Aromatic Amino Acid-Derived Microbial Metabolites and Mortality Risk in ESKD

Background: Two novel gut microbiota-derived metabolites from aromatic amino acids, 4-OH-hippuric acid (from dietary tyrosine) and 5-OH-indole-3-acetic acid (from dietary tryptophan), have been identified as the strongest predictors of adverse outcomes in individuals with preserved kidney function. However, their prognostic significance in patients with end-stage kidney disease (ESKD) undergoing hemodialysis remains unclear. Methods: We conducted a prospective cohort study of 329 hemodialysis patients (median age 67.5 years; 48.9% female; median dialysis vintage 5.5 years). Plasma concentrations of aromatic amino acids and their metabolites were quantified using stable isotope dilution liquid chromatography–tandem mass spectrometry. Cox proportional hazards models were used to estimate hazard ratios for all-cause mortality, adjusting for age, sex, diabetes, cardiovascular disease, dialysis vintage, C-reactive protein, and normalized protein catabolic rate. Results: During a median follow-up of 5.0 years, 96 patients (35.7%) died. Higher plasma levels of 4-OH-hippuric acid (adjusted HR 1.65; 95% CI: 1.08–2.53; P = 0.022) and 5-OH-indole-3-acetic acid (adjusted HR 2.33; 95% CI: 1.13–4.80; P = 0.021) showed the strongest links to increased all-cause mortality. Compared to the lowest quartile, patients in the highest quartile of each metabolite conferred significantly higher mortality risks (HR 2.57 for 4-OH-hippuric acid and HR 2.73 for 5-OH-indole-3-acetic acid). In contrast, traditional uremic toxins such as p-cresol sulfate and indoxyl sulfate showed weaker or non-significant associations. Conclusion: Elevated plasma concentrations of 4-OH-hippuric acid and 5-OH-indole-3-acetic acid are independently associated with higher all-cause mortality in hemodialysis patients. These findings extend previous observations from non-CKD populations and suggest that these gut-derived metabolites may serve as novel prognostic biomarkers or therapeutic targets in ESKD. Funding: Private Foundation Support, Government Support – Non-U.S.