28th Acute Disease Quality Initiative workgroup. Nat Rev Nephrol. 2023;19(6):401\u201317.","journal-title":"Nat Rev Nephrol"},{"key":"5947_CR3","first-page":"1","volume":"2","author":"KDIGO","year":"2012","unstructured":"KDIGO. KDIGO clinical practice guideline for acute kidney injury. Kidney Int. 2012;2:1\u2013138.","journal-title":"Kidney Int"},{"issue":"17","key":"5947_CR4","doi-asserted-by":"publisher","first-page":"1752","DOI":"10.1016\/j.jacc.2010.11.051","volume":"57","author":"M Haase","year":"2011","unstructured":"Haase M, Devarajan P, Haase-Fielitz A, Bellomo R, Cruz DN, Wagener G, et al. The outcome of neutrophil gelatinase-associated lipocalin-positive subclinical acute kidney injury: a multicenter pooled analysis of prospective studies. J Am Coll Cardiol. 2011;57(17):1752\u201361.","journal-title":"J Am Coll Cardiol"},{"issue":"10","key":"5947_CR5","doi-asserted-by":"publisher","first-page":"e820","DOI":"10.1097\/CCM.0000000000003907","volume":"47","author":"M Joannidis","year":"2019","unstructured":"Joannidis M, Forni LG, Haase M, Koyner J, Shi J, Kashani K, et al. Use of Cell Cycle Arrest Biomarkers in Conjunction With Classical Markers of Acute Kidney Injury. 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Intensive Care Med. 2023;49(10):1191\u2013202.","journal-title":"Intensive Care Med"},{"issue":"1","key":"5947_CR8","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1186\/s13054-022-04121-x","volume":"26","author":"ST Vaara","year":"2022","unstructured":"Vaara ST, Bhatraju PK, Stanski NL, McMahon BA, Liu K, Joannidis M, et al. Subphenotypes in acute kidney injury: a narrative review. Crit Care. 2022;26(1):251.","journal-title":"Crit Care"},{"issue":"6","key":"5947_CR9","first-page":"1560","volume":"38","author":"L Molinari","year":"2023","unstructured":"Molinari L, Landsittel DP, Kellum JA. Use of kidney injury molecule-1 for sepsis-associated acute kidney injury staging. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association -. 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Clinical performance of proenkephalin A 119\u2013159 for the early diagnosis of acute kidney injury in patients with sepsis or septic shock. p. 1\u201326. 2024.","DOI":"10.1101\/2024.10.11.24315291"},{"issue":"9","key":"5947_CR12","doi-asserted-by":"publisher","first-page":"1361","DOI":"10.1373\/clinchem.2018.288068","volume":"64","author":"P Caironi","year":"2018","unstructured":"Caironi P, Latini R, Struck J, Hartmann O, Bergmann A, Bellato V, et al. Circulating Proenkephalin, Acute Kidney Injury, and Its Improvement in Patients with Severe Sepsis or Shock. Clin Chem. 2018;64(9):1361\u20139.","journal-title":"Clin Chem"},{"key":"5947_CR13","first-page":"n71","volume":"372","author":"MJ Page","year":"2021","unstructured":"Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. 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Circulating adrenomedullin estimates survival and reversibility of organ failure in sepsis: the prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock-1 (AdrenOSS-1) study. Crit Care. 2018;22(1):354.","journal-title":"Crit Care"},{"issue":"10","key":"5947_CR18","doi-asserted-by":"publisher","first-page":"e2019209","DOI":"10.1001\/jamanetworkopen.2020.19209","volume":"3","author":"M Ostermann","year":"2020","unstructured":"Ostermann M, Zarbock A, Goldstein S, Kashani K, Macedo E, Murugan R, et al. Recommendations on Acute Kidney Injury Biomarkers From the Acute Disease Quality Initiative Consensus Conference: A Consensus Statement. 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Circulation Heart Fail. 2024;17(11):e011751.","journal-title":"Circulation Heart Fail"}],"container-title":["Critical Care"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13054-026-05947-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13054-026-05947-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13054-026-05947-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T20:48:07Z","timestamp":1781642887000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13054-026-05947-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,24]]},"references-count":19,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["5947"],"URL":"https:\/\/doi.org\/10.1186\/s13054-026-05947-5","relation":{},"ISSN":["1364-8535"],"issn-type":[{"value":"1364-8535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,24]]},"assertion":[{"value":"13 January 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 March 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 March 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Ethics approval has been obtained for each study separately by the respective principle investigators. The AdrenOSS-1 study protocol was approved by the local ethics committees and registered at Clinicaltrials.gov (NCT02393781). Informed consent was obtained from all patients or their lawful representatives. The ALBIOS study protocol and informed-consent process were approved by the ethics committee at each participating institution. The study was registered at Clinicaltrials.gov (NCT00707122). The FROG ICU study has been validated by the ethical committee (Comit\u00e9 de Protection des Personnes \u2013 Ile de France IV, IRB n\u00b000003835. Comission d\u2019\u00e9thique biom\u00e9dicale hospitalo-facultaire de l\u2019h\u00f4pital de Louvain, IRB n\u00b0B403201213352) and registered on Clinicaltrials.gov (NCT01367093). As the ethical committee waived the need for written consent, all patients and\/or next of kin were informed and orally consented to participate. The PredARRT-Sep study was approved by the local Ethics Committee of the Medical Faculty of Heidelberg (S-200\/2017) and registered at the German Clinical Trials Register (DRKS00012446). Written informed consent was obtained from all participants or their legal representatives.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"ML is supported by grant R01-GM151494-01 and R01DK139484-01 from the NIH and received consulting fees from Viatris, Idorsia, Vantive and speaker fees from Vantive and Estor. BA and FU are employed at SphingoTec GmbH, OH has been employed at SphingoTec GmbH, the manufacturer of the sphingotest\n \u00ae\n penKid\n \u00ae\n assay.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"164"}}