Glutamine metabolic reprogramming in acute and chronic kidney diseases: mechanistic insights and therapeutic implications

Acute kidney injury (AKI) and chronic kidney disease (CKD) are common clinical disorders that have high incidence and mortality. Their pathogenesis and the mechanisms underlying AKI-to-CKD progression remain unclear. Metabolic reprogramming has emerged as a core mechanism driving the onset and progression of kidney diseases. Glutamine (Gln) metabolism, a central component of renal energy metabolism, not only maintains acid-base balance and cellular homeostasis but also actively participates in pathophysiological processes including ischemic injury, oxidative stress, inflammatory regulation and fibrosis. Multi-omics studies have revealed stage-specific alterations in Gln metabolism-associated signatures during kidney injury. In AKI, altered Gln levels and redox-related metabolites may suggest disturbances in metabolic pathways, whereas in CKD, elevated glutaminase 1 (GLS1) expression and glutaminolysis-associated metabolic reprogramming are associated with fibrosis. Gln, as an immunonutrient, also serves as a critical energy substrate to sustain the proliferation, activation, and effector functions of immune cells. Gln metabolism may reshape the immune microenvironment within the injured kidney, thereby modulating disease progression. Targeting the Gln metabolic axis may offer new therapeutic insights for AKI and CKD. However, the changes in Gln metabolism and its consequent immunometabolic effects during the AKI-to-CKD transition remain poorly understood. This narrative review aims to provide a comprehensive overview of the dynamic changes in Gln metabolism during acute and chronic kidney diseases, its stage-specific mechanisms, and its potential as a therapeutic target. We also seek to provide a theoretical basis for developing novel biomarkers and targeted therapies based on Gln metabolic reprogramming.