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Renal ischemia/reperfusion injury is a major cause of acute kidney injury (AKI). The lack of early biomarkers for predicting AKI has hampered our ability to initiate preventive and therapeutic measures in an opportune way. Fibroblast growth factor 23 (FGF-23) is elevated in chronic kidney disease, but data on FGF-23 in humans with AKI are limited. Herein, we tested whether FGF-23 levels rise early in the course of AKI following cardiac surgery. We prospectively evaluated eighty adult patients who underwent cardiac surgery. Patients were divided into two groups (AKI and non-AKI group) on the basis of whether they developed postoperative AKI within 24 h after surgery. Plasma FGF-23 levels were measured before surgery and 24 h after surgery. The primary outcome was AKI diagnosed using the AKI Network criteria. Forty-five patients (56.2.5%) developed AKI after surgery. Plasma FGF-23 increased significantly from a mean of 26.8 ± 2.47 ng/mL at baseline to 341.7 ± 38.1 ng/mL 24 h after cardiopulmonary bypass. Univariate analysis showed a significant correlation between AKI and the following: percent change in plasma FGF-23, postoperative serum level of creatinine, FGF-23, and neutrophil gelatinase-associated lipocalin. Receiver operating characteristic curve analysis revealed that, for percent change in plasma FGF-23 concentrations at 24 h, the area under the curve was 0.9, sensitivity was 100%, and specificity was 97.1%. Plasma FGF-23 percent change is more valid compared with FGF-23 before or after procedure in the prediction of AKI and represents a novel and highly predictive early biomarker for AKI after cardiac surgery.