Novel Plasma Biomarkers For Early Prediction Of Cardiac Surgery-associated Acute Kidney Injury

Part 1.Identification of circulating cytokines as potential biomarkers for cardiac surgery-associated acute kidney injuryBackground:Acute kidney injury(AKI)occurs in about 30%of patients with cardiac surgery,but the pathogenesis of cardiac surgery-associated acute kidney injury(CSA-AKI)remains unclear and there are no predictive biomarkers or diagnostic criteria specific for CSA-AKI beyond the general clinical variables for AKI like serum creatinine(SCr).Methods:We measured the plasma levels of 48 cytokines within 24 h after cardiac surgery in a total of 306 adult patients including 204 with and 102 without AKI,and then evaluated the diagnostic efficacy of these cytokines for the development of CSA-AKI via ANOVA and Pearson correlation analysis.Results:Among these 48 cytokines,20 of them were significantly different in the AKI patients compared with the non-AKI patients.In particularly,13 cytokines displayed tremendous changes with the P<1E-5.Moreover,10 of the 48 cytokines in the plasma were significantly different among the patients with different stages of AKI.Specifically,6 cytokines exhibited immense differences with the P<1E-5.Additionally,7 of the 48 cytokines have the correlation coefficient of r>0.5 with the postoperative changes of SCr after cardiac surgery.Conclusion:Taken all the results together,IFN-? and SCGF-? were the most relevant two cytokines that were not only remarkably changed in adult CSA-AKI patients during the first 24 h after cardiac surgery,but also significantly correlated with the postoperative changes of SCr after cardiac surgery.Therefore,IFN-y and SCGF-?might be novel predictive plasma biomarker,as well as potential therapeutic targets specific for adult CSA-AKI.Part 2.High-resolution metabolomics reveals plasma gluconic acid,fumaric acid,and pseudouridine as novel biomarkers for the early prediction of cardiac surgery-associated acute kidney injuryBackground:Cardiac surgery-associated acute kidney injury(CSA-AKI)is a common postoperative complication following cardiac surgery.Currently,there are no reliable methods for the early prediction of CSA-AKI in hospitalized patients.This study developed and evaluated the diagnostic utility of metabolomics-based biomarkers in patients with CSA-AKI.Methods:A total of 195 individuals(106 AKI patients,89 non-AKI controls)were enrolled in this study.Plasma samples were analyzed by liquid chromatography tandem mass spectrometry using untargeted and targeted metabolomic approaches.Binary logistic regression models were constructed using the biomarkers and their predictive abilities were assessed using area under the curve(AUC).Results:Metabolomic analyses from plasma samples taken within 24 h following cardiac surgery were useful for distinguishing AKI patients from non-AKI controls.Gluconic acid,fumaric acid,and pseudouridine were significantly upregulated in AKI patients.We developed a predictive panel consisting of these three metabolites for predicting AKI in a discovery cohort(47 AKI patients,48 non-AKI controls),AUC=0.873.The utility of the biomarkers for AKI prediction was then confirmed in the validation cohort(59 AKI patients,41 non-AKI controls),AUC=0.974.The predictive biomarker panel was also investigated in a subset of the validation cohort(early-stage AKI patients,n=16;non-AKI patients,n=41).The AUC of the early-stage AKI patient analysis was 0.909.Conclusions:High-resolution metabolomics is sufficiently powerful for developing novel biomarkers.Plasma levels of three metabolites were useful for the early identification of CSA-AKI.