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Cited by 340Dialysis and Renal Disease ManagementChronic Kidney Disease and DiabetesMetabolomics and Mass Spectrometry Studies

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Serum Trimethylamine-N-Oxide Is Strongly Related to Renal Function and Predicts Outcome in Chronic Kidney Disease

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Missailidis, Catharina, Hällqvist, Jenny, Qureshi, Abdel Rashid, Barany, Peter, Heimbürger, Olof, Lindholm, Bengt, Stenvinkel, Peter, Bergman, Peter·2016·PLOS ONE
DOI 10.1371/journal.pone.0141738PMC PMC4709190
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Abstract

BACKGROUND: The microbial metabolite Trimethylamine-N-oxide (TMAO) has been linked to adverse cardiovascular outcome and mortality in the general population. OBJECTIVE: To assess the contribution of TMAO to inflammation and mortality in chronic kidney disease (CKD) patients ranging from mild-moderate to end-stage disease and 1) associations with glomerular filtration rate (GFR) 2) effect of dialysis and renal transplantation (Rtx) 3) association with inflammatory biomarkers and 4) its predictive value for all-cause mortality. METHODS: Levels of metabolites were quantified by a novel liquid chromatography/tandem mass spectrometry-based method in fasting plasma samples from 80 controls and 179 CKD 3-5 patients. Comorbidities, nutritional status, biomarkers of inflammation and GFR were assessed. RESULTS: GFR was the dominant variable affecting TMAO (β = -0.41; p<0.001), choline (β = -0.38; p<0.001), and betaine (β = 0.45; p<0.001) levels. A longitudinal study of 74 CKD 5 patients starting renal replacement therapy demonstrated that whereas dialysis treatment did not affect TMAO, Rtx reduced levels of TMAO to that of controls (p<0.001). Following Rtx choline and betaine levels continued to increase. In CKD 3-5, TMAO levels were associated with IL-6 (Rho = 0.42; p<0.0001), fibrinogen (Rho = 0.43; p<0.0001) and hsCRP (Rho = 0.17; p = 0.022). Higher TMAO levels were associated with an increased risk for all-cause mortality that remained significant after multivariate adjustment (HR 4.32, 95% CI 1.32-14.2; p = 0.016). CONCLUSION: Elevated TMAO levels are strongly associated with degree of renal function in CKD and normalize after renal transplantation. TMAO levels correlates with increased systemic inflammation and is an independent predictor of mortality in CKD 3-5 patients.

