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 to 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 [eGFR] <60 ml/min/1.73m2). Median TMAO level among CKD subjects was 7.9 υM (interquartile range 5.2-12.4υM), which was markedly higher (P<0.001) than in non-CKD subjects (n=3,166). Within CKD subjects, higher (4th vs. 1st quartile) plasma TMAO level was associated with a 2.8-fold increased mortality risk. Following adjustments for traditional risk factors, hsCRP and eGFR, elevated TMAO levels remained predictive of 5-year mortality risk (HR 1.93 [95%CI 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% vs. 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 appear to directly contribute to progressive renal fibrosis and dysfunction.
- Received September 28, 2014.
- Revision received October 25, 2014.
- Accepted November 5, 2014.