KEY POINTS: In patients with acute decompensated heart failure and AKI, higher urinary cytokeratin 20 (CK20) associated with higher risk of AKI-to-CKD progression. Urinary CK20, particularly combined with clinical variables, improved the ability of predicting AKI-CKD transition with an accuracy of 90%. Urinary CK20 might be used as a novel tool for early identifying patients at high risk of kidney function loss after AKI. BACKGROUND: Predicting the risk of AKI-CKD transition remains a major challenge in the management of acute decompensated heart failure (ADHF) and AKI. This study investigated the clinical utility of urinary cytokeratin 20 (CK20), a novel biomarker reflecting the severity of histological acute tubular injury, for identifying patients at risk of AKI-to-CKD progression. METHODS: This prospective cohort study included a test set comprising 279 consecutive hospitalized patients with ADHF and AKI in five centers and a validation set enrolling 206 similar patients at an external center. Urinary CK20 and seven reported renal tubular injury biomarkers at the time of AKI diagnosis were measured. The primary outcome was a composite of AKI-CKD transition 90 days after AKI or all-cause death within 90 days. The secondary outcome was AKI-to-CKD progression 90 days after AKI. RESULTS: In the test set, 115 patients (41%) reached the primary end point. Concentrations of urinary CK20 peaked on the day of AKI diagnosis and remained elevated 14 days after AKI. After multivariable adjustment, the highest tertile of urinary CK20 was associated with 21-fold higher risk of the primary outcome and 29-fold higher risk of the secondary outcome. For predicting the primary and secondary outcomes, urinary CK20 at the time of AKI diagnosis had an area under the receiver operating characteristic curve of 0.82 (95% confidence interval [CI], 0.77 to 0.87) and 0.81 (95% CI, 0.75 to 0.87), respectively, and outperformed other reported biomarkers reflecting acute tubular injury and risk of CKD. Adding urinary CK20 to the clinical variables improved the ability for predicting the primary outcome with an area under the receiver operating characteristic curve of 0.90 (95% CI, 0.85 to 0.94) and largely improved risk reclassification. The ability of urinary CK20 in predicting AKI-CKD transition was further confirmed in the validation set. CONCLUSIONS: Urinary CK20 improved prediction of the risk of transition from AKI to CKD in patients with ADHF and AKI.