Gut Microbiota-Dependent Trimethylamine N-Oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease
RATIONALE: Trimethylamine-N-oxide (TMAO), a gut microbial-dependent metabolite of dietary choline, phosphatidylcholine (lecithin), and l-carnitine, is elevated in chronic kidney diseases (CKD) and associated with coronary artery disease pathogenesis. OBJECTIVE: To both investigate the clinical prognostic value of TMAO in subjects with versus without CKD, and test the hypothesis that TMAO plays a direct contributory role in the development and progression of renal dysfunction. METHODS AND RESULTS: We first examined the relationship between fasting plasma TMAO and all-cause mortality over 5-year follow-up in 521 stable subjects with CKD (estimated glomerular filtration rate, <60 mL/min per 1.73 m(2)). Median TMAO level among CKD subjects was 7.9 μmol/L (interquartile range, 5.2-12.4 μmol/L), which was markedly higher (P<0.001) than in non-CKD subjects (n=3166). Within CKD subjects, higher (fourth versus first quartile) plasma TMAO level was associated with a 2.8-fold increased mortality risk. After adjustments for traditional risk factors, high-sensitivity C-reactive protein, estimated glomerular filtration rate, elevated TMAO levels remained predictive of 5-year mortality risk (hazard ratio, 1.93; 95% confidence interval, 1.13-3.29; P<0.05). TMAO provided significant incremental prognostic value (net reclassification index, 17.26%; P<0.001 and differences in area under receiver operator characteristic curve, 63.26% versus 65.95%; P=0.036). Among non-CKD subjects, elevated TMAO levels portend poorer prognosis within cohorts of high and low cystatin C. In animal models, elevated dietary choline or TMAO directly led to progressive renal tubulointerstitial fibrosis and dysfunction. CONCLUSIONS: Plasma TMAO levels are both elevated in patients with CKD and portend poorer long-term survival. Chronic dietary exposures that increase TMAO directly contributes to progressive renal fibrosis and dysfunction in animal models.
Tang, W.H. Wilson; Wang, Zeneng; Kennedy, David J.; Wu, Yuping; Buffa, Jennifer A.; Boyle, Brendan Agatisa; Li, Xinmin S.; Levison, Bruce S.; and Hazen, Stanley L., "Gut Microbiota-Dependent Trimethylamine N-Oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease" (2015). Mathematics Faculty Publications. 198.
This research was supported by grants from the National Institutes of Health and the Office of Dietary Supplements (R01HL103866, P20HL113452). The GeneBank study has been supported by National Institutes of Health grants P01HL076491, P01HL098055, R01HL103931, and the Cleveland Clinic Clinical Research Unit of the Case Western Reserve University Clinical and Translational Sciences Award (UL1TR 000439). Dr Wang was partially supported by an American Heart Association Scientist Development Grant 12SDG12050473. Dr Kennedy was partially supported by an American Heart Association Scientist Development Grant 14SDG18650010.