The Association of Serial Measures of Plasma Trimethylamine N-Oxide with Incident Chronic Kidney Disease and Renal Function Decline among Older Adults: the Cardiovascular Health Study

Introduction: Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite of dietary phosphatidylcholine and carnitine. Experimentally, TMAO causes renal tubulointerstitial fibrosis and kidney injury. Yet, little is known about prospective associations between TMAO and renal outcomes. Hypothesis: Higher plasma TMAO levels are prospectively associated with higher risk of incident chronic kidney disease (CKD) and greater renal function decline. Methods: We included 4,131 US adults from the Cardiovascular Health Study, a community-based cohort, with normal baseline renal function (estimated glomerular filtration rate [eGFR] ≥ 60 mL/min/1.73m 2 ). TMAO was measured using liquid chromatography-mass spectrometry at baseline and year 7. Creatinine and Cystatin C were measured 4 times during serial follow-up and used to compute eGFR. Incident CKD was defined by eGFR (decline ≥ 30% plus eGFR<60 at a follow-up visit) or presence of CKD hospitalization ICD codes. Time-varying Cox models assessed how serial TMAO measures related to incident CKD, adjusting for sociodemographic, lifestyle, diet, and CVD risk factors. Linear regression models assessed how baseline TMAO related to annualized eGFR change in 3,997 participants with at least one follow-up eGFR measure. Results: During a median follow-up of 14 years, 1,136 participants developed CKD. There was a non-linear dose-response relationship of TMAO with CKD incidence: higher TMAO levels were associated with higher risk of incident CKD with a plateauing of risk above the ~75 th percentile of TMAO levels (top Figure ). Higher baseline TMAO levels were also associated with greater annualized eGFR decline (P-linearity=0.004. bottom Figure ) after adjusting for baseline eGFR and other covariates. Conclusions: In this community-based cohort of older US adults, higher serial measures of plasma TMAO were associated with a higher risk of incident CKD and a greater rate of annualized renal function decline.