{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:46:33Z","timestamp":1760060793007,"version":"build-2065373602"},"reference-count":41,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T00:00:00Z","timestamp":1758153600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"National Science Centre, Poland (MINIATURA 4)","doi-asserted-by":"publisher","award":["2020\/04\/X\/NZ5\/00395","B.SUB.25.556"],"award-info":[{"award-number":["2020\/04\/X\/NZ5\/00395","B.SUB.25.556"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Medical University of Bialystok","award":["2020\/04\/X\/NZ5\/00395","B.SUB.25.556"],"award-info":[{"award-number":["2020\/04\/X\/NZ5\/00395","B.SUB.25.556"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>TNF-related apoptosis-inducing ligand (TRAIL), a protein involved in apoptosis, and receptor-interacting serine\/threonine protein kinase-3 (RIPK3), implicated in necroptosis, are known to change during organ damage and have been studied as prognostic markers in sepsis; however, cell death mechanisms also play a role in other critical illnesses. This study aimed to assess the utility of TRAIL and RIPK3 in predicting mortality and acute kidney injury (AKI) among unselected intensive care unit (ICU) patients. We performed a single-center prospective cohort study including 142 consecutive ICU admissions, collecting blood samples for TRAIL and RIPK3 measurement within 24 h of admission. The primary endpoints were in-hospital mortality and incident AKI during the ICU stay, with additional analysis of mortality over a two-year follow-up. Neither TRAIL nor RIPK3 levels at admission were significantly associated with in-hospital mortality, long-term mortality, or AKI incidence. However, higher RIPK3 levels correlated with shorter time to AKI occurrence. These results suggest that despite earlier evidence supporting their prognostic value in sepsis, TRAIL and RIPK3 did not reliably predict outcomes in a heterogeneous ICU population, underscoring the complexity of critical illness and the need for multiparametric biomarker strategies to improve risk stratification.<\/jats:p>","DOI":"10.3390\/ijms26189090","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T12:54:26Z","timestamp":1758200066000},"page":"9090","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["TRAIL and RIPK3 Do Not Predict Mortality and Acute Kidney Injury in Critically Ill Patients at Admission to the Intensive Care Unit\u2014A Single-Center Cohort Study"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8046-4179","authenticated-orcid":false,"given":"Katarzyna","family":"Kakareko","sequence":"first","affiliation":[{"name":"2nd Department of Nephrology, Hypertension and Internal Medicine with Dialysis Unit, Medical University of Bialystok, 15-089 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8126-3085","authenticated-orcid":false,"given":"Alicja","family":"Rydzewska-Rosolowska","sequence":"additional","affiliation":[{"name":"2nd Department of Nephrology, Hypertension and Internal Medicine with Dialysis Unit, Medical University of Bialystok, 15-089 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irena","family":"Glowinska","sequence":"additional","affiliation":[{"name":"2nd Department of Nephrology, Hypertension and Internal Medicine with Dialysis Unit, Medical University of Bialystok, 15-089 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0054-8802","authenticated-orcid":false,"given":"Elzbieta","family":"Regulska","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, University of Castilla-La Mancha, 02008 Albacete, Spain"},{"name":"Faculty of Chemistry, University of Bialystok, 15-089 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karolina","family":"Rygasiewicz","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care, Medical University of Bialystok, 15-089 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ewa","family":"Koc-Zorawska","sequence":"additional","affiliation":[{"name":"2nd Department of Nephrology, Hypertension and Internal Medicine with Dialysis Unit, Medical University of Bialystok, 15-089 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0145-3103","authenticated-orcid":false,"given":"Tomasz","family":"Hryszko","sequence":"additional","affiliation":[{"name":"2nd Department of Nephrology, Hypertension and Internal Medicine with Dialysis Unit, Medical University of Bialystok, 15-089 Bialystok, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/S2213-2600(14)70061-X","article-title":"Assessment of the worldwide burden of critical illness: The intensive care over nations (ICON) audit","volume":"2","author":"Vincent","year":"2014","journal-title":"Lancet Respir. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"128","DOI":"10.5152\/ttd.2015.4510","article-title":"Determination of Factors Affecting Mortality of Patients with Sepsis in a Tertiary Intensive Care Unit","volume":"16","author":"Balcan","year":"2015","journal-title":"Turk. Thorac. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"121","DOI":"10.4103\/ijciis.ijciis_98_21","article-title":"Evaluation of time to death after admission to an intensive care unit and factors associated with mortality: A retrospective longitudinal study","volume":"12","author":"Mezzaroba","year":"2022","journal-title":"Int. J. Crit. Illn. Inj. