BACKGROUNDAcute kidney injury (AKI) predicts adverse outcomes after cardiac surgery. The accuracy of using changes in serum creatinine for diagnosis and grading of AKI is limited in the peri-operative cardiac surgical setting and AKI may be underdiagnosed due to haemodilution from cardiopulmonary bypass priming and the need for intra-operative and postoperative volume resuscitation. OBJECTIVESTo determine whether the urinary biomarker neprilysin can be used as a marker for the early detection of AKI after cardiac surgery. DESIGNProspective, observational cohort study. SETTINGAustrian tertiary referral centre. PATIENTS96 Patients undergoing elective cardiac surgery with cardiopulmonary bypass. MAIN OUTCOME MEASURESDifferences and discriminatory power of neprilysin levels early after cardiac surgery and on postoperative day 1 between patients with or without AKI, as defined by the Kidney Disease Improving Global Outcomes Group. RESULTSAKI was found in 27% (n=26). The median neprilysin levels on postoperative day 1 were significantly higher in the AKI than in the non-AKI group, 4.0 interquartile range (IQR)2 to 6.25 vs. 2.0 ng ml IQR1.0 to 4.5, P = 0.0246, respectively. In addition, the median neprilysin levels at the end of surgery were significantly different between both groups, 5.0 IQR2.0 to 9.0 vs. 2.0 ng ml IQR1.0 to 4.0, P = 0.0055, respectively. The discriminatory power of neprilysin for detecting early AKI corresponded to an area under the curve of 0.77 (95% confidence interval, 0.65 to 0.90). CONCLUSIONUrinary neprilysin has potential as a biomarker for the early detection of AKI after cardiac surgery and has comparable discriminatory power to recently studied AKI biomarkers. TRIAL REGISTRATIONThe trial was registered at ClinicalTrials.gov (NCT03854825, https://clinicaltrials.gov/ct2/show/NCT03854825).