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Cardiac surgery–associated acute kidney injury is common in children and associates with negative outcomes. Novel interventions to reduce cardiac surgery–associated acute kidney injury require knowledge of its pathophysiology. States of altered perfusion, oxygen delivery, and energy consumption occur during cardiopulmonary bypass and could protect against or contribute to renal cellular injury and recovery. Near-infrared spectroscopy is noninvasive technology for monitoring regional blood flow and tissue oxygenation. This study evaluated the relationship between renal regional oxygen saturation and cardiac surgery–associated acute kidney injury, using near-infrared spectroscopy monitoring before, during, and after cardiopulmonary bypass in children.Prospective cohort study.Single-center, tertiary care pediatric hospital (Stollery Children’s Hospital, Edmonton, AB, Canada).Children less than or equal to 10 kg undergoing congenital heart disease repair with cardiopulmonary bypass. Heart transplant, preoperative dialysis, sepsis, extracorporeal life support, congenital renal disease, and preoperative nephrotoxins were exclusions.Renal regional near-infrared spectroscopy monitoring before, during, and after cardiopulmonary bypass.Outcome measure was cardiac surgery–associated acute kidney injury (defined according to Kidney Disease: Improving Global Outcomes criteria). Regional oxygen saturation was measured continuously using near-infrared spectroscopy (INVOS 5100C Cerebral/Somatic Oximeter; Medronic, Troy, MI) from time of anesthesia to time of transfer to intensive care. Cardiac surgery–associated acute kidney injury occurred in 65%. Lower baseline (precardiopulmonary bypass) regional oxygen saturation was associated with decreased risk of cardiac surgery–associated acute kidney injury (p = 0.01); children with baseline regional oxygen saturation in the highest tertile were 7.14 times more likely to get cardiac surgery– associated acute kidney injury (vs lowest tertile). Area under the curve for ability of baseline regional oxygen saturation to predict cardiac surgery–associated acute kidney injury was 0.73 (95% CI, 0.60–0.85). Children with lower baseline glomerular filtration rate had lower mean renal regional oxygen saturation.Findings demonstrate that preoperative oxygen supply/demand balance is an important predictor of cardiac surgery–associated acute kidney injury, suggesting lower preoperative (and intraoperative) renal blood flow may be protective. There is not yet a definite link between remote ischemic preconditioning and prevention of cardiac surgery–associated acute kidney injury; however, renal protective effects of sublethal ischemia should continue to be explored.