Associations of Plasma Trimethylamine N-Oxide–Related Metabolites with the Development and Progression of Albuminuria

Key Points – In community-based adults, higher plasma trimethylamine N-oxide levels associated with higher risk of the development and progression of albuminuria.Findings from our study raise the need to investigate the role of targeting the trimethylamine N-oxide pathway on albuminuria.Background – Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite of dietary phosphatidylcholine and carnitine. Mechanistically, TMAO raises urine albumin-to-creatinine ratio (UACR). However, little is known in humans about prospective associations between TMAO-related biomarkers and albuminuria, an early, sensitive marker of kidney damage.Methods – We included 6723 participants with TMAO-related biomarkers and UACR at baseline and follow-up data from July 2000 to May 2019 from a diverse cohort of community-based US adults. Plasma TMAO-related biomarkers (TMAO, γ-butyrobetaine, and crotonobetaine and, secondarily, carnitine, choline, and betaine) were measured using liquid chromatography tandem mass spectrometry at baseline and year 5. UACR was measured at up to five visits. The coprimary outcomes were incident increased albuminuria, defined as at least two consecutive UACR measures ≥30 mg/g during follow-up, and rate of UACR change over time. The secondary outcome was severely increased albuminuria, defined as a new UACR ≥300 mg/g. Time-varying Cox models assessed associations of biomarkers with incident albuminuria and linear mixed models with rate of UACR change, adjusting for sociodemographic, lifestyle, diet, and cardiovascular disease risk factors.Results – During a median follow-up of 15.7 years, 648 participants experienced increased albuminuria and 197 experienced severely increased albuminuria. TMAO levels positively associated with both outcomes (highest versus lowest quintile hazard ratio [95% confidence interval]=1.41 [1.05 to 1.89] and 1.73 [0.99 to 3.00], respectively, P trend < 0.01 each). TMAO also associated with greater rate of UACR increase (adjusted percent change per 10 years=22.1% in the lowest versus 40.6% in the highest quintile, P trend < 0.001). Crotonobetaine and γ-butyrobetaine levels also associated with rate of UACR increase, as did carnitine, while choline levels positively associated with all three outcomes.Conclusions – TMAO-related gut microbial metabolites may be a novel risk factor for albuminuria and its progression, raising the need to investigate the role of targeting the TMAO pathway on albuminuria.