Al Awadhi, SolafMyint, LeslieGuallar, EliseoClish, Clary B.Wulczyn, Kendra E.Kalim, SahirThadhani, RaviSegev, Dorry L.McAdams DeMarco, MaraMoe, Sharon M.Moorthi, Ranjani N.Hostetter, Thomas H.Himmelfarb, JonathanMeyer, Timothy W.Powe, Neil R.Tonelli, MarcelloRhee, Eugene P.Shafi, Tariq2024-10-302024-10-302024-06-29Al Awadhi S, Myint L, Guallar E, et al. A Metabolomics Approach to Identify Metabolites Associated With Mortality in Patients Receiving Maintenance Hemodialysis. Kidney Int Rep. 2024;9(9):2718-2726. Published 2024 Jun 29. doi:10.1016/j.ekir.2024.06.039https://hdl.handle.net/1805/44357Introduction: Uremic toxins contributing to increased risk of death remain largely unknown. We used untargeted metabolomics to identify plasma metabolites associated with mortality in patients receiving maintenance hemodialysis. Methods: We measured metabolites in serum samples from 522 Longitudinal US/Canada Incident Dialysis (LUCID) study participants. We assessed the association between metabolites and 1-year mortality, adjusting for age, sex, race, cardiovascular disease, diabetes, body mass index, serum albumin, Kt/Vurea, dialysis duration, and country. We modeled these associations using limma, a metabolite-wise linear model with empirical Bayesian inference, and 2 machine learning (ML) models: Least absolute shrinkage and selection operator (LASSO) and random forest (RF). We accounted for multiple testing using a false discovery rate (pFDR) adjustment. We defined significant mortality-metabolite associations as pFDR < 0.1 in the limma model and metabolites of at least medium importance in both ML models. Results: The mean age of the participants was 64 years, the mean dialysis duration was 35 days, and there were 44 deaths (8.4%) during a 1-year follow-up period. Two metabolites were significantly associated with 1-year mortality. Quinolinate levels (a kynurenine pathway metabolite) were 1.72-fold higher in patients who died within year 1 compared with those who did not (pFDR, 0.009), wheras mesaconate levels (an emerging immunometabolite) were 1.57-fold higher (pFDR, 0.002). An additional 42 metabolites had high importance as per LASSO, 46 per RF, and 9 per both ML models but were not significant per limma. Conclusion: Quinolinate and mesaconate were significantly associated with a 1-year risk of death in incident patients receiving maintenance hemodialysis. External validation of our findings is needed.en-USAttribution-NonCommercial-NoDerivatives 4.0 InternationalArtificial intelligenceHemodialysisMetabolomicsMortalityArticle