{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T10:08:40Z","timestamp":1792663720395,"version":"4.5.0"},"reference-count":101,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T00:00:00Z","timestamp":1770249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Acute kidney injury (AKI) is a systemic syndrome capable of inducing remote organ dysfunction. Kidney\u2013lung crosstalk is a form of interorgan communication in acute nephrology, with the heart acting as a pivotal intermediary. Emerging evidence supports the involvement of a gut\u2013lung\u2013kidney axis. Complement activation in these multiorgan crosstalk has emerged as a central amplifier of multiorgan damage. We reviewed the literature on kidney\u2013lung interactions and complement activation in AKI through a bibliographic search of PubMed, Scopus, and Web of Science. Most available data derive from experimental studies or intensive care unit (ICU) populations, often reported in reviews. We further report our real-world experience in a non-ICU nephrology setting, including 186 consecutive patients with AKI. Pulmonary involvement was present at hospital admission in 118 patients (63%). AKI stage 1 was observed in 20\/118 patients (17%) with pulmonary involvement compared with 18\/68 patients (27%) without pulmonary involvement (p &lt; 0.001). In conclusion, AKI should be regarded as a systemic disease from its earliest stages. Kidney\u2013lung interactions are clinically relevant even in mild AKI and outside critical care settings, underscoring the need for integrated organ assessment in routine nephrology practice. This review integrates complement activation as a central amplifier of kidney\u2013lung crosstalk and multiorgan dysfunction, bridging experimental evidence with real-world observations from a non-critical care AKI population. By focusing on early AKI stages and the timing of pulmonary involvement, we highlight AKI as an active driver of systemic organ interactions rather than a late consequence of critical illness.<\/jats:p>","DOI":"10.3390\/life16020276","type":"journal-article","created":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T10:35:37Z","timestamp":1770287737000},"page":"276","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Kidney\u2013Lung Crosstalk in Acute Nephrologic Involvement: Mechanisms, Complement Activation, and Implications for Multiorgan Dysfunction"],"prefix":"10.3390","volume":"16","author":[{"given":"Giuliana","family":"Martino","sequence":"first","affiliation":[{"name":"Nephrology and Dialysis Unit, University Hospital Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8867-3979","authenticated-orcid":false,"given":"Francesca","family":"Tinti","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Nephrology and Dialysis Unit, University Hospital S. Andrea, Sapienza University of Rome, 00189 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0511-2621","authenticated-orcid":false,"given":"Marco Alfonso","family":"Perrone","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Cond\u00f2","sequence":"additional","affiliation":[{"name":"Nephrology and Dialysis Unit, University Hospital Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Castagnola","sequence":"additional","affiliation":[{"name":"Nephrology and Dialysis Unit, University Hospital Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3546-6604","authenticated-orcid":false,"given":"Simone","family":"Manca de Villahermosa","sequence":"additional","affiliation":[{"name":"Nephrology and Dialysis Unit, University Hospital Tor Vergata, 00133 Rome, Italy"},{"name":"Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Triggianese","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3028-1061","authenticated-orcid":false,"given":"Marzena","family":"Olesinska","sequence":"additional","affiliation":[{"name":"Department of Connective Tissue Diseases, National Institute of Geriatrics, Rheumatology and Rehabilitation, 02-637 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Valentini","sequence":"additional","affiliation":[{"name":"Clinical Biochemistry Unit, University Hospital Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"Bernardini","sequence":"additional","affiliation":[{"name":"Clinical Biochemistry Unit, University Hospital Tor Vergata, 00133 Rome, Italy"},{"name":"Department of Experimental Medicine, University of Rome Tor Vergata, 00133 Rome, Italy"},{"name":"Department of Biology and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Della