Autosomal dominant polycystic kidney disease (ADPKD) is the predominant hereditary factor leading to end-stage renal disease (ESRD) worldwide, affecting individuals across all races with a prevalence of 1 in 400 to 1 in 1000. The disease presents significant challenges in management, particularly with limited options for slowing cyst progression, as well as the use of tolvaptan being restricted to high-risk patients due to potential liver injury. However, determining high-risk status typically requires magnetic resonance imaging (MRI) to calculate total kidney volume (TKV), a time-consuming process demanding specialized expertise. Motivated by these challenges, this study proposes alternative methods for high-risk categorization that do not rely on TKV data. Utilizing historical patient data, we aim to predict rapid kidney enlargement in ADPKD patients to support clinical decision-making. We applied seven machine learning algorithms—Random Forest, Logistic Regression, Support Vector Machine (SVM), Light Gradient Boosting Machine (LightGBM), Gradient Boosting Tree, XGBoost, and Deep Neural Network (DNN)—to data from the Polycystic Kidney Disease Outcomes Consortium (PKDOC) database. The XGBoost model, combined with the Synthetic Minority Oversampling Technique (SMOTE), yielded the best performance. We also leveraged explainable artificial intelligence (XAI) techniques, specifically Local Interpretable Model-Agnostic Explanations (LIME) and Shapley Additive Explanations (SHAP), to visualize and clarify the model’s predictions. Furthermore, we generated text summaries to enhance interpretability. To evaluate the effectiveness of our approach, we proposed new metrics to assess explainability and conducted a survey with 27 doctors to compare models with and without XAI techniques. The results indicated that incorporating XAI and textual summaries significantly improved expert explainability and increased confidence in the model’s ability to support treatment decisions for ADPKD patients.