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. 2024 Jun 29;9(9):2718-2726.
doi: 10.1016/j.ekir.2024.06.039. eCollection 2024 Sep.

A Metabolomics Approach to Identify Metabolites Associated With Mortality in Patients Receiving Maintenance Hemodialysis

Solaf Al Awadhi  1 , Leslie Myint  2 , Eliseo Guallar  3 , Clary B Clish  4 , Kendra E Wulczyn  5 , Sahir Kalim  5 , Ravi Thadhani  6 , Dorry L Segev  7 , Mara McAdams DeMarco  7 , Sharon M Moe  8 , Ranjani N Moorthi  8 , Thomas H Hostetter  9 , Jonathan Himmelfarb  10 , Timothy W Meyer  11 , Neil R Powe  12 , Marcello Tonelli  13 , Eugene P Rhee  5 , Tariq Shafi  1
Affiliations

A Metabolomics Approach to Identify Metabolites Associated With Mortality in Patients Receiving Maintenance Hemodialysis

Solaf Al Awadhi et al. Kidney Int Rep. .

Abstract

Introduction: 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.

Keywords: artificial intelligence; hemodialysis; metabolomics; mortality.

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Graphical abstract
Figure 1
Figure 1
Consort diagram of evaluated patients. LUCID, Longitudinal US/Canada Incident Dialysis.
See this image and copyright information in PMC

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