Pediatric sepsis–associated acute kidney injury: leveraging pathophysiology for risk stratification and identification of treatable traits

Sepsis-associated acute kidney injury (SA-AKI) is a common and morbid complication of pediatric critical illness that affects up to half of children with septic shock and is associated with independent risk for death and new disability. Once attributed primarily to systemic hypotension, SA-AKI is now recognized as a heterogeneous syndrome driven by diverse pathophysiologic mechanisms, including immune dysregulation, endothelial injury, microcirculatory alterations, mitochondrial dysfunction, metabolic reprogramming, and renin-angiotensin-aldosterone system (RAAS) derangement. This pathophysiologic complexity demands a precision medicine approach to improve risk stratification, diagnosis, and treatment. Precision medicine in SA-AKI relies on the identification of phenotypes, subphenotypes, endotypes, and treatable traits, distinct but complementary frameworks for characterizing patients by clinical features and underlying biology. Prognostic enrichment strategies, including novel biomarkers, clinical risk scores, and data-driven subphenotype models, are increasingly available to identify children at highest risk for persistent severe AKI, receipt of kidney replacement therapy, and death. Predictive enrichment strategies, designed to optimize therapy based on underlying pathophysiology, remain limited but are emerging. In this review, we summarize contemporary knowledge of pediatric SA-AKI pathophysiology, highlight clinical tools evaluated specifically in children, and outline a framework for translating mechanistic insights into actionable precision medicine strategies at the bedside.