Morte","sequence":"additional","affiliation":[{"name":"Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8421-5065","authenticated-orcid":false,"given":"Ferdinando","family":"Iellamo","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1929-3044","authenticated-orcid":false,"given":"Luca","family":"Salomone","sequence":"additional","affiliation":[{"name":"Department of Clinical and Molecular Medicine, Nephrology and Dialysis Unit, University Hospital S. Andrea, Sapienza University of Rome, 00189 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7199-2954","authenticated-orcid":false,"given":"Silvia","family":"Lai","sequence":"additional","affiliation":[{"name":"Department of Translational and Precision Medicine, Nephrology Unit, Umberto I University Hospital, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0132-386X","authenticated-orcid":false,"given":"Anna Paola","family":"Mitterhofer","sequence":"additional","affiliation":[{"name":"Nephrology and Dialysis Unit, University Hospital Tor Vergata, 00133 Rome, Italy"},{"name":"Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1002\/1873-3468.14262","article-title":"Interorgan crosstalk mechanisms in disease: The case of acute kidney injury-induced remote lung injury","volume":"596","author":"Herrlich","year":"2022","journal-title":"FEBS Lett."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1016\/j.kint.2023.03.025","article-title":"Acute kidney injury and distant organ dysfunction\u2013network system analysis","volume":"103","author":"Matsuura","year":"2023","journal-title":"Kidney Int."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1053\/j.ajkd.2018.03.028","article-title":"Distant Organ Dysfunction in Acute Kidney Injury: A Review","volume":"72","author":"Lee","year":"2018","journal-title":"Am. J. Kidney Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1038\/s41581-023-00760-7","article-title":"Interorgan communication networks in the kidney\u2013lung axis","volume":"20","author":"Komaru","year":"2024","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/S0140-6736(24)02385-7","article-title":"Acute kidney injury","volume":"405","author":"Ostermann","year":"2025","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Li, X., Yuan, F., and Zhou, L. (2022). Organ Crosstalk in Acute Kidney Injury: Evidence and Mechanisms. J. Clin. Med., 11.","DOI":"10.3390\/jcm11226637"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.semnephrol.2018.10.007","article-title":"Kidney-Immune System Crosstalk in AKI","volume":"39","author":"Singbartl","year":"2019","journal-title":"Semin. Nephrol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1053\/j.ajkd.2021.06.023","article-title":"Concomitant Lung and Kidney Disorders in Critically Ill Patients: Core Curriculum 2022","volume":"79","author":"Sanghavi","year":"2022","journal-title":"Am. J. Kidney Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s40620-016-0276-7","article-title":"Kidney-lung connections in acute and chronic diseases: Current perspectives","volume":"29","author":"Visconti","year":"2016","journal-title":"J. Nephrol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e70021","DOI":"10.1002\/cph4.70021","article-title":"Kidney-Heart-Lung Interorgan Communication Networks in Health and Disease","volume":"15","author":"Herrlich","year":"2025","journal-title":"Compr. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1164\/rccm.201602-0420CP","article-title":"Lung\u2013Kidney Cross-Talk in the Critically Ill Patient","volume":"194","author":"Slutsky","year":"2016","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_12","first-page":"20","article-title":"Chronic lung diseases and kidney disease: Pathophysiology and management","volume":"41","author":"Lassola","year":"2026","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Kumar, A., Epler, K., DeWolf, S., Barnes, L., and Hepokoski, M. (2024). Bidirectional pressure: A mini review of ventilator-lung-kidney interactions. Front. Physiol., 15.","DOI":"10.3389\/fphys.2024.1428177"},{"key":"ref_14","first-page":"646","article-title":"Kidney-organ interactions: Recent advances and clinical implications","volume":"31","author":"Legrand","year":"2025","journal-title":"Curr. Opin. Crit. Care"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"933","DOI":"10.2215\/CJN.0000000000000064","article-title":"Cardiorenal Syndrome in the Hospital","volume":"18","author":"McCallum","year":"2023","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1161\/CIRCULATIONAHA.116.022362","article-title":"Systemic Consequences of Pulmonary Hypertension and Right-Sided Heart Failure","volume":"141","author":"Rosenkranz","year":"2020","journal-title":"Circulation"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1161\/CIRCRESAHA.124.325488","article-title":"Renal-Cardiac Crosstalk in the Pathogenesis and Progression of Heart Failure","volume":"136","author":"Noels","year":"2025","journal-title":"Circ. