The Gut Microbial Metabolite Trimethylamine N -oxide, Incident CKD, and Kidney Function Decline

Abstract

Key Points:

1. In community-based US adults, higher plasma trimethylamine N-oxide levels associated with higher risk of incident CKD and greater rate of kidney function decline.

2. Findings from our study support future clinical trials to examine whether lowering plasma trimethylamine N-oxide levels may prevent CKD development and progression.

Background: Trimethylamine N-oxide (TMAO) is a gut microbiota–derived metabolite of dietary phosphatidylcholine and carnitine. Experimentally, TMAO causes kidney injury and tubulointerstitial fibrosis. Little is known about prospective associations between TMAO and kidney outcomes, especially incident CKD. We hypothesized that higher plasma TMAO levels would be associated with higher risk of incident CKD and greater rate of kidney function decline.

Methods: We included 10,564 participants from two community-based, prospective cohorts with eGFR ≥60 ml/min per 1.73 m² to assess incident CKD. TMAO was measured using targeted mass spectrometry at baseline and one follow-up visit. Creatinine and cystatin C were measured up to four times during follow-up and used to compute eGFR. Incident CKD was defined as an eGFR decline ≥30% from baseline and a resulting eGFR <60 ml/min per 1.73 m². Time-varying Cox models assessed the association of serial TMAO measures with incident CKD, adjusting for sociodemographic, lifestyle, diet, and cardiovascular disease risk factors. Linear mixed models assessed the association with annualized eGFR change in 10,009 participants with at least one follow-up eGFR measure without exclusions for baseline eGFR levels.

Results: During a median follow-up of 9.4 years (interquartile range, 9.1–11.6 years), 979 incident CKD events occurred. Higher TMAO levels were associated with higher risk of incident CKD (second to fifth versus first quintile hazard ratio [95% confidence interval]=1.65 [1.22 to 2.23], 1.68 [1.26 to 2.25], 2.28 [1.72 to 3.02], and 2.24 [1.68 to 2.98], respectively) and greater annualized eGFR decline (second to fifth versus first quintile annualized eGFR change=−0.21 [−0.32 to −0.09], −0.17 [−0.29 to −0.05], −0.35 [−0.47 to −0.22], and −0.43 [−0.56 to −0.30] ml/min per 1.73 m², respectively) with monotonic dose–response relationships. These associations were consistent across different racial/ethnic groups examined. The association with eGFR decline was similar to or larger than that seen for established CKD risk factors, including diabetes, per 10 mm Hg of higher systolic BP, per 10 years of older age, and Black race.

Conclusions: In community-based US adults, higher serial measures of plasma TMAO were associated with higher risk of incident CKD and greater annualized kidney function decline.