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1007\/BF01709751","article-title":"The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction\/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine","volume":"22","author":"Vincent","year":"1996","journal-title":"Intensive Care Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1001\/jama.286.14.1754","article-title":"Serial evaluation of the SOFA score to predict outcome in critically ill patients","volume":"286","author":"Ferreira","year":"2001","journal-title":"JAMA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1615\/CritRevImmunol.2013006721","article-title":"T-cell-mediated immunity and the role of TRAIL in sepsis-induced immunosuppression","volume":"33","author":"Condotta","year":"2013","journal-title":"Crit. Rev. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Chen, X., Chen, B., and Zhao, H. (2025). Role of Neutrophils in Anti-Tumor Activity: Characteristics and Mechanisms of Action. Cancers, 17.","DOI":"10.3390\/cancers17081298"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e127143","DOI":"10.1172\/jci.insight.127143","article-title":"Circulating cell death biomarker TRAIL is associated with increased organ dysfunction in sepsis","volume":"4","author":"Schenck","year":"2019","journal-title":"JCI Insight"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Tian, Y., Tao, T., Zhu, J., Zou, Y., Wang, J., Li, J., Bo, L., and Deng, X. (2013). Soluble tumor necrosis factor related apoptosis inducing ligand level as a predictor of severity of sepsis and the risk of mortality in septic patients. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0082204"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e98411","DOI":"10.1172\/jci.insight.98411","article-title":"RIPK3 promotes sepsis-induced acute kidney injury via mitochondrial dysfunction","volume":"3","author":"Sureshbabu","year":"2018","journal-title":"JCI Insight"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1189\/jlb.0211062","article-title":"TNF-related apoptosis-inducing ligand (TRAIL) regulates inflammatory neutrophil apoptosis and enhances resolution of inflammation","volume":"90","author":"McGrath","year":"2011","journal-title":"J. Leukoc. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"330","DOI":"10.3390\/cells2020330","article-title":"Targeting neutrophil apoptosis for enhancing the resolution of inflammation","volume":"2","author":"Filep","year":"2013","journal-title":"Cells"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1097\/CCM.0b013e3181eedaa8","article-title":"Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) improves the innate immune response and enhances survival in murine polymicrobial sepsis","volume":"38","author":"Cziupka","year":"2010","journal-title":"Crit. Care Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2148","DOI":"10.4049\/jimmunol.1101180","article-title":"Immune unresponsiveness to secondary heterologous bacterial infection after sepsis induction is TRAIL dependent","volume":"187","author":"Gurung","year":"2011","journal-title":"J. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Yoo, H., Lee, J.Y., Park, J., Yang, J.H., Suh, G.Y., and Jeon, K. (2020). Association of Plasma Level of TNF-Related Apoptosis-Inducing Ligand with Severity and Outcome of Sepsis. J. Clin. Med., 9.","DOI":"10.3390\/jcm9061661"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1126\/science.277.5327.818","article-title":"Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors","volume":"277","author":"Sheridan","year":"1997","journal-title":"Science"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2279","DOI":"10.1007\/s11739-022-03086-7","article-title":"Serum TRAIL predicts severity and prognosis in patients with community-acquired pneumonia: A prospective cohort study","volume":"17","author":"Hua","year":"2022","journal-title":"Intern. Emerg. Med."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Molinero, M., G\u00f3mez, S., Ben\u00edtez, I.D., Vengoechea, J.J., Gonz\u00e1lez, J., Polanco, D., Gort-Paniello, C., Moncus\u00ed-Moix, A., Garc\u00eda-Hidalgo, M.C., and Perez-Pons, M. (2022). Multiplex protein profiling of bronchial aspirates reveals disease-, mortality- and respiratory sequelae-associated signatures in critically ill patients with ARDS secondary to SARS-CoV-2 infection. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.942443"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Snajdauf, M., Havlova, K., Vachtenheim, J., Ozaniak, A., Lischke, R., Bartunkova, J., Smrz, D., and Strizova, Z. (2021). The TRAIL in the Treatment of Human Cancer: An Update on Clinical Trials. Front. Mol. Biosci., 8.","DOI":"10.3389\/fmolb.2021.628332"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1965","DOI":"10.1007\/s00018-004-4197-6","article-title":"TRAIL promotes the survival, migration and proliferation of vascular smooth muscle cells","volume":"61","author":"Secchiero","year":"2004","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1369\/jhc.3A6112.2004","article-title":"Tissue distribution of the death ligand TRAIL and its receptors","volume":"52","author":"Spierings","year":"2004","journal-title":"J. Histochem. Cytochem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.yjmcc.2019.08.011","article-title":"Death receptor 5 contributes to cardiomyocyte hypertrophy through epidermal growth factor receptor transactivation","volume":"136","author":"Tanner","year":"2019","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Di Bartolo, B.A., Cartland, S.P., Harith, H.H., Bobryshev, Y.V., Schoppet, M., and