Untangling amino acid metabolism in renal diseases: mechanisms, dysregulation, and critical gaps

Amino acid metabolism is closely linked with kidney physiology and pathology. In acute kidney injury, chronic kidney disease, diabetic kidney disease, and autosomal dominant polycystic kidney disease, disturbances in the branched-chain amino acids, tryptophan, glutamine, taurine, and sulfur amino acids pathways are consistently observed. Specific metabolites such as D-serine, kynurenine intermediates, and branched-chain keto acids are associated with disease progression. Taurine and indoxyl sulfate have also been proposed as therapeutic targets. At the nephron level, transporters and enzymes controlling amino acid flux influence nitrogen balance, oxidative stress, fibrosis, inflammation, and tubular injury. In chronic kidney disease, impaired amino acid handling contributes to protein-energy wasting, altered muscle metabolism, and systemic complications. In autosomal dominant polycystic kidney disease, cyst fluid metabolomics has revealed alterations in tryptophan and polyamine metabolism. The use of nutritional interventions, microbiome modulation, and selective supplementation as therapeutic strategies is being explored, although clinical trial evidence remains limited. Several key issues remain unresolved, including the need for isotope tracer studies to define renal amino acid kinetics in humans, the rigorous validation of metabolite biomarkers across diverse populations, the integration of diet and microbiome-derived metabolites into mechanistic frameworks, and the systematic evaluation of sex-specific differences. Longitudinal studies are scarce, thus restricting predictive power and therapeutic translation. Further mechanistic clarification may support the development of biomarkers and targeted therapies.