Background:Acute kidney injury (AKI), with an increase in serum creatinine, is a common adverse drug event. Although various clinical studies have investigated whether a combination of two nephrotoxic drugs has an increased risk of AKI using traditional statistical models such as multivariable logistic regression (MLR), the evaluation metrics have not been evaluated despite the fact that traditional statistical models may over-fit the data. The aim of the present study was to detect drug-drug interactions with an increased risk of AKI by interpreting machine-learning models to avoid overfitting.Methods:We developed six machine-learning models trained using electronic medical records: MLR, logistic least absolute shrinkage and selection operator regression (LLR), random forest, extreme gradient boosting (XGB) tree, and two support vector machine models (kernel = linear function and radial basis function). In order to detect drug-drug interactions, the XGB and LLR models that showed good predictive performance were interpreted by SHapley Additive exPlanations (SHAP) and relative excess risk due to interaction (RERI), respectively.Results:Among approximately 2.5 million patients, 65,667 patients were extracted from the electronic medical records, and assigned to case (N= 5,319) and control (N= 60,348) groups. In the XGB model, a combination of loop diuretic and histamine H2blocker [mean (|SHAP|) = 0.011] was identified as a relatively important risk factor for AKI. The combination of loop diuretic and H2blocker showed a significant synergistic interaction on an additive scale (RERI 1.289, 95% confidence interval 0.226–5.591) also in the LLR model.Conclusion:The present population-based case-control study using interpretable machine-learning models suggested that although the relative importance of the individual and combined effects of loop diuretics and H2blockers is lower than that of well-known risk factors such as older age and sex, concomitant use of a loop diuretic and histamine H2blocker is associated with increased risk of AKI.