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.ijcard.2013.09.014","article-title":"Pathophysiology of cardiorenal syndrome in decompensated heart failure: Role of lung\u2013right heart\u2013kidney interaction","volume":"169","author":"Guazzi","year":"2013","journal-title":"Int. J. Cardiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1161\/CIRCRESAHA.123.321763","article-title":"Role of the Microbiome in Gut-Heart-Kidney Cross Talk","volume":"132","author":"Glorieux","year":"2023","journal-title":"Circ. Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Liu, X., Wang, X., Zhang, P., Fang, Y., Liu, Y., Ding, Y., and Zhang, W. (2023). Intestinal homeostasis in the gut-lung-kidney axis: A prospective therapeutic target in immune-related chronic kidney diseases. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1266792"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.jacc.2013.04.070","article-title":"Abdominal Contributions to Cardiorenal Dysfunction in Congestive Heart Failure","volume":"62","author":"Verbrugge","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e192917","DOI":"10.1172\/JCI192917","article-title":"Traffic jam in lung capillaries: Inter-organ communication impedes gas exchange after acute kidney injury","volume":"135","author":"Matt","year":"2025","journal-title":"J. Clin. Investig."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1016\/j.mayocp.2025.06.005","article-title":"Role of the Complement System in Acute Kidney Injury: A Narrative Review","volume":"100","author":"Wei","year":"2025","journal-title":"Mayo Clin. Proc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/j.semnephrol.2013.08.005","article-title":"The Role of the Complement System in Acute Kidney Injury","volume":"33","author":"McCullough","year":"2013","journal-title":"Semin. Nephrol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1681\/ASN.2011111072","article-title":"C3a and C5a Promote Renal Ischemia-Reperfusion Injury","volume":"23","author":"Peng","year":"2012","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Arias-Cabrales, C., Rodriguez-Garcia, E., Gimeno, J., Benito, D., P\u00e9rez-S\u00e1ez, M.J., Redondo-Pach\u00f3n, D., Buxeda, A., Burballa, C., Crespo, M., and Pascual, J. (2021). Role of C5aR1 and C5L2 Receptors in Ischemia-Reperfusion Injury. J. Clin. Med., 10.","DOI":"10.3390\/jcm10050974"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/s41581-023-00766-1","article-title":"The role of complement in kidney disease","volume":"19","author":"Petr","year":"2023","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.semnephrol.2013.08.001","article-title":"Overview of Complement Activation and Regulation","volume":"33","author":"Noris","year":"2013","journal-title":"Semin. Nephrol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1159\/000538241","article-title":"The Complement C3a and C5a Signaling in Renal Diseases: A Bridge between Acute and Chronic Inflammation","volume":"148","author":"Buelli","year":"2024","journal-title":"Nephron"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Anliker-Ort, M., Dingemanse, J., Van Den Anker, J., and Kaufmann, P. (2020). Treatment of Rare Inflammatory Kidney Diseases: Drugs Targeting the Terminal Complement Pathway. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.599417"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Niederreiter, J., Eck, C., Ries, T., Hartmann, A., M\u00e4rkl, B., B\u00fcttner-Herold, M., Amann, K., and Daniel, C. (2022). Complement Activation via the Lectin and Alternative Pathway in Patients With Severe COVID-19. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.835156"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1016\/S0140-6736(23)01524-6","article-title":"Complement in human disease: Approved and up-and-coming therapeutics","volume":"403","author":"West","year":"2024","journal-title":"Lancet"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Lasorsa, F., Rutigliano, M., Milella, M., Ferro, M., Pandolfo, S.D., Crocetta, F., Simone, S., Gesualdo, L., Battaglia, M., and Battaglia, M. (2023). Complement System and the Kidney: Its Role in Renal Diseases, Kidney Transplantation and Renal Cell Carcinoma. