A Low Tacrolimus Concentration/Dose Ratio Increases the Risk for the Development of Acute Calcineurin Inhibitor-Induced Nephrotoxicity

Fast tacrolimus metabolism is linked to inferior outcomes such as rejection and lower renal function after kidney transplantation. Renal calcineurin-inhibitor toxicity is a common adverse effect of tacrolimus therapy. The present contribution hypothesized that tacrolimus-induced nephrotoxicity is re...

Authors: Thölking, Gerold Bernhard
Schütte-Nütgen, Katharina
Schmitz, Julia
Rovas, Alexandros
Dahmen, Maximilian
Bautz, Joachim
Jehn, Ulrich
Pavenstädt, Hermann
Heitplatz, Barbara
Van Marck, Veerle
Suwelack, Barbara
Reuter, Stefan Johannes
Division/Institute:FB 05: Medizinische Fakultät
Document types:Article
Media types:Text
Publication date:2019
Date of publication on miami:28.01.2021
Modification date:28.01.2021
Edition statement:[Electronic ed.]
Source:Journal of Clinical Medicine 8 (2019) 10, 1586, 1-14
Subjects:calcineurin inhibitor nephrotoxcity; tacrolimus; C/D ratio; tacrolimus metabolism; kidney transplantation
DDC Subject:610: Medizin und Gesundheit
License:CC BY 4.0
Language:English
Funding:Finanziert durch den Open-Access-Publikationsfonds der Westfälischen Wilhelms-Universität Münster (WWU Münster)
Format:PDF document
URN:urn:nbn:de:hbz:6-48079527367
Other Identifiers:DOI: 10.3390/jcm8101586
Permalink:https://nbn-resolving.de/urn:nbn:de:hbz:6-48079527367
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Digital documents:10.3390_jcm8101586.pdf
10.3390_jcm8101586_zusatzmaterial.pdf
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Fast tacrolimus metabolism is linked to inferior outcomes such as rejection and lower renal function after kidney transplantation. Renal calcineurin-inhibitor toxicity is a common adverse effect of tacrolimus therapy. The present contribution hypothesized that tacrolimus-induced nephrotoxicity is related to a low concentration/dose (C/D) ratio. We analyzed renal tubular epithelial cell cultures and 55 consecutive kidney transplant biopsy samples with tacrolimus-induced toxicity, the C/D ratio, C0, C2, and C4 Tac levels, pulse wave velocity analyses, and sublingual endothelial glycocalyx dimensions in the selected kidney transplant patients. A low C/D ratio (C/D ratio < 1.05 ng/mL×1/mg) was linked with higher C2 tacrolimus blood concentrations (19.2 ± 8.7 µg/L vs. 12.2 ± 5.2 µg/L respectively; p = 0.001) and higher degrees of nephrotoxicity despite comparable trough levels (6.3 ± 2.4 µg/L vs. 6.6 ± 2.2 µg/L respectively; p = 0.669). However, the tacrolimus metabolism rate did not affect the pulse wave velocity or glycocalyx in patients. In renal tubular epithelial cells exposed to tacrolimus according to a fast metabolism pharmacokinetic profile it led to reduced viability and increased Fn14 expression. We conclude from our data that the C/D ratio may be an appropriate tool for identifying patients at risk of developing calcineurin-inhibitor toxicity.