Intra-erythrocyte creatine, plasma creatine and long-term outcomes in stable kidney transplant recipients: Results from the TransplantLines Biobank and Cohort study

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.

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Publication Details

Journal
Clinical Nutrition Open Science
Published
2025-12-03
DOI
https://doi.org/10.1016/j.nutos.2025.11.013
Primary Topic
Muscle metabolism and nutrition
Type
article
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article

Intra-erythrocyte creatine, plasma creatine and long-term outcomes in stable kidney transplant recipients: Results from the TransplantLines Biobank and Cohort study

António W. Gomes‐Neto, C. Tji Gan, Yvonne van der Veen, Margery A. Connelly et al.
Clinical Nutrition Open Science
Muscle metabolism and nutrition
article

Intra-erythrocyte creatine, plasma creatine and long-term outcomes in stable kidney transplant recipients: Results from the TransplantLines Biobank and Cohort study

António W. Gomes‐Neto, C. Tji Gan, Yvonne van der Veen, Margery A. Connelly, Jessica M. González-Delgado, Marius C. van den Heuvel, Adrian Post, Coby Annema, Erik A.M. Verschuuren, Daan J. Touw, Bouke G. Hepkema, J. Casper Swarte, S.P. Berger, Coretta van Leer‐Buter, Eelko Hak, Rianne M. Douwes, Stephan J. L. Bakker, Frank Klont, Vincent Erwin de Meijer, T.J. Knobbe, Frank A.J.A. Bodewes, Robert A. Pol, H. Blokzijl, Kevin Damman, Michiel E. Erasmus, Robin P.F. Dullaart, Casper F. M. Franssen, Charlotte A. te Velde‐Keyzer, Jan‐Stephan Sanders, Caecilia S E Doorenbos, Jacqueline T. Jonker, Michel J. Vos, Gerard D. H. Dijkstra, Adelita V. Ranchor, Marco van Londen, Martin H. de Borst, Qinglin Wu, Marion J. Siebelink, Willem S. Lexmond, R.K. Weersma, Arjan Diepstra, Michele F. Eisenga, L. Joost van Pelt, D. Kremer, Gertrude J. Nieuwenhuis-Moeke, HGM Niesters, R. H. J. A. Slart, Leuvenink Hgd., Gerjan Navis, Marieke T. de Boer, Anna M Posthumus, IJC Dielwart
article en

Abstract

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.

Clinical Nutrition Open ScienceVol. 65
Openalex Percentile: Top 60%
Muscle metabolism and nutrition
DOIOpen Access PDFOpenAlex
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