BACKGROUND AND AIMS: Circulating proenkephalin (PENK) is a stable endogenous polypeptide with fast response to glomerular dysfunction and tubular damage. This study examined the predictive value of PENK for renal outcomes and mortality in patients with acute coronary syndrome (ACS). METHODS: Proenkephalin was measured in plasma in a prospective multicentre ACS cohort from Switzerland (n = 4787) and in validation cohorts from the UK (n = 1141), Czechia (n = 927), and Germany (n = 220). A biomarker-enhanced risk score (KID-ACS score) for simultaneous prediction of in-hospital acute kidney injury (AKI) and 30-day mortality was derived and externally validated. RESULTS: On multivariable adjustment for established risk factors, circulating PENK remained associated with in-hospital AKI [per log2 increase: adjusted odds ratio 1.53, 95% confidence interval (CI) 1.13-2.09, P = .007] and 30-day mortality (adjusted hazard ratio 2.73, 95% CI 1.85-4.02, P < .001). The KID-ACS score integrates PENK and showed an area under the receiver operating characteristic curve (AUC) of .72 (95% CI .68-.76) for in-hospital AKI and .91 (95% CI .87-.95) for 30-day mortality in the derivation cohort. Upon external validation, KID-ACS achieved similarly high performance for in-hospital AKI (Zurich: AUC .73, 95% CI .70-.77; Czechia: AUC .75, 95% CI .68-.81; Germany: AUC .71, 95% CI .55-.87) and 30-day mortality (UK: AUC .87, 95% CI .83-.91; Czechia: AUC .91, 95% CI .87-.94; Germany: AUC .96, 95% CI .92-1.00), outperforming the contrast-associated AKI score and the Global Registry of Acute Coronary Events 2.0 score, respectively. CONCLUSIONS: Circulating PENK offers incremental value for predicting in-hospital AKI and mortality in ACS. The simple six-item KID-ACS risk score integrates PENK and provides a novel tool for simultaneous assessment of renal and mortality risk in patients with ACS.

1st Clinic of Internal Medicine Department of Internal Medicine University of Genoa 6 viale Benedetto XV 16132 Genoa Italy

Center for Molecular Cardiology University of Zurich Wagistrasse 12 8952 Schlieren Switzerland

Department of Anesthesiology and Critical Care and Burn Unit Saint Louis and Lariboisière Hospitals FHU PROMICE DMU Parabol APHP Nord Paris France

Department of Cardiology Cardiovascular Center University Hospital Bern Bern Switzerland

Department of Cardiology Geneva University Hospital Geneva Switzerland

Department of Cardiology National Clinical Research Center for Cardiovascular Diseases Fuwai Hospital National Center for Cardiovascular Diseases Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China

Department of Cardiology University Hospital Zurich Zurich Switzerland

Department of Cardiovascular Sciences Glenfield Hospital University of Leicester Leicester UK

Department of Cardiovascular Sciences University of Leicester Leicester UK

Department of Clinical Sciences Karolinska Institutet Stockholm Sweden

Department of Internal Medicine 1 University Hospital Aachen Pauwelsstraße 30 52074 Aachen Germany

Department of Internal Medicine 2 University Hospital Regensburg Franz Josef Strauss Allee 11 93053 Regensburg Germany

Department of Internal Medicine Stadtspital Zurich Zurich Switzerland

Department of Laboratory Medicine Division of Clinical Biochemistry University Hospital Brno Brno Czechia

Department of Research and Education University Hospital Zurich Zurich Switzerland

Division of Cardiology Cardiovascular and Thoracic Department Molinette Hospital Città della Salute e della Scienza Turin Italy

Division of Cardiology Department of Medicine Basel Cantonal Hospital Basel Switzerland

Faculty of Medicine Institute of Biostatistics and Analysis Masaryk University Brno Czechia

Institute of Clinical Chemistry University Hospital Zurich and University of Zuich Zurich Switzerland

Institute of Health Information and Statistics of the Czech Republic Prague Czechia

Internal and Cardiology Department University Hospital Brno and Faculty of Medicine Masaryk University Brno Czechia

IRCCS Ospedale Policlinico San Martino Genoa Italian Cardiovascular Network L go R Benzi 10 16132 Genoa Italy

Leicester Cancer Research Centre and Department of Genetics and Genome Biology RKCSB University of Leicester Leicester UK

Leicester van Geest Multi OMICS Facility University of Leicester Leicester UK

National Disease Registration and Analysis Service NHS London UK

National Heart and Lung Institute Imperial College London UK

National Institute for Health and Care Research Leicester UK

Royal Brompton and Harefield Hospitals Sydney Street London SW3 6NP UK

School of Cardiovascular Medicine and Sciences Kings College London London UK

Service of Cardiology Lausanne University Hospital Lausanne Switzerland

teen4 Pharmaceuticals 16761 Hennigsdorf Germany

Université Paris Cité INSERM UMR S 942 Paris France

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