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 6,723 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 five. UACR was measured at up to five visits. The co-primary outcomes were incident increased albuminuria, defined as at least two consecutive UACR measures ≥ 30mg/g during follow-up; and rate of UACR change over time. The secondary outcome was severely increased albuminuria, defined as a new UACR ≥ 300mg/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 vs. lowest quintile HR 95%CI = 1.41 1.05-1.89 and 1.73 0.99-3.00, 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 vs. 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.
Wang et al. (Thu,) studied this question.