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242216515"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Henry, B.M., Sinkovits, G.S., de Oliveira, M.H.S., Lippi, G., Bernait, J.L., Favaloro, E.J., Pode-Sakked, N., Benoit, S.V., Copper, D.S., and Iv\u00e1nyi, Z. (2022). Complement Levels at Admission Reflecting Progression to Severe Acute Kidney Injury (AKI) in Coronavirus Disease 2019 (COVID-19): A Multicenter Prospective Cohort Study. Front. Med., 9.","DOI":"10.3389\/fmed.2022.796109"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1007\/s00134-024-07611-4","article-title":"Complement system activation: Bridging physiology, pathophysiology, and therapy","volume":"50","author":"Azoulay","year":"2024","journal-title":"Intensive Care Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/S0008-6363(01)00327-3","article-title":"Molecular biology of natriuretic peptides and nitric oxide synthases","volume":"51","author":"Kone","year":"2001","journal-title":"Cardiovasc. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"fasebj.2022.36.S1.0I149","DOI":"10.1096\/fasebj.2022.36.S1.0I149","article-title":"Interorgan crosstalk and metabolism regulation in Drosophila","volume":"36","author":"Perrimon","year":"2022","journal-title":"FASEB J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1146\/annurev-neuro-111020-105359","article-title":"Neuroimmune Interactions in Peripheral Organs","volume":"45","author":"Wolterink","year":"2022","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"F235","DOI":"10.1152\/ajprenal.00454.2004","article-title":"Prostacyclin signaling in the kidney: Implications for health and disease","volume":"289","author":"Nasrallah","year":"2005","journal-title":"Am. J. Physiol.-Ren. Physiol."},{"key":"ref_40","first-page":"5447","article-title":"A Nuclear Factor Induced by Hypoxia via De Novo Protein Synthesis Binds to the Human Erythropoietin Gene Enhancer at a Site Required for Transcriptional Activation","volume":"12","author":"Semenza","year":"1992","journal-title":"Mol. Cell. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1038\/s41581-019-0182-z","article-title":"Mechanisms of hypoxia signalling: New implications for nephrology","volume":"15","author":"Ratcliffe","year":"2019","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1038\/embor.2010.170","article-title":"The hypoxia-inducible transcription factor pathway regulates oxygen sensing in the simplest animal, Trichoplax adhaerens","volume":"12","author":"Loenarz","year":"2011","journal-title":"EMBO Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1152\/physrev.00017.2003","article-title":"Neuroendocrine Control of Body Fluid Metabolism","volume":"84","author":"Elias","year":"2004","journal-title":"Physiol. Rev."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/s12931-023-02657-2","article-title":"The complement cascade in lung injury and disease","volume":"25","author":"Detsika","year":"2024","journal-title":"Respir. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"L790","DOI":"10.1152\/ajplung.2000.279.5.L790","article-title":"Complement-mediated host defense in the lung","volume":"279","author":"Watford","year":"2000","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Fu, Y., Wang, W., Gong, N., Zheng, X., Guo, X., Zhuang, K., Han, Q., Feng, Z., Chen, X., and Cai, G. (2025). Neutrophil and neutrophil extracellular traps in acute kidney injury: From mechanisms to treatments. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1688207"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1038\/nri2620","article-title":"Complement regulators and inhibitory proteins","volume":"9","author":"Zipfel","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"ref_48","first-page":"1178","article-title":"NETosis: Molecular Mechanisms, Role in Physiology and Pathology","volume":"85","author":"Vorobjeva","year":"2020","journal-title":"Biochemistry"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Maeda, A., Hayase, N., and Doi, K. (2020). Acute Kidney Injury Induces Innate Immune Response and Neutrophil Activation in the Lung. Front. Med., 7.","DOI":"10.3389\/fmed.2020.565010"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e186705","DOI":"10.1172\/JCI186705","article-title":"Acute kidney injury triggers hypoxemia by lung intravascular neutrophil retention that reduces capillary blood flow","volume":"135","author":"Komaru","year":"2025","journal-title":"J. Clin. Investig."