Kavurma, M.M. (2013). TRAIL-deficiency accelerates vascular calcification in atherosclerosis via modulation of RANKL. PLoS ONE, 8.","DOI":"10.1371\/annotation\/9732ca63-7532-4b92-8d6e-65c0863f25aa"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Bate, K.A., Genetzakis, E., Vescovi, J., Gray, M.P., Celermajer, D.S., McGuire, H.M., Grieve, S.M., Vernon, S.T., Cartland, S.P., and Yang, J.Y. (2024). Vascular Cytokines and Atherosclerosis: Differential Serum Levels of TRAIL, IL-18, and OPG in Obstructive Coronary Artery Disease. Biomolecules, 14.","DOI":"10.3390\/biom14091119"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1919","DOI":"10.1084\/jem.20112716","article-title":"Inhibition of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) reverses experimental pulmonary hypertension","volume":"209","author":"Hameed","year":"2012","journal-title":"J. Exp. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1002\/ejhf.980","article-title":"Circulating proteins as predictors of incident heart failure in the elderly","volume":"20","author":"Stenemo","year":"2018","journal-title":"Eur. J. Heart Fail."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1016\/j.atherosclerosis.2010.11.004","article-title":"Association of tumor necrosis factor-related apoptosis-inducing ligand with total and cardiovascular mortality in older adults","volume":"215","author":"Volpato","year":"2011","journal-title":"Atherosclerosis"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Bernardi, S., Bossi, F., Toffoli, B., and Fabris, B. (2016). Roles and Clinical Applications of OPG and TRAIL as Biomarkers in Cardiovascular Disease. BioMed Res. Int., 2016.","DOI":"10.1155\/2016\/1752854"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.imlet.2020.12.009","article-title":"Distinct cell death markers identified in critical care patient survivors diagnosed with sepsis","volume":"231","author":"Mallarpu","year":"2021","journal-title":"Immunol. Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e97102","DOI":"10.1172\/jci.insight.97102","article-title":"RIPK3 mediates pathogenesis of experimental ventilator-induced lung injury","volume":"3","author":"Siempos","year":"2018","journal-title":"JCI Insight"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e99692","DOI":"10.1172\/jci.insight.99692","article-title":"Circulating RIPK3 levels are associated with mortality and organ failure during critical illness","volume":"3","author":"Ma","year":"2018","journal-title":"JCI Insight"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Dundar, N.B., Inci, K., Pamuk, I., Aygencel, G., and Turkoglu, M. (2025). Predictors of Intensive Care Unit Outcomes in Elderly Patients with Acute Respiratory Failure: A Retrospective Cohort Study. J. Clin. Med., 14.","DOI":"10.3390\/jcm14165761"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13613-023-01102-3","article-title":"Critically ill patient mortality by age: Long-term follow-up (CIMbA-LT)","volume":"13","author":"Oliveira","year":"2023","journal-title":"Ann. Intensive Care"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s13054-017-1922-8","article-title":"Determinants of long-term outcome in ICU survivors: Results from the FROG-ICU study","volume":"22","author":"Gayat","year":"2018","journal-title":"Crit. Care"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1186\/s13054-020-03100-4","article-title":"Long-term survival of elderly patients after intensive care unit admission for acute respiratory infection: A population-based, propensity score-matched cohort study","volume":"24","author":"Guillon","year":"2020","journal-title":"Crit. Care"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1097\/SHK.0000000000000596","article-title":"Plasma Levels of Receptor Interacting Protein Kinase-3 (RIP3), an Essential Mediator of Necroptosis, are Associated with Acute Kidney Injury in Critically Ill Trauma Patients","volume":"46","author":"Shashaty","year":"2016","journal-title":"Shock"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"980","DOI":"10.1164\/rccm.201807-1419OC","article-title":"Transcriptomic Signatures in Sepsis and a Differential Response to Steroids. From the VANISH Randomized Trial","volume":"199","author":"Antcliffe","year":"2019","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1186\/s13054-023-04364-2","article-title":"The Role of Transcriptomics in Redefining Critical Illness","volume":"27","author":"Pelaia","year":"2023","journal-title":"Crit. Care"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.cyto.2017.12.024","article-title":"C-terminal and intact FGF23 in critical illness and their associations with acute kidney injury and in-hospital mortality","volume":"103","author":"Rygasiewicz","year":"2018","journal-title":"Cytokine"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Wagner-Golbs, A., Neuber, S., Kamlage, B., Christiansen, N., Bethan, B., Rennefahrt, U., Schatz, P., and Lind, L. (2019). Effects of Long-Term Storage at \u221280 degrees C on the Human Plasma Metabolome. Metabolites, 9.","DOI":"10.3390\/metabo9050099"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.1515\/cclm-2022-0845","article-title":"Long-term stability of thyroid peroxidase antibody (anti-TPO) in serum in the Danish General Suburban Population Study","volume":"61","author":"Jensen","year":"2023","journal-title":"Clin. Chem. Lab. 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