GENERAL COMMENTARY article
Commentary: The Clinical Impact of the C0/D Ratio and the CYP3A5 Genotype on Outcome in Tacrolimus Treated Kidney Transplant Recipients
- 1Department of Internal Medicine and Nephrology, University Hospital of Münster Marienhospital Steinfurt, Steinfurt, Germany
- 2Department of Medicine D, Division of General Internal Medicine, Nephrology and Rheumatology, University Hospital of Münster, Münster, Germany
by Gerold Thölking and Stefan Reuter (2021). Front. Pharmacol. 12:3. doi: 10.3389/fphar.2020.01142
Van Gelder et al. nicely reviewed about the influence of the C0/D ratio and the CYP3A5 genotype on the outcome of kidney transplant (KTx) recipients treated with tacrolimus (Tac) (van Gelder et al., 2020). The authors report that our group has shown that fast Tac metabolism (C0/D ratio <1.05 ng/ml/mg) is associated with a faster decline in renal function, a higher incidence of calcineurin inhibitor nephrotoxicity (CNIT) and BK nephropathy and a lower survival rate (Tholking et al., 2014; Tholking et al., 2016; Schutte-Nutgen et al., 2019; Tholking et al., 2019). They comment that there is no evidence that switching from Tac to a mammalian target of rapamycin inhibitor (mTORi) or other substances improves long-term outcome.
Conversion of Fast Metabolizers to mTORi
Recently, we published data of 34 KTx recipients (17 patients with a Tac C0/D ratio <1.05 ng/mL/mg vs. 17 patients with a C0/D ratio ≥1.05 ng/ml/mg (slow metabolizers)) whose therapy was converted to the mTORi everolimus within 24 months after KTx (Tholking et al., 2020). 36 months after switching from immediate-release Tac (IR-Tac) to everolimus, the estimated glomerular filtration rate (eGFR) increased noticeably in fast metabolizers and slow metabolizers, respectively, compared to baseline (+11.0 ± 11.7 (p = 0.005) and +9.4 ± 15.9 ml/min/1.73 m2 (p = 0.049). Adverse events did not differ noticeably between both groups. Although our reported single center sample size data has limitations, we believe that a conversion from Tac to everolimus is safe and beneficial for renal function in KTx recipients who developed CNIT in particular.
Conversion of Fast Metabolizers to LCPT
In a subsequent study on liver transplant recipients (LTR), we analyzed whether the renal function benefits from an increase of the bioavailability of tacrolimus (von Einsiedel et al., 2020). LTR were converted from IR-Tac or once-daily extended-release Tac (ER-Tac)) to MeltDose® Tac (LCPT). In LTR switched to LCPT, the daily Tac dose decreased by 33.3% and the C0/D ratio had increased by 50% 12 months after conversion due to the higher bioavailability of LCPT. Patients converted to LCPT showed a significant increase in mean eGFR already 6 months after the switch (67.5 vs. 65.3 ml/min/1.73 m2 at baseline; p = 0.029), which was even more pronounced 12 months after the conversion (70.9 vs. 65.3 ml/min/1.73 m2 at baseline; p = 0.001). We concluded that a conversion from IR-Tac to LCPT increased the C0/D ratio and improved renal function in LTR possibly by flattening the Tac blood concentration curve and lowering peak levels.
Despite limited data on long-term outcome in recipients of solid organ transplants after conversion from IR- or ER-Tac to other immunosuppressants, we have already shown it can be safe and useful in transplant patients with Tac-related adverse effects.
GT developed the idea on the General Commentary. GT and SR wrote the draft. All authors contributed to the article and approved the submitted version.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Schutte-Nutgen, K., Tholking, G., Steinke, J., Pavenstadt, H., Schmidt, R., Suwelack, B., et al. (2019). Fast tac metabolizers at risk (-) it is time for a C/D ratio calculation. J. Clin. Med. 8 (5), 587. doi:10.3390/jcm8050587
Thölking, G., Fortmann, C., Koch, R., Gerth, H. U., Pabst, D., Pavenstädt, H., et al. (2014). The tacrolimus metabolism rate influences renal function after kidney transplantation. PloS One 9 (10), e111128. doi:10.1371/journal.pone.0111128
Thölking, G., Schmidt, C., Koch, R., Schuette-Nuetgen, K., Pabst, D., Wolters, H., et al. (2016). Influence of tacrolimus metabolism rate on BKV infection after kidney transplantation. Sci. Rep. 6, 32273. doi:10.1038/srep32273
Tholking, G., Gillhaus, N. H., Schutte-Nutgen, K., Pavenstadt, H., Koch, R., Suwelack, B., et al. (2020). Conversion to everolimus was beneficial and safe for fast and slow tacrolimus metabolizers after renal transplantation. J. Clin. Med. 9 (2), 328. doi:10.3390/jcm9020328
Tholking, G., Schutte-Nutgen, K., Schmitz, J., Rovas, A., Dahmen, M., Bautz, J., et al. (2019). A low tacrolimus concentration/dose ratio increases the risk for the development of acute calcineurin inhibitor-induced nephrotoxicity. J. Clin. Med. 8 (10), 1586. doi:10.3390/jcm8101586
van Gelder, T., Meziyerh, S., Swen, J. J., de Vries, A. P. J., and Moes, D. J. A. R. (2020). The clinical impact of the C0/D ratio and the CYP3A5 genotype on outcome in tacrolimus treated kidney transplant recipients. Front. Pharmacol. 11, 1142. doi:10.3389/fphar.2020.01142
von Einsiedel, J., Thölking, G., Wilms, C., Vorona, E., Bokemeyer, A., Schmidt, H. H., et al. (2020). Conversion from standard-release tacrolimus to MeltDose® tacrolimus (LCPT) improves renal function after liver transplantation. J. Clin. Med. 9 (6), 1654. doi:10.3390/jcm9061654
Keywords: kidney, metabolism, C/D ratio, tacrolimus, transplantation, renal
Citation: Thölking G and Reuter S (2021) Commentary: The Clinical Impact of the C0/D Ratio and the CYP3A5 Genotype on Outcome in Tacrolimus Treated Kidney Transplant Recipients. Front. Pharmacol. 12:603345. doi: 10.3389/fphar.2021.603345
Received: 07 October 2020; Accepted: 11 January 2021;
Published: 23 February 2021.
Edited by:Vita Dolzan, University of Ljubljana, Slovenia
Reviewