{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T02:48:25Z","timestamp":1788922105127,"version":"build-2803163510"},"reference-count":22,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T00:00:00Z","timestamp":1755043200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Enkephalins are endogenous opioid peptides that modulate cardiovascular and renal function and are overexpressed in patients with acute heart failure (AHF). Although biologically active enkephalins lack a favorable biomarker profile, their stable surrogate proenkephalin 119\u2013159 (PENK) appears to display prognostic value in AHF settings. The aim of the present study was to evaluate the role of point-of-care (POC) PENK in predicting mortality and worsening renal function (WRF) in patients presenting to the emergency department (ED) with AHF. Methods: In this single-center observational study, 107 patients presenting to the ED with AHF were prospectively enrolled. We measured PENK levels upon ED presentation with a commercially available POC immunoassay and investigated their association with WRF within 48 h and all-cause mortality during a 1-year follow-up. Results: The patients had a mean age of 72 \u00b1 13 years, and 58% were men. Moreover, 62% had acutely decompensated chronic heart failure (HF), 24% had pulmonary edema, 9% had cardiogenic shock, and 5% had right HF. The median PENK levels were 111 [60\u2013193] pmol\/L. PENK was independently associated with WRF (adjusted OR, 95% CI: 15.4 [2.0\u2013120.2]; p = 0.009), with levels of \u226590.5 pmol\/L identified as the optimal cut-off for predicting WRF (AUC: 0.690; p &lt; 0.001). PENK was also an independent predictor of short- and long-term all-cause mortality, with an optimal cut-off of \u226595.8 pmol\/L (AUC for 30-day, 90-day, and 1-year mortality: 0.717, 0.723, and 0.724, respectively; all p &lt; 0.001). Conclusions: In patients presenting to the ED with AHF, POC PENK may serve as an early prognostic marker of WRF and short- and long-term mortality.<\/jats:p>","DOI":"10.3390\/jcm14165730","type":"journal-article","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T15:53:27Z","timestamp":1755100407000},"page":"5730","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Predictive Value of Point-of-Care Proenkephalin for Worsening Renal Function and Mortality in Patients Presenting to Emergency Department with Acute Heart Failure"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1405-0346","authenticated-orcid":false,"given":"Dionysis","family":"Matsiras","sequence":"first","affiliation":[{"name":"Department of Emergency Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7585-1203","authenticated-orcid":false,"given":"Effie","family":"Polyzogopoulou","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7572-4527","authenticated-orcid":false,"given":"Ioannis","family":"Ventoulis","sequence":"additional","affiliation":[{"name":"Department of Occupational Therapy, University of Western Macedonia, Keptse Area, 50200 Ptolemaida, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3734-5443","authenticated-orcid":false,"given":"Vasiliki","family":"Bistola","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3041-4787","authenticated-orcid":false,"given":"Christos","family":"Verras","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8241-7886","authenticated-orcid":false,"given":"Ignatios","family":"Ikonomidis","sequence":"additional","affiliation":[{"name":"2nd Department of Cardiology, Medical School, Attikon University Hospital, National and Kapodistrian University of Athens, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Parissis","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"132693","DOI":"10.1016\/j.ijcard.2024.132693","article-title":"Temporal Trends (2003\u20132018) of in-Hospital and 30-Day Mortality in Patients Hospitalized with Acute Heart Failure","volume":"419","author":"Marenzi","year":"2025","journal-title":"Int. J. Cardiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"565","DOI":"10.4070\/kcj.2011.41.10.565","article-title":"Renal Dysfunction in Acute Heart Failure","volume":"41","author":"Han","year":"2011","journal-title":"Korean Circ. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ejim.2019.10.025","article-title":"Creatinine: From Physiology to Clinical Application","volume":"72","author":"Kashani","year":"2020","journal-title":"Eur. J. Intern. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1161\/CIRCRESAHA.118.312706","article-title":"Established and Emerging Roles of Biomarkers in Heart Failure","volume":"123","author":"Ibrahim","year":"2018","journal-title":"Circ. Res."