Metabolic Pathway Signatures of Amino Acids Across the Spectrum of Dialysis-Associated Fatigue.

OBJECTIVE: Fatigue is among the most common and burdensome symptoms in patients with end-stage kidney disease (ESKD) undergoing maintenance hemodialysis, yet its metabolic drivers are not well defined. The aim of our study was to evaluate amino acid profiles in relation to dialysis-related fatigue. METHODS: In a post hoc analysis of 115 adults with ESKD receiving hemodialysis, fatigue was measured on dialysis and non-dialysis day using the validated Brief Fatigue Inventory (BFI) test. Twenty-four plasma amino acid were measured pre- and post-dialysis. Differences in amino acid concentrations and metabolic pathways were evaluated across global BFI score categories (low, intermediate, high) on each day. Ordinal logistic regression examined associations between amino acids and shifts in global BFI score categories from dialysis to non-dialysis days. RESULTS: On dialysis day, levels of tyrosine (p=0.01), asparagine (p=0.02), and ornithine (p=0.03) were lower in participants with high global BFI scores. Pathway-level analyses demonstrated lower branched-chain amino acid and essential amino acid pathway activity with high global BFI scores. On non-dialysis day, no differences in individual amino acids and metabolic pathways across global BFI score categories were observed. Aspartic acid (p=0.01), glycyl-histidine (p=0.04), and alanine, aspartate, and glutamate metabolism pathway (p=0.04) were associated with a shift toward lower global BFI score categories from dialysis to non-dialysis days. CONCLUSIONS: Fatigue in hemodialysis patients is linked to specific amino acid and metabolic changes on dialysis days, but not on non-dialysis days. These findings support exploring amino acid-targeted interventions, especially when fatigue is most severe.