Background: Acute kidney injury (AKI) represents a significant global health challenge, leading to increased patient distress and financial health care burdens. The development of AKI in intensive care unit (ICU) settings is linked to prolonged ICU stays, a heightened risk of long-term renal dysfunction, and elevated short- and long-term mortality rates. The current diagnostic approach for AKI is based on late indicators, such as elevated serum creatinine and decreased urine output, which can only detect AKI after renal injury has transpired. There are no treatments to reverse or restore renal function once AKI has developed, other than supportive care. Early prediction of AKI enables proactive management and may improve patient outcomes., Objective: The primary aim was to develop a machine learning algorithm, NAVOY Acute Kidney Injury, capable of predicting the onset of AKI in ICU patients using data routinely collected in ICU electronic health records. The ultimate goal was to create a clinical decision support tool that empowers ICU clinicians to proactively manage AKI and, consequently, enhance patient outcomes., Methods: We developed the NAVOY Acute Kidney Injury algorithm using a hybrid ensemble model, which combines the strengths of both a Random Forest (Leo Breiman and Adele Cutler) and an XGBoost model (Tianqi Chen). To ensure the accuracy of predictions, the algorithm used 22 clinical variables for hourly predictions of AKI as defined by the Kidney Disease: Improving Global Outcomes guidelines. Data for algorithm development were sourced from the Massachusetts Institute of Technology Lab for Computational Physiology Medical Information Mart for Intensive Care IV clinical database, focusing on ICU patients aged 18 years or older., Results: The developed algorithm, NAVOY Acute Kidney Injury, uses 4 hours of input and can, with high accuracy, predict patients with a high risk of developing AKI 12 hours before onset. The prediction performance compares well with previously published prediction algorithms designed to predict AKI onset in accordance with Kidney Disease: Improving Global Outcomes diagnosis criteria, with an impressive area under the receiver operating characteristics curve (AUROC) of 0.91 and an area under the precision-recall curve (AUPRC) of 0.75. The algorithm's predictive performance was externally validated on an independent hold-out test data set, confirming its ability to predict AKI with exceptional accuracy., Conclusions: NAVOY Acute Kidney Injury is an important development in the field of critical care medicine. It offers the ability to predict the onset of AKI with high accuracy using only 4 hours of data routinely collected in ICU electronic health records. This early detection capability has the potential to strengthen patient monitoring and management, ultimately leading to improved patient outcomes. Furthermore, NAVOY Acute Kidney Injury has been granted Conformite Europeenne (CE)-marking, marking a significant milestone as the first CE-marked AKI prediction algorithm for commercial use in European ICUs., (©Inger Persson, Adam Grünwald, Ludivine Morvan, David Becedas, Martin Arlbrandt. Originally published in JMIR Formative Research (https://formative.jmir.org), 14.12.2023.)