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Cardiopulmonary bypass surgery occurs in nearly 1 million patients per year. Acute kidney injury requiring dialysis can occur in up to 1% of these patients. The development of acute kidney injury is associated with substantial morbidity and mortality independent of all other factors, and many patients are left dependent on dialysis therapies. The pathogenesis of acute kidney injury involves multiple pathways. Hemodynamic, inflammatory, and nephrotoxic factors are involved and overlap each other in leading to kidney injury. Clinical studies have identified risk factors for acute kidney injury that can be used to effectively determine the risk of acute kidney injury in patients undergoing bypass surgery. These high-risk patients can then be targeted for renal protective strategies. Thus far, no single strategy has conclusively demonstrated its ability to prevent renal injury post-bypass surgery. Novel anti-inflammatory agents are in development and offer hope as potential therapies.