Background and Aims: Tacrolimus(TAC)-induced nephrotoxicity, which has a large individual variation, may lead to treatment failure or even the end-stage renal disease. However, there is still a lack of effective models for the early prediction of TAC-induced nephrotoxicity, especially in nephrotic syndrome(NS). We aimed to develop and validate a predictive model of TAC-induced tubular toxicity in children with NS using machine learning based on comprehensive clinical and genetic variables. Materials and Methods: A retrospective cohort of 218 children with NS admitted between June 2013 and December 2018 was used to establish the models, and 11 children were prospectively enrolled for external validation. We screened 47 clinical features and 244 genetic variables. The changes in urine N- acetyl- β-D- glucosaminidase(NAG) levels before and after administration was used as an indicator of renal tubular toxicity. Results: Five machine learning algorithms, including extreme gradient boosting (XGBoost), gradient boosting decision tree (GBDT), extremely random trees (ET), random forest (RF), and logistic regression (LR) were used for model generation and validation. Four genetic variables, including TRPC6 rs3824934_GG, HSD11B1 rs846910_AG, MAP2K6 rs17823202_GG, and SCARB2 rs6823680_CC were incorporated into the final model. The XGBoost model has the best performance: sensitivity 75%, specificity 77.8%, accuracy 77.3%, and AUC 78.9%. Conclusion: A pre-administration model with good performance for predicting TAC-induced nephrotoxicity in NS was developed and validated using machine learning based on genetic factors. Physicians can estimate the possibility of nephrotoxicity in NS patients using this simple and accurate model to optimize treatment regimen before administration or to intervene in time after administration to avoid kidney damage.

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