Urine metabolites imply metabolic rewiring of kidney and predict acute kidney injury after cardiac surgery

Abstract

Acute kidney injury (AKI) is a serious complication in patients undergoing cardiac surgery, with the underlying mechanism remaining elusive, and lack of specific biomarkers for cardiac surgery-associated AKI (CS-AKI). We performed an untargeted metabolomics analysis of urine samples procured from a cohort of patients with or without AKI at 6 and 24 hours following cardiac surgery. Based on the differential urinary metabolites discovered, we further examined the expressions of the key metabolic enzymes that regulates these metabolites in kidney during AKI using a mouse model of ischemia-reperfusion injury (IRI) and in hypoxia-treated tubular epithelial cells (TECs). The urine metabolomic profiles in AKI patients were significantly different from those in non-AKI patients, including upregulation of tryptophan metabolism- and aerobic glycolysis-related metabolites, such as L-tryptophan and D-glucose 1-phosphate, downregulation of fatty acid oxidation (FAO) and tricarboxylic acid (TCA) cycle-related metabolites. Spearman correlation analysis showed that serum creatinine (Scr) was positively correlated with urinary L-tryptophan and indole, which had high accuracy for predicting AKI. In animal experiments, we demonstrated that the expression of rate-limiting enzymes in glycolysis, such as hexokinase II (HK2), was significantly upregulated during renal IRI. However, TCA cycle-related key enzymes citrate synthase (CS) was significantly downregulated after IRI. In vitro, hypoxia induced downregulation of CS in TECs. In addition, FAO-related gene peroxisome proliferator-activated receptor alpha (PPARα) was remarkably downregulated in kidney during renal IRI. This study presents urinary metabolites related to CS-AKI, indicating the rewiring of the metabolism in kidney during AKI, identifying potential AKI biomarkers.