Plasma Trimethylamine N-oxide Concentration and All-Cause Mortality in Kidney Transplant Recipients.

Background and hypothesis: Trimethylamine N-oxide (TMAO) is a pro-atherosclerotic molecule produced by intestinal microbiome. TMAO has been linked to increased mortality risk in chronic kidney disease, but its effect in kidney transplant recipients (KTR) is unclear. We investigated the pre-post-transplantation plasma TMAO change, and the association of post-transplantation plasma TMAO with all-cause mortality in KTR.

Methods: This prospective study included two cohorts. Cohort A comprised 623 KTR from the TransplantLines Cohort and Biobank Study (ClinicalTrials.gov: NCT03272841), assessed pre-transplantation and at 3, 6, 12, and 24 months post-transplantation. Cohort B included 544 KTR with a functioning graft for ≥1 year (median 7.4 [3.9-13.0] years post-transplantation) to study late associations. Potential kidney donors (n=315) served as healthy controls. Plasma TMAO was measured by proton nuclear magnetic resonance. Time-dependent coefficient Cox regression analyses were performed to assess TMAO association with all-cause mortality.

Results: Plasma TMAO concentration significantly declined after transplantation (from 29.0 [IQR 20.6-48.5] µmol/L to 4.5 [IQR 2.7-8.6] mol/L at 3-months post-transplantation, P<0.001). Afterwards it remained stable (β=-0.4 (95% CI -2.2-1.34) µmol/L per post-transplantation year, P=0.63), remaining consistently higher than that of healthy control (2.6 [IQR 1.8-4.3] µmol/L). In cohort A, during a median follow-up of 2.2 years, 41 KTR (7%) died. In cohort B, over a median follow-up of 4.1 years, 78 KTR (14%) died. A 1-standard deviation higher plasma TMAO concentration was independently associated with an increased risk of all-cause mortality in both cohorts (HR 1.35 [95% CI 1.19‒1.53]; P<0.001, and HR 1.34 [95% CI 1.23‒1.47]; P<0.001; respectively).

Conclusion: Plasma TMAO decreases sharply after kidney transplantation, without reaching healthy controls levels. A higher plasma TMAO concentration was independently associated with an increased mortality risk in KTR. Further research is warranted to assess whether accounting for gut dysbiosis and TMAO could improve clinical outcomes in KTR.