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1080\/15548627.2022.2084862","article-title":"Mitochondria ROS and mitophagy in acute kidney injury","volume":"19","author":"Su","year":"2023","journal-title":"Autophagy"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1158\/2326-6066.CIR-24-0250","article-title":"The C5a\/C5aR1 Axis Promotes Migration of Tolerogenic Dendritic Cells to Lymph Nodes, Impairing the Anticancer Immune Response","volume":"13","author":"Senent","year":"2025","journal-title":"Cancer Immunol. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1111\/j.1523-1755.2005.67109.x","article-title":"Acute tubular necrosis is characterized by activation of the alternative pathway of complement","volume":"67","author":"Thurman","year":"2005","journal-title":"Kidney Int."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1002\/JLB.3MIR1218-497R","article-title":"Location is the key to function: HMGB1 in sepsis and trauma-induced inflammation","volume":"106","author":"Deng","year":"2019","journal-title":"J. Leukoc. Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1038\/s41598-019-57205-0","article-title":"Recombinant thrombomodulin prevents acute lung injury induced by renal ischemia-reperfusion injury","volume":"10","author":"Hayase","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1038\/s12276-022-00736-w","article-title":"The mechanism of HMGB1 secretion and release","volume":"54","author":"Chen","year":"2022","journal-title":"Exp. Mol. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1111\/1440-1681.12694","article-title":"R1 autonomic nervous system in acute kidney injury","volume":"44","author":"Hering","year":"2017","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/S0140-6736(22)01485-4","article-title":"Acute respiratory distress syndrome: Causes, pathophysiology, and phenotypes","volume":"400","author":"Bos","year":"2022","journal-title":"Lancet"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1186\/s13054-025-05343-5","article-title":"Ventilation-induced acute kidney injury in acute respiratory failure: Do PEEP levels matter?","volume":"29","author":"Benites","year":"2025","journal-title":"Crit. Care"},{"key":"ref_60","first-page":"11374","article-title":"Effects of non-invasive ventilation on renal and endothelial function in patients with respiratory failure","volume":"24","author":"Lai","year":"2020","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"F654","DOI":"10.1152\/ajprenal.00523.2016","article-title":"Ventilator-induced lung injury increases expression of endothelial inflammatory mediators in the kidney","volume":"312","author":"Hepokoski","year":"2017","journal-title":"Am. J. Physiol.-Ren. Physiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1161\/CIR.0000000000000664","article-title":"Cardiorenal Syndrome: Classification, Pathophysiology, Diagnosis, and Treatment Strategies: A Scientific Statement From the American Heart Association","volume":"139","author":"Rangaswami","year":"2019","journal-title":"Circulation"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1093\/ndt\/gfaa297","article-title":"Renohepatic crosstalk: A review of the effects of acute kidney injury on the liver","volume":"37","author":"Bonavia","year":"2022","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"5409","DOI":"10.1038\/s41467-022-33152-9","article-title":"The complement C3-complement factor D-C3a receptor signalling axis regulates cardiac remodelling in right ventricular failure","volume":"13","author":"Ito","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1042\/CS20257865","article-title":"Complement C3 in panvascular disease: A central integrator of immune signaling and vascular remodeling","volume":"139","author":"Li","year":"2025","journal-title":"Clin. Sci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"120158","DOI":"10.1016\/j.lfs.2021.120158","article-title":"NETosis in ischemic\/reperfusion injuries: An organ-based review","volume":"290","author":"Hashemi","year":"2022","journal-title":"Life Sci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e71263","DOI":"10.1096\/fj.202502028R","article-title":"Nicotinamide Attenuates Complement and Coagulation Pathways and Resultant Renal Fibrosis","volume":"39","author":"Kin","year":"2025","journal-title":"FASEB J."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.kint.2019.01.039","article-title":"The C5a\/C5aR1 axis promotes progression of renal tubulointerstitial fibrosis in a mouse model of renal ischemia\/reperfusion injury","volume":"96","author":"Peng","year":"2019","journal-title":"Kidney Int."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1038\/s12276-021-00589-9","article-title":"Sublytic C5b-9 induces glomerular mesangial cell proliferation via ERK1\/2-dependent SOX9 phosphorylation and acetylation by enhancing Cyclin D1 in rat Thy-1 nephritis","volume":"53","author":"Xie","year":"2021","journal-title":"Exp. Mol. