Amino acid homeostasis in the kidney: Physiological roles and pathological dysregulation

Amino acids are fundamental to life as protein building blocks and key regulators of metabolism and signaling. The kidney plays a critical, yet underappreciated, role in amino acid homeostasis through three interconnected pillars: selective glomerular filtration, efficient tubular reabsorption, and metabolic processing, which includes de novo synthesis and interconversion of amino acids, as well as their catabolism for energy production and gluconeogenesis. These processes are tightly coupled to systemic acid-base regulation, gluconeogenesis, and whole-body nitrogen clearance. When kidney function declines, the resulting alterations in amino acid profiles are not merely passive markers of reduced filtration but are increasingly recognized as potential mediators that may actively contribute to disease progression, as supported by a growing body of preclinical and clinical evidence. This Review synthesizes current knowledge on renal amino acid homeostasis and proposes four dysregulation patterns in kidney disease: metabolic rewiring, branched-chain amino acids paradox, uremic toxin accumulation, and organelle dysfunction. We further discuss emerging therapeutic strategies aimed at restoring amino acid homeostasis, including dietary modulation, pharmacological targeting of metabolic enzymes and transporters, and microbiome-directed interventions. Finally, we identify key unanswered questions that should guide future research in this rapidly evolving field.