{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T13:48:04Z","timestamp":1792072084884,"version":"4.4.0"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"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. Nephrol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Continuous renal replacement therapy (CRRT) is the preferred extracorporeal renal support modality for haemodynamically unstable critically ill patients with acute kidney injury (AKI). Although regional citrate anticoagulation (RCA) is primarily used to maintain circuit patency, its biological effects may extend beyond anticoagulation itself. We hypothesized that different anticoagulation strategies are associated with distinct biological modulation across complementary pathophysiological domains during CRRT.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a prospective randomized pilot trial comparing RCA with systemic unfractionated heparin in critically ill adults with AKI requiring CRRT (1:1 allocation). Serial blood samples were obtained before CRRT initiation, at 1 hour and at 24 hours, with paired pre- and post-filter sampling at 1 and 24 hours. Biomarkers represented redox homeostasis (glutathione -GSH, GSSG- and their ratio), neutrophil activation (myeloperoxidase -MPO-), cellular injury (cell-free DNA -cfDNA-) and systemic inflammation (C-reactive protein -CRP-). Healthy reference participants established physiological reference values. Longitudinal analyses used linear mixed-effects models with fixed effects for time, anticoagulation strategy and their interaction. This trial was registered in the European Clinical Trials Database (EudraCT No. 2016-004361-12) and at ClinicalTrials.gov (NCT06646328).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Twenty patients were randomized equally to RCA or systemic heparin; baseline characteristics were comparable between groups. Among six biomarkers spanning four pathophysiological domains, only MPO showed a significant systemic time \u00d7 anticoagulation interaction (P\u00a0= .008); although baseline-adjusted sensitivity analyses did not confirm a significant between-group difference. GSH and cfDNA changed significantly over time irrespective of anticoagulation strategy (both P\u00a0= .016), while the GSSG\/GSH ratio approached a treatment-level difference (P\u00a0= .067). Across the extracorporeal circuit, CRP increased significantly post-filter at both timepoints, MPO increased at 1h, and GSH showed an anticoagulation-dependent pre-to-post change at 1h. No significant differences were observed in secondary clinical outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These pilot findings suggest that different anticoagulation strategies during CRRT may show domain-specific, rather than uniform, biological modulation, most evident within the neutrophil activation domain, with additional evidence of biomarker-specific kinetics across the extracorporeal circuit. These exploratory results are compatible with the concept that extracorporeal therapies may influence distinct domains differently, a hypothesis warranting confirmation in adequately powered, prospectively designed studies before implications for precision extracorporeal therapy can be drawn.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fneph.2026.1932419","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T04:32:25Z","timestamp":1789705945000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond renal support: biological modulation across pathophysiological domains during continuous renal replacement therapy \u2014 a randomized pilot study"],"prefix":"10.3389","volume":"6","author":[{"given":"Fernando","family":"S\u00e1nchez-Mor\u00e1n","sequence":"first","affiliation":[{"name":"Department of Intensive Care Medicine, General University Hospital of Castell\u00f3n","place":["Castell\u00f3n de la Plana, Spain"]},{"name":"Department of Medicine, Jaume I University","place":["Castell\u00f3n de la Plana, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvador","family":"P\u00e9rez","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Pharmacy, University of Valencia","place":["Valencia, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Sastre-Belloch","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Pharmacy, University of Valencia","place":["Valencia, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Lid\u00f3n","family":"Mateu-Campos","sequence":"additional","affiliation":[{"name":"Department of Intensive Care Medicine, General University Hospital of Castell\u00f3n","place":["Castell\u00f3n de la Plana, Spain"]},{"name":"Department of Medicine, Jaume I University","place":["Castell\u00f3n de la Plana, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"S10","DOI":"10.1186\/cc14728","article-title":"Paradigm shifts in critical care medicine: the progress we have made","volume":"19","author":"Vincent","year":"2015","journal-title":"Crit Care"},{"key":"B2","doi-asserted-by":"publisher","first-page":"90176","DOI":"10.5492\/wjccm.v13.i1.90176","article-title":"21st century critical care medicine: an overview","volume":"13","author":"Padte","year":"2024","journal-title":"World J Crit Care Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202311-2086SO","article-title":"From ICU syndromes to ICU subphenotypes: consensus report and recommendations for developing precision medicine in the ICU","volume":"210","author":"Gordon","year":"2024","journal-title":"Am J Respir Crit Care Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201602-0420CP","article-title":"Lung\u2013kidney cross-talk in the critically ill patient","volume":"194","author":"Husain-Syed","year":"2016","journal-title":"Am J Respir Crit Care Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3390\/jcm11226637","article-title":"Organ crosstalk in acute kidney injury: evidence and mechanisms","volume":"11","author":"Li","year":"2022","journal-title":"J Clin Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.75992","article-title":"Sepsis-associated acute kidney injury: pathophysiology and treatment modalities","volume":"16","author":"Aguilar","year":"2024","journal-title":"Cureus"},{"key":"B7","doi-asserted-by":"publisher","first-page":"2353128","DOI":"10.1155\/2018\/2353128","article-title":"Oxidative stress in the critically ill patients: pathophysiology and potential interventions","volume":"2018","author":"Makris","year":"2018","journal-title":"Oxid Med Cell Longev"},{"key":"B8","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1097\/SHK.0000000000000052","article-title":"A unified theory of sepsis-induced acute kidney injury","volume":"41","author":"Gomez","year":"2014","journal-title":"Shock"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-015-3934-7","article-title":"Epidemiology of acute kidney injury in critically ill patients: the multinational AKI-EPI study","volume":"41","author":"Hoste","year":"2015","journal-title":"Intensive Care Med"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1097\/ccm.0b013e318168c4a4","article-title":"Kidney disease: improving global outcomes (KDIGO) acute kidney injury work group. 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