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.kint.2020.05.013","article-title":"The case of complement activation in COVID-19 multiorgan impact","volume":"98","author":"Noris","year":"2020","journal-title":"Kidney Int."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1038\/s41581-023-00704-1","article-title":"Complosome\u2014The intracellular complement system","volume":"19","author":"West","year":"2023","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1111\/imr.13167","article-title":"Kidney diseases","volume":"313","author":"Daina","year":"2023","journal-title":"Immunol. Rev."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1016\/j.semnephrol.2013.08.009","article-title":"Complement-Mediated Cellular Injury","volume":"33","author":"Takano","year":"2013","journal-title":"Semin. Nephrol."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Yang, Z., Nicholson, S.E., Cancio, T.S., Cancio, L.C., and Li, Y. (2023). Complement as a vital nexus of the pathobiological connectome for acute respiratory distress syndrome: An emerging therapeutic target. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1100461"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1097\/SLA.0b013e3181a38f45","article-title":"Complement-Mediated Ischemia-Reperfusion Injury: Lessons Learned From Animal and Clinical Studies","volume":"249","author":"Diepenhorst","year":"2009","journal-title":"Ann. Surg."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1681\/ASN.2016080925","article-title":"Histones and Neutrophil Extracellular Traps Enhance Tubular Necrosis and Remote Organ Injury in Ischemic AKI","volume":"28","author":"Nakazawa","year":"2017","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"152580","DOI":"10.1016\/j.bbrc.2025.152580","article-title":"Complement system: A key player in hepatic ischemia-reperfusion injury","volume":"783","year":"2025","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e29769","DOI":"10.1016\/j.heliyon.2024.e29769","article-title":"The critical impacts of cytokine storms in respiratory disorders","volume":"10","author":"Tramboo","year":"2024","journal-title":"Heliyon"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1038\/s41581-022-00539-2","article-title":"Experimental models of acute kidney injury for translational research","volume":"18","author":"Hukriede","year":"2022","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"F563","DOI":"10.1152\/ajprenal.00402.2023","article-title":"Rodent models of AKI and AKI-CKD transition: An update in 2024","volume":"326","author":"Fu","year":"2024","journal-title":"Am. J. Physiol.-Ren. Physiol."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Chun, N., Zhang, J., Shi, X., Zhou, X., Wang, Y., Li, M., Chen, Z., Liu, Y., Huang, H., and Wang, J. (2017). Activation of complement factor B contributes to murine and human myocardial ischemia\/reperfusion injury. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0179450"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1053\/j.ajkd.2022.08.007","article-title":"Plasma Soluble Tumor Necrosis Factor Receptor Concentrations and Clinical Events After Hospitalization: Findings From the ASSESS-AKI and ARID Studies","volume":"81","author":"Coca","year":"2023","journal-title":"Am. J. Kidney Dis."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"S159","DOI":"10.1097\/CCM.0b013e318168c652","article-title":"New biomarkers of acute kidney injury","volume":"36","author":"Parikh","year":"2008","journal-title":"Crit. Care Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1038\/sj.ki.5002729","article-title":"Biomarkers for the diagnosis and risk stratification of acute kidney injury: A systematic review","volume":"73","author":"Coca","year":"2008","journal-title":"Kidney Int."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1681\/ASN.2006050494","article-title":"Acute Renal Failure after Bilateral Nephrectomy Is Associated with Cytokine-Mediated Pulmonary Injury","volume":"18","author":"Hoke","year":"2007","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/ki.2014.62","article-title":"The high-mobility group protein B1\u2013Toll-like receptor 4 pathway contributes to the acute lung injury induced by bilateral nephrectomy","volume":"86","author":"Doi","year":"2014","journal-title":"Kidney Int."