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Fig 1 Increasing plasma levels of TMAO in CKD patients stage 3 (n = 30), stage 4 (n = 28) and stage 5 (n = 116) compared to healthy controls (n = 80). Values are expressed as median (10th -90th percentile). P-values analyzed by Kruskal–Wallis’ one-way ANOVA, followed by Dunn’s multiple comparison test.
Fig 1 Increasing plasma levels of TMAO in CKD patients stage 3 (n = 30), stage 4 (n = 28) and stage 5 (n = 116) compared to healthy controls (n = 80). Values are expressed as median (10th -90th percentile). P-values analyzed by Kruskal–Wallis’ one-way ANOVA, followed by Dunn’s multiple comparison test.CC BY · PubMed Central
Fig 2 Comparison of plasma levels of metabolites in a cohort of CKD 5 patients (n = 74) followed from baseline and reassessed 12 months after start of dialysis and/or 12 months and 24 months after renal transplantation (Rtx). Choline and betaine levels increased with dialysis and Rtx whereas TMAO levels remained unchanged during dialysis and normalized after Rtx. Due to missing samples box-plots represents 34/74 patients at 12 months of dialysis, 47/74 patients at 12 months and 29/74 patients at 24 months follow-up after Rtx. Values are expressed as median (10th -90th percentile) P-values analyzed by Kruskal–Wallis’ one-way ANOVA, followed by Dunn’s multiple comparison test.
Fig 2 Comparison of plasma levels of metabolites in a cohort of CKD 5 patients (n = 74) followed from baseline and reassessed 12 months after start of dialysis and/or 12 months and 24 months after renal transplantation (Rtx). Choline and betaine levels increased with dialysis and Rtx whereas TMAO levels remained unchanged during dialysis and normalized after Rtx. Due to missing samples box-plots represents 34/74 patients at 12 months of dialysis, 47/74 patients at 12 months and 29/74 patients at 24 months follow-up after Rtx. Values are expressed as median (10th -90th percentile) P-values analyzed by Kruskal–Wallis’ one-way ANOVA, followed by Dunn’s multiple comparison test.CC BY · PubMed Central
Fig 3 Comparative analysis of metabolites in inflamed (hsCRP ≥10 mg/L) and non-inflamed (hsCRP < 10 mg/L) CKD 3–5 patients (n = 179). Higher hsCRP levels associated with higher TMAO levels and decreased betaine levels. Values are expressed as median (10th -90th percentile). P-values analyzed by Kruskal–Wallis’ one-way ANOVA, followed by Dunn’s multiple comparison test.
Fig 3 Comparative analysis of metabolites in inflamed (hsCRP ≥10 mg/L) and non-inflamed (hsCRP < 10 mg/L) CKD 3–5 patients (n = 179). Higher hsCRP levels associated with higher TMAO levels and decreased betaine levels. Values are expressed as median (10th -90th percentile). P-values analyzed by Kruskal–Wallis’ one-way ANOVA, followed by Dunn’s multiple comparison test.CC BY · PubMed Central
Fig 4 Kaplan-Meier analysis of TMAO levels and all-cause mortality in CKD 3–5 patient (n = 179). Data presented as tertiles. CKD patients with the highest TMAO levels (Combined middle (32.2–75.2 μM/L) + high tertile (>72.2 μM/L)) had a significantly lower survival compared with patients in the lowest TMAO tertile.
Fig 4 Kaplan-Meier analysis of TMAO levels and all-cause mortality in CKD 3–5 patient (n = 179). Data presented as tertiles. CKD patients with the highest TMAO levels (Combined middle (32.2–75.2 μM/L) + high tertile (>72.2 μM/L)) had a significantly lower survival compared with patients in the lowest TMAO tertile.CC BY · PubMed Central

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Metadata

Authors
Missailidis, C., Hällqvist, J., Qureshi, A. R., Barany, P., Heimbürger, O., Lindholm, B., Stenvinkel, P., & Bergman, P.
Affiliations
  • Karolinska University Hospital (SE)
  • Swedish University of Agricultural Sciences (SE)
Corresponding author
Missailidis, Catharina
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2016-01-11
Volume
11
Issue
1
Pages
e0141738
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0141738
PMC
PMC4709190
OpenAlex
W2232990799
Cited by
338
References
34
Citations by year
2026: 22 · 2025: 32 · 2024: 27 · 2023: 36 · 2022: 44 · 2021: 34 · 2020: 42 · 2019: 33 · 2018: 28 · 2017: 27 · 2016: 13
FWCI
34.20
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • Stockholms Läns Landsting (2013-0317)
  • Vetenskapsrådet
Topics
  • Health Sciences › Medicine › Nephrology › Dialysis and Renal Disease Management
  • Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
Keywords
trimethylamine N-oxide, chronic kidney disease, glomerular filtration rate, renal function, kidney transplantation, dialysis, all-cause mortality, systemic inflammation, interleukin-6, fibrinogen, C-reactive protein, choline, betaine, microbial metabolites, prognostic factors
MeSH terms
Adult, Aged, Betaine, C-Reactive Protein, Cardiovascular Diseases, Choline, Female, Fibrinogen, Glomerular Filtration Rate, Renal Dialysis, Humans, Inflammation, Longitudinal Studies, Male, Methylamines, Middle Aged, Prognosis, Severity of Illness Index, Biomarkers, Interleukin-6, Multivariate Analysis, Survival Analysis, Kidney Transplantation, Renal Insufficiency, Chronic

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