Abstract
Background and Aims
Trimethylamine N-oxide (TMAO) is a gut microbial metabolite derived from dietary phosphatidylcholine and carnitine. Recently, we have shown that TMAO accumulates in patients with chronic kidney disease (CKD), not only due to impaired kidney clearance, but also due to altered microbial production. Increasing evidence points to TMAO as an emerging contributor to ...
Abstract
Background and Aims
Trimethylamine N-oxide (TMAO) is a gut microbial metabolite derived from dietary phosphatidylcholine and carnitine. Recently, we have shown that TMAO accumulates in patients with chronic kidney disease (CKD), not only due to impaired kidney clearance, but also due to altered microbial production. Increasing evidence points to TMAO as an emerging contributor to cardiovascular disease. However, the prognostic impact of TMAO on adverse kidney outcomes in patients with established CKD remains unclear. Thus, the aim of this study was to determine the prevalence and prognostic implications of TMAO in patients with CKD.
Method
We analyzed data from 4724 participants of the German Chronic Kidney Disease (GCKD) cohort, a prospective observational cohort of CKD patients with an eGFR of 30-60 mL/min/1.73 m2 or overt proteinuria in the presence of an eGFR>60 mL/min/1.73 m2 at enrollment. TMAO levels were quantified in plasma at baseline using proton nuclear magnetic resonance spectroscopy. Creatinine and cystatin C measurements were obtained up to four times during follow-up, enabling the calculation of eGFR trajectories. The primary outcomes were all-cause mortality as well as the incidence of composite kidney endpoint (CKE), defined as eGFR decline >40% from baseline, eGFR <15 ml/min/1.73 m², initiation of kidney replacement therapy (dialysis or transplantation), or renal death, within 6.5 years. Time-to-event analyses were conducted using multivariate proportional hazards regression models.
Results
Median TMAO levels increased with higher CKD GFR and albuminuria categories. Over a median follow-up of 6.5 years, 479 deaths were recorded. Elevated TMAO concentrations at baseline (fourth versus first quartile) were significantly associated with increased all-cause mortality risk. This association remained robust after adjustment for traditional risk factors, history of cardiovascular disease, high-sensitivity C-reactive protein, and eGFR as well as albuminuria. Further, higher TMAO levels were consistently associated with increased incidence of CKE and after multivariate analyses independently predicted CKE risk, underscoring its potential as a prognostic kidney biomarker in CKD.
Conclusion
Among patients with CKD, TMAO levels were increased progressively with lower GFR and higher albuminuria. Elevated TMAO levels were independently associated with a greater risk of all-cause mortality and CKE. These findings emphasize the critical role of gut microbiota-derived metabolites in the progression and outcomes of CKD, highlighting TMAO as a potential biomarker for risk stratification and as a potential target for therapeutic intervention.
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