LAUSR

Introduction/Hypothesis: The pathologic tissue and urine metabolic fingerprints of cardiac surgery-induced acute kidney injury (AKI) have not been well defined. In this study, we utilized a porcine model of infant cardiopulmonary bypass (CPB) with deep hypothermic circulatory arrest (DHCA) to determine the changes in tissue and urine metabolites associated with postCPB/DHCA AKI. Methods: Infant pigs underwent CPB with 75min of DHCA (n=20) or anesthesia with mechanical ventilation (controls; n=7). Renal tissue and urine samples were obtained at 4hrs post-CPB or after a comparable duration of mechanical ventilation. AKI severity was measured by a blinded pathologist using a previously published AKI histology scoring system evaluating percent of affected renal cortical tissue. Targeted analysis of 192 metabolites was performed on urine and tissue by HPLCtandem mass spectroscopy. Partial least squares discriminant analysis (PLS-DA) and one-way ANOVA/t-testing were used to evaluate differences in metabolic fingerprints and individual metabolites respectively. Results: Nine of 20 animals developed histologic AKI (5 mild, 4 severe). There were no differences in the metabolic fingerprint of CPB/DHCA kidneys without AKI and control kidneys. Injured kidneys could be differentiated from uninjured kidneys by their tissue metabolic fingerprint (R2Y=0.82; Q2Y=0.22). Injured kidneys demonstrated 9 metabolites that differed significantly at an adjusted false discovery rate (aFDR) of <0.05 (2-oxogluconate, lipoate, anthranilate, indoleacrylic acid, p-hydroxybenzoate, quinolate, 4-pyridoxic acid, allantoin, and uric acid) and an additional 10 metabolites with an aFDR between 0.05 and 0.1. Urine metabolic fingerprinting differentiated between CPB/DHCA vs controls (R2Y=0.94; Q2Y=0.73) but poorly discriminated between animals with/without AKI (R2Y=0.56; Q2Y=0.08). Conclusions: Infant piglets with CPB/DHCA-induced histologic AKI demonstrate a pathologic metabolic renal tissue fingerprint with prominent changes in metabolites involved in oxidative stress, tryptophan metabolism, and uric acid metabolism. CPB/DHCA resulted in a significant change in urine metabolites, however urine metabolites did not reliably differentiate between animals with or without AKI.