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Fast Tacrolimus Metabolism Does Not Promote Post-Transplant Diabetes Mellitus after Kidney Transplantation

Post-transplant diabetes mellitus (PTDM) after kidney transplantation induced by tacrolimus is an important issue. Fast tacrolimus metabolism, which can be estimated by concentration-to-dose (C/D) ratio, is associated with increased nephrotoxicity and unfavorable outcomes after kidney transplantatio...

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Autores principales: Jehn, Ulrich, Wiedmer, Nathalie, Boeckel, Göran Ramin, Pavenstädt, Hermann, Thölking, Gerold, Reuter, Stefan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9408810/
https://www.ncbi.nlm.nih.gov/pubmed/36012395
http://dx.doi.org/10.3390/ijms23169131
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author Jehn, Ulrich
Wiedmer, Nathalie
Boeckel, Göran Ramin
Pavenstädt, Hermann
Thölking, Gerold
Reuter, Stefan
author_facet Jehn, Ulrich
Wiedmer, Nathalie
Boeckel, Göran Ramin
Pavenstädt, Hermann
Thölking, Gerold
Reuter, Stefan
author_sort Jehn, Ulrich
collection PubMed
description Post-transplant diabetes mellitus (PTDM) after kidney transplantation induced by tacrolimus is an important issue. Fast tacrolimus metabolism, which can be estimated by concentration-to-dose (C/D) ratio, is associated with increased nephrotoxicity and unfavorable outcomes after kidney transplantation. Herein, we elucidate whether fast tacrolimus metabolism also increases the risk for PTDM. Data from 596 non-diabetic patients treated with tacrolimus-based immunosuppression at the time of kidney transplantation between 2007 and 2015 were retrospectively analyzed. The median follow-up time after kidney transplantation was 4.7 years (IQR 4.2 years). Our analysis was complemented by experimental modeling of fast and slow tacrolimus metabolism kinetics in cultured insulin-producing pancreatic cells (INS-1 cells). During the follow-up period, 117 (19.6%) patients developed PTDM. Of all patients, 210 (35.2%) were classified as fast metabolizers (C/D ratio < 1.05 ng/mL × 1/mg). Fast tacrolimus metabolizers did not have a higher incidence of PTDM than slow tacrolimus metabolizers (p = 0.496). Consistent with this, insulin secretion and the viability of tacrolimus-treated INS-1 cells exposed to 12 h of tacrolimus concentrations analogous to the serum profiles of fast or slow tacrolimus metabolizers or to continuous exposure did not differ (p = 0.286). In conclusion, fast tacrolimus metabolism is not associated with increased incidence of PTDM after kidney transplantation, either in vitro or in vivo. A short period of incubation of INS-1 cells with tacrolimus using different concentration profiles led to comparable effects on cell viability and insulin secretion in vitro. Consistent with this, in our patient, collective fast Tac metabolizers did not show a higher PTDM incidence compared to slow metabolizers.
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spelling pubmed-94088102022-08-26 Fast Tacrolimus Metabolism Does Not Promote Post-Transplant Diabetes Mellitus after Kidney Transplantation Jehn, Ulrich Wiedmer, Nathalie Boeckel, Göran Ramin Pavenstädt, Hermann Thölking, Gerold Reuter, Stefan Int J Mol Sci Article Post-transplant diabetes mellitus (PTDM) after kidney transplantation induced by tacrolimus is an important issue. Fast tacrolimus metabolism, which can be estimated by concentration-to-dose (C/D) ratio, is associated with increased nephrotoxicity and unfavorable outcomes after kidney transplantation. Herein, we elucidate whether fast tacrolimus metabolism also increases the risk for PTDM. Data from 596 non-diabetic patients treated with tacrolimus-based immunosuppression at the time of kidney transplantation between 2007 and 2015 were retrospectively analyzed. The median follow-up time after kidney transplantation was 4.7 years (IQR 4.2 years). Our analysis was complemented by experimental modeling of fast and slow tacrolimus metabolism kinetics in cultured insulin-producing pancreatic cells (INS-1 cells). During the follow-up period, 117 (19.6%) patients developed PTDM. Of all patients, 210 (35.2%) were classified as fast metabolizers (C/D ratio < 1.05 ng/mL × 1/mg). Fast tacrolimus metabolizers did not have a higher incidence of PTDM than slow tacrolimus metabolizers (p = 0.496). Consistent with this, insulin secretion and the viability of tacrolimus-treated INS-1 cells exposed to 12 h of tacrolimus concentrations analogous to the serum profiles of fast or slow tacrolimus metabolizers or to continuous exposure did not differ (p = 0.286). In conclusion, fast tacrolimus metabolism is not associated with increased incidence of PTDM after kidney transplantation, either in vitro or in vivo. A short period of incubation of INS-1 cells with tacrolimus using different concentration profiles led to comparable effects on cell viability and insulin secretion in vitro. Consistent with this, in our patient, collective fast Tac metabolizers did not show a higher PTDM incidence compared to slow metabolizers. MDPI 2022-08-15 /pmc/articles/PMC9408810/ /pubmed/36012395 http://dx.doi.org/10.3390/ijms23169131 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Jehn, Ulrich
Wiedmer, Nathalie
Boeckel, Göran Ramin
Pavenstädt, Hermann
Thölking, Gerold
Reuter, Stefan
Fast Tacrolimus Metabolism Does Not Promote Post-Transplant Diabetes Mellitus after Kidney Transplantation
title Fast Tacrolimus Metabolism Does Not Promote Post-Transplant Diabetes Mellitus after Kidney Transplantation
title_full Fast Tacrolimus Metabolism Does Not Promote Post-Transplant Diabetes Mellitus after Kidney Transplantation
title_fullStr Fast Tacrolimus Metabolism Does Not Promote Post-Transplant Diabetes Mellitus after Kidney Transplantation
title_full_unstemmed Fast Tacrolimus Metabolism Does Not Promote Post-Transplant Diabetes Mellitus after Kidney Transplantation
title_short Fast Tacrolimus Metabolism Does Not Promote Post-Transplant Diabetes Mellitus after Kidney Transplantation
title_sort fast tacrolimus metabolism does not promote post-transplant diabetes mellitus after kidney transplantation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9408810/
https://www.ncbi.nlm.nih.gov/pubmed/36012395
http://dx.doi.org/10.3390/ijms23169131
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