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. 2017 Oct 23;7(1):13781.
doi: 10.1038/s41598-017-13739-9.

TMAO is Associated with Mortality: Impact of Modestly Impaired Renal Function

Eke G Gruppen  1   2 , Erwin Garcia  3 , Margery A Connelly  3 , Elias J Jeyarajah  3 , James D Otvos  3 , Stephan J L Bakker  1 , Robin P F Dullaart  4
Affiliations

TMAO is Associated with Mortality: Impact of Modestly Impaired Renal Function

Eke G Gruppen et al. Sci Rep. .

Abstract

Trimethylamine-N-Oxide (TMAO) is a microbiome-related metabolite that is cleared by the kidney and linked to renal function. We explored the relationship between TMAO and all-cause mortality, and determined whether this association was modified by renal function. A prospective study was performed among PREVEND participants to examine associations of plasma TMAO with all-cause mortality. After median follow-up of 8.3 years in 5,469 participants, 322 subjects died. TMAO was positively associated with age, body mass index, type 2 diabetes mellitus and inversely with estimated glomerular filtration rate (eGFRcreatcysC)(all P < 0.001). Subjects in the highest versus lowest TMAO quartile had a crude 1.86-fold higher mortality risk (Ptrend < 0.001). After adjustment for several risk factors, TMAO remained associated with all-cause mortality [HR:1.36 (95% CI, 0.97-1.91),Ptrend = 0.016]. This association was lost after further adjustment for urinary albumin excretion and eGFR [HR:1.15 (95% CI, 0.81-1.64),Ptrend = 0.22]. The association of TMAO with mortality was modified by eGFR in crude and age- and sex-adjusted analyses (interaction P = 0.002). When participants were stratified by renal function (eGFR < vs. ≥90 mL/min/1.73 m2), TMAO was associated with all-cause mortality only in subjects with eGFR <90 mL/min/1.73 m2 [adjusted HR:1.18 (95% CI, 1.02-1.36),P = 0.023]. In conclusion, TMAO is associated with all-cause mortality, particularly in subjects with eGFR <90 mL/min/1.73 m2.

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Conflict of interest statement

E.G., M.A.C., E.J.J. and J.D.O. are employees of LabCorp.

Figures

Figure 1
Figure 1
Kaplan-Meier curves of all-cause mortality according to quartiles of trimethylamine N-oxide (TMAO), P ≤ 0.001by log-rank test.
Figure 2
Figure 2
Association between trimethylamine N-oxide (TMAO) and all-cause mortality. Data were fit by a Cox proportional hazards regression model that was based on restricted cubic splines and adjusted for age and sex. The reference standard was mean TMAO level of 2.92 µM (antilog). The gray areas represent 95% CIs.
Figure 3
Figure 3
Mediation analysis on the association of TMAO with all-cause mortality. A, b and c are the standard regression coefficients between variables. The indirect effect is calculated as a * b. Total effect (c) is a * b + c’. Magnitude of mediation is calculated as indirect effect divided by total effect.
See this image and copyright information in PMC

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