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Matsiras, D., Ventoulis, I., Verras, C., Bistola, V., Bezati, S., Fyntanidou, B., Polyzogopoulou, E., and Parissis, J.T. (2025). Proenkephalin 119\u2013159 in Heart Failure: From Pathophysiology to Clinical Implications. J. Clin. Med., 14.","DOI":"10.3390\/jcm14082657"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1093\/eurheartj\/14.2.219","article-title":"Relationship between Plasma Atrial Natriuretic Factor and Opioid Peptide Levels in Healthy Subjects and in Patients with Acute Congestive Heart Failure","volume":"14","author":"Fontana","year":"1993","journal-title":"Eur. Heart J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1016\/j.peptides.2006.03.008","article-title":"Proenkephalin A 119\u2013159, a Stable Proenkephalin a Precursor Fragment Identified in Human Circulation","volume":"27","author":"Ernst","year":"2006","journal-title":"Peptides"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Siranart, N., Laohasurayotin, K., Phanthong, T., Sowalertrat, W., Ariyachaipanich, A., and Chokesuwattanaskul, R. (2023). Proenkephalin as a Novel Prognostic Marker in Heart Failure Patients: A Systematic Review and Meta-Analysis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24054887"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1373\/jalm.2017.023598","article-title":"Proenkephalin (PENK) as a Novel Biomarker for Kidney Function","volume":"2","author":"Beunders","year":"2017","journal-title":"J. Appl. Lab. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3599","DOI":"10.1093\/eurheartj\/ehab368","article-title":"2021 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure","volume":"42","author":"McDonagh","year":"2021","journal-title":"Eur. Heart J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1737","DOI":"10.1056\/NEJMoa2102953","article-title":"New Creatinine- and Cystatin C\u2013Based Equations to Estimate GFR without Race","volume":"385","author":"Inker","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e121","DOI":"10.1515\/cclm-2022-1187","article-title":"Proenkephalin A 119\u2013159 (penKid)\u2014A Novel Biomarker and Its Quantification on the Nexus IB10 POC System for Assessing Kidney Function","volume":"61","author":"Cobb","year":"2023","journal-title":"Clin. Chem. Lab. Med. CCLM"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.clinbiochem.2018.05.010","article-title":"Analytical Performance of an Immunoassay to Measure Proenkephalin","volume":"58","author":"Donato","year":"2018","journal-title":"Clin. Biochem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.echo.2018.06.004","article-title":"Guidelines for Performing a Comprehensive Transthoracic Echocardiographic Examination in Adults: Recommendations from the American Society of Echocardiography","volume":"32","author":"Mitchell","year":"2019","journal-title":"J. Am. Soc. Echocardiogr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.jacc.2016.10.038","article-title":"Proenkephalin, Renal Dysfunction, and Prognosis in Patients with Acute Heart Failure","volume":"69","author":"Ng","year":"2017","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1080\/0886022X.2022.2114367","article-title":"Urine N-Terminal pro-B-Type Natriuretic Peptide and Plasma Proenkephalin Are Promising Biomarkers for Early Diagnosis of Cardiorenal Syndrome Type 1 in Acute Decompensated Heart Failure: A Prospective, Double-Center, Observational Study in Real-World","volume":"44","author":"Zhao","year":"2022","journal-title":"Ren. Fail."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e001048","DOI":"10.1136\/openhrt-2019-001048","article-title":"Bioactive Adrenomedullin, Proenkephalin A and Clinical Outcomes in an Acute Heart Failure Setting","volume":"6","author":"Molvin","year":"2019","journal-title":"Open Heart"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e005544","DOI":"10.1161\/CIRCHEARTFAILURE.118.005544","article-title":"Proenkephalin, an Opioid System Surrogate, as a Novel Comprehensive Renal Marker in Heart Failure","volume":"12","author":"Emmens","year":"2019","journal-title":"Circ. Heart Fail."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s13613-021-00814-8","article-title":"Predictive Value of Plasma Proenkephalin and Neutrophil Gelatinase-Associated Lipocalin in Acute Kidney Injury and Mortality in Cardiogenic Shock","volume":"11","author":"Harjola","year":"2021","journal-title":"Ann. Intensive Care"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.cardfail.2016.09.007","article-title":"Clinical Correlates and Prognostic Value of Proenkephalin in Acute and Chronic Heart Failure","volume":"23","author":"Matsue","year":"2017","journal-title":"J. Card. Fail."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2016","DOI":"10.1002\/ehf2.13278","article-title":"Neprilysin Inhibition Does Not Alter Dynamic of proenkephalin-A 119\u2013159 and Pro-substance P in Heart Failure","volume":"8","author":"Arfsten","year":"2021","journal-title":"ESC Heart Fail."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Grycuk, W., Jakubowska, Z., and Ma\u0142yszko, J. (2023). Proenkephalin Levels and Its Determinants in Patients with End-Stage Kidney Disease Treated with Hemodialysis and Peritoneal Dialysis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241915015"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/16\/5730\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:26:47Z","timestamp":1760034407000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/16\/5730"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,13]]},"references-count":22,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["jcm14165730"],"URL":"https:\/\/doi.org\/10.3390\/jcm14165730","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,13]]}}}