TY - JOUR
T1 - Plasma trimethylamine N-oxide concentration and all-cause mortality in kidney transplant recipients
AU - TransplantLines Investigators
AU - Yepes-Calderón, Manuela
AU - Martín Del Campo Sanchez, Fernando
AU - Kremer, Daan
AU - Knobbe, Tim J.
AU - Gomes Neto, Antonio W.
AU - Connelley, Margery A.
AU - Dullaart, Robin P.F.
AU - Corpeleijn, Eva
AU - De Borst, Martin H.
AU - Bakker, Stephan J.L.
AU - Ranchor, Adelta V.
AU - Diepstra, Arjan
AU - Hepkema, Bouke G.
AU - Gan, C. Tji
AU - Doorenbos, Caecilia S.E.
AU - Velde-Keyzer, Charlotte A.Te
AU - Van Leer-Buter, Coretta
AU - Touw, Daan J.
AU - Hak, Eelko
AU - Verschuuren, Erik A.M.
AU - Bodewes, Frank A.J.A.
AU - Klont, Frank
AU - Dijk-Stra, Gerard
AU - Nieuwenhuis-Moeke, Gertrude J.
AU - Blokzijl, Hans
AU - Leu-Venink, Henri G.D.
AU - Niesters, Hubert G.M.
AU - Swarte, J. Cas
AU - Sanders, Jan Stephan F.
AU - Damman, Kevin
AU - Van Pelt, L. Joost
AU - Van Londen, Marco
AU - De Boer, Marieke T.
AU - Siebelink, Marion J.
AU - Van Den Heuvel, Marius C.
AU - Vos, Michel J.
AU - Erasmus, Michiel E.
AU - Douwes, Rianne M.
AU - Slart, Riemer J.H.J.A.
AU - Weersma, Rinse K.
AU - Pol, Robert A.
AU - Porte, Robert J.
AU - De Meijer, Vincent E.
AU - Lexmond, Willem S.
N1 - © The Author(s) 2025. Published by Oxford University Press on behalf of the ERA.
PY - 2025/10/1
Y1 - 2025/10/1
N2 - 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.
AB - 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.
KW - cohort study
KW - kidney transplantation
KW - mortality
KW - TMAO
KW - trimethylamine
UR - https://www.scopus.com/pages/publications/105017464073
U2 - 10.1093/ndt/gfaf071
DO - 10.1093/ndt/gfaf071
M3 - Article
C2 - 40275497
SN - 0931-0509
VL - 40
SP - 1931
EP - 1940
JO - Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
JF - Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
IS - 10
ER -