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Navigating Hemolysis and the Renal Implications of Hemoglobin Toxicity in Cardiac Surgery. Acute kidney injury (AKI) affects 20% to 30% of patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). This review synthesizes clinical evidence indicating that CPB-induced hemolysis plays a pivotal role in the development of AKI. The pathogenesis involves cell-free hemoglobin, which triggers oxidative stress, depletes nitric oxide, and incites inflammation, culminating in renal damage. We highlight emerging interventions, including haptoglobin administration, nitric oxide supplementation, and antioxidants, which are promising in reducing the toxicity of cell-free hemoglobin and the incidence of AKI. Current clinical data support the potential efficacy of these treatments. Our analysis concludes that sufficient proof of concept exists to further develop and test these targeted therapies for preventing hemoglobin-induced AKI in patients undergoing CPB.