OBJECTIVE: This study was designed to investigate the risk factors of postoperative acute kidney injury (AKI) in patients with complex congenital heart disease (CHD) and the significance of early detection of serum transcription factor Nkx2.5. METHODS: A total of 121 CHD patients admitted to the Shengli Clinical Medical College of Fujian Medical University were selected as study participants, among whom 69 patients with AKI after cardiac surgery were set as the research group (RG), and the rest of the 52 patients without AKI were set as the control group (CG). Cardiopulmonary bypass (CPB) duration, aortic occlusion time, postoperative creatinine (Cr) level and mechanical ventilation (MV) time were compared between the two groups. The expression and clinical significance of Nkx2.5 in the two groups were detected. Intensive Care Unit (ICU) residence time and total hospital stay were compared, and the risk factors were analyzed. RESULTS: The RG presented remarkably longer CPB duration and aortic occlusion time, evidently higher postoperative Cr level and longer MV time, and observably lower Nkx2.5 level in comparison to the CG (all P<0.05). According to the analysis of receiver operating characteristic (ROC) curves, Nkx2.5 displayed a favorable diagnostic value in predicting the occurrence of CHD complicated with AKI. ICU residence time and total hospital stay were longer in the RG than in the CG (P<0.05). CPB time and aortic occlusion time were independent risk factors for AKI in CHD patients, while surgical methods and Nkx2.5 detection were independent protective factors (P<0.05). CONCLUSIONS: CPB time, aortic occlusion time and surgical methods, as well as Nkx2.5 detection are independent factors affecting AKI in patients with CHD. Early detection of serum transcription factor Nkx2.5 is of particular importance for clinical diagnosis of CHD patients complicated with AKI.