},{"key":"ref_87","first-page":"496","article-title":"Regulatory Effect of the HMGB1-TLR4 Signaling Pathway in Pulmonary Ischemia\/Reperfusion","volume":"55","author":"Tan","year":"2025","journal-title":"Ann. Clin. Lab. Sci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"S302","DOI":"10.1097\/00003246-200205001-00021","article-title":"Markers of endothelial damage in organ dysfunction and sepsis","volume":"30","author":"Reinhart","year":"2002","journal-title":"Crit. Care Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/1465-9921-10-54","article-title":"Alveolar hypoxia, alveolar macrophages, and systemic inflammation","volume":"10","author":"Chao","year":"2009","journal-title":"Respir. Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1093\/ndt\/gfx256","article-title":"Glomerular function in relation to circulating adhesion molecules and inflammation markers in a general population","volume":"33","author":"Feng","year":"2018","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_91","unstructured":"Liu, B.-C., Lan, H.-Y., and Lv, L.-L. (2019). Complement Activation in Progression of Chronic Kidney Disease. Renal Fibrosis: Mechanisms and Therapies, Springer. Advances in Experimental Medicine and Biology."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"e188345","DOI":"10.1172\/JCI188345","article-title":"Role of local complement activation in kidney fibrosis and repair","volume":"135","author":"Portilla","year":"2025","journal-title":"J. Clin. Investig."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"ii29","DOI":"10.1093\/ndt\/gfad079","article-title":"Complement inhibitors for kidney disease","volume":"38","author":"Wooden","year":"2023","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"2868","DOI":"10.1172\/JCI39421","article-title":"Animal models of sepsis and sepsis-induced kidney injury","volume":"119","author":"Doi","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Bhargava, R., Janssen, W., Altmann, C., Andr\u00e9s-Hernando, A., Okamura, K., Vandivier, R.W., Ahuja, N., He, Z., Kelley, V.R., and Faubel, S. (2013). Acute Lung Injury and Acute Kidney Injury Are Established by Four Hours in Experimental Sepsis and Are Improved with Pre, but Not Post, Sepsis Administration of TNF-\u03b1 Antibodies. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0079037"},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Kuiper, J.W., Groeneveld, A.B.J., Slutsky, A.S., Pl\u00f6tz, F.B., de Mol, B.A.J.M., Schultz, M.J., van der Poll, T., Levi, M., van der Sluijs, K.F., and van Westerloo, D.J. (2014). Injurious mechanical ventilation causes kidney apoptosis and dysfunction during sepsis but not after intra-tracheal acid instillation: An experimental study. BMC Nephrol., 15.","DOI":"10.1186\/1471-2369-15-126"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"985","DOI":"10.21037\/atm-20-2050","article-title":"Protecting the lungs but hurting the kidneys: Causal inference study for the risk of ventilation-induced kidney injury in ARDS","volume":"8","author":"Yang","year":"2020","journal-title":"Ann. Transl. Med."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Maqsood, M., Wang, Y., Mishra, A., Xu, H., Zhang, Z., Khan, A.A., Zheng, Z., Li, J., Liu, X., and Qiu, Y. (2024). Complement-Mediated Two-Step NETosis: Serum-Induced Complement Activation and Calcium Influx Generate NADPH Oxidase-Dependent NETs in Serum-Free Conditions. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25179625"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/j.injury.2011.02.011","article-title":"Second hit phenomenon: Existing evidence of clinical implications","volume":"42","author":"Lasanianos","year":"2011","journal-title":"Injury"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"697193","DOI":"10.1155\/2015\/697193","article-title":"Reconciling the IPC and Two-Hit Models: Dissecting the Underlying Cellular and Molecular Mechanisms of Two Seemingly Opposing Frameworks","volume":"2015","author":"Morris","year":"2015","journal-title":"J. Immunol. Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"20185","DOI":"10.1038\/s41598-020-76499-z","article-title":"Different experimental multiple trauma models induce comparable inflammation and organ injury","volume":"10","author":"Relja","year":"2020","journal-title":"Sci. Rep."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/2\/276\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T10:48:49Z","timestamp":1770288529000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/16\/2\/276"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,5]]},"references-count":101,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["life16020276"],"URL":"https:\/\/doi.org\/10.3390\/life16020276","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,5]]}}}