TY - JOUR
T1 - Intra-erythrocyte creatine, plasma creatine and long-term outcomes in stable kidney transplant recipients
T2 - Results from the TransplantLines Biobank and Cohort study
AU - TransplantLines Investigators
AU - Doorenbos, Caecilia S.E.
AU - Post, Adrian
AU - van der Veen, Yvonne
AU - Franssen, Casper F.M.
AU - Eisenga, Michele F.
AU - Dullaart, Robin P.F.
AU - Navis, Gerjan
AU - Wu, Qinglin
AU - Gonzalez-Delgado, Jessica M.
AU - Connelly, Margery A.
AU - Bakker, Stephan J.L.
AU - Annema, C.
AU - Berger, S.P.
AU - Blokzijl, H.
AU - Bodewes, F.A.J.A.
AU - de Boer, M.T.
AU - Damman, K.
AU - de Borst, M.H.
AU - Dielwart, I.J.C.
AU - Diepstra, A.
AU - Dijkstra, G.
AU - Douwes, R.M.
AU - Erasmus, M.E.
AU - Gan, C.T.
AU - Neto, A.W. Gomes
AU - Posthumus, A.M.
AU - Hak, E.
AU - Hepkema, B.G.
AU - Jonker, J.
AU - Klont, F.
AU - Knobbe, T.J.
AU - Kremer, D.
AU - Leuvenink, H.G.D.
AU - de Meijer, V.E.
AU - Nieuwenhuis-Moeke, G.J.
AU - Niesters, H.G.M.
AU - van Pelt, L.J.
AU - Pol, R.A.
AU - Ranchor, A.V.
AU - Sanders, J.S.F.
AU - Siebelink, M.J.
AU - Slart, R.J.H.J.A.
AU - Swarte, J.C.
AU - Touw, D.J.
AU - van den Heuvel, M.C.
AU - van Leer-Buter, C.
AU - van Londen, M.
AU - te Velde-Keyzer, Charlotte A.
AU - Verschuuren, E.A.M.
AU - Vos, M. J.
N1 - Publisher Copyright:
© 2025 The Authors
PY - 2026/2
Y1 - 2026/2
N2 - Introduction: Kidney transplant recipients (KTR) have excess mortality compared to the general population and show altered creatine homeostasis. Creatine, an endogenous nitrogenous compound, is essential for energy metabolism. We investigated determinants of circulating creatine and their sex-specific associations with mortality in KTR.Methods: Intra-erythrocyte and plasma creatine were quantified by nuclear magnetic resonance in samples from KTR and living kidney donors (healthy controls) from the TransplantLines Biobank and Cohort study (ClinicalTrials.gov: NCT03272841). Determinants of intra-erythrocyte and plasma creatine were assessed using linear regression; associations with mortality were evaluated with Cox regression.Results: 815 KTR and 53 healthy controls were included. Compared with controls, KTR had higher intra-erythrocyte but lower plasma creatine, with women having higher concentrations of each in both groups. In KTR, plasma creatine, BMI, erythrocyte count, reticulocyte count, lactate dehydrogenase, and erythropoietin use were positively associated with intra-erythrocyte creatine, whereas hemoglobin, haptoglobin, ferritin, transferrin saturation, proliferation inhibitor use were negatively associated. In univariable analyses, higher intra-erythrocyte creatine was associated with higher risk of mortality in male KTR (HR: 2.30 (1.50; 3.54), P<0.001), with a weaker, nonsignificant trend in female KTR (HR: 1.51 (0.76; 3.02), P=0.23). Furthermore, higher plasma creatine was associated with higher risk of mortality in male KTR (HR: 1.36 (1.07; 1.73), P=0.01), but not in female KTR (HR: 0.94 (0.68; 1.28), P=0.68). These associations persisted after adjustment for potential confounders.Conclusion: KTR have increased intra-erythrocyte and decreased plasma creatine compared with healthy controls. Intra-erythrocyte creatine was linked to markers of erythrocyte turnover, suggesting potential mechanisms. Elevated intra-erythrocyte and plasma creatine were associated with higher mortality in male, but not female, KTR. These findings highlight the need to further explore sex-specific mechanisms underlying creatine metabolism and clinical outcomes in KTR.
AB - Introduction: Kidney transplant recipients (KTR) have excess mortality compared to the general population and show altered creatine homeostasis. Creatine, an endogenous nitrogenous compound, is essential for energy metabolism. We investigated determinants of circulating creatine and their sex-specific associations with mortality in KTR.Methods: Intra-erythrocyte and plasma creatine were quantified by nuclear magnetic resonance in samples from KTR and living kidney donors (healthy controls) from the TransplantLines Biobank and Cohort study (ClinicalTrials.gov: NCT03272841). Determinants of intra-erythrocyte and plasma creatine were assessed using linear regression; associations with mortality were evaluated with Cox regression.Results: 815 KTR and 53 healthy controls were included. Compared with controls, KTR had higher intra-erythrocyte but lower plasma creatine, with women having higher concentrations of each in both groups. In KTR, plasma creatine, BMI, erythrocyte count, reticulocyte count, lactate dehydrogenase, and erythropoietin use were positively associated with intra-erythrocyte creatine, whereas hemoglobin, haptoglobin, ferritin, transferrin saturation, proliferation inhibitor use were negatively associated. In univariable analyses, higher intra-erythrocyte creatine was associated with higher risk of mortality in male KTR (HR: 2.30 (1.50; 3.54), P<0.001), with a weaker, nonsignificant trend in female KTR (HR: 1.51 (0.76; 3.02), P=0.23). Furthermore, higher plasma creatine was associated with higher risk of mortality in male KTR (HR: 1.36 (1.07; 1.73), P=0.01), but not in female KTR (HR: 0.94 (0.68; 1.28), P=0.68). These associations persisted after adjustment for potential confounders.Conclusion: KTR have increased intra-erythrocyte and decreased plasma creatine compared with healthy controls. Intra-erythrocyte creatine was linked to markers of erythrocyte turnover, suggesting potential mechanisms. Elevated intra-erythrocyte and plasma creatine were associated with higher mortality in male, but not female, KTR. These findings highlight the need to further explore sex-specific mechanisms underlying creatine metabolism and clinical outcomes in KTR.
KW - Creatine
KW - Erythrocytes
KW - Erythropoiesis
KW - Graft-failure
KW - Kidney transplantation
KW - Mortality
UR - https://www.scopus.com/pages/publications/105025575111
U2 - 10.1016/j.nutos.2025.11.013
DO - 10.1016/j.nutos.2025.11.013
M3 - Article
AN - SCOPUS:105025575111
SN - 2667-2685
VL - 65
JO - Clinical Nutrition Open Science
JF - Clinical Nutrition Open Science
M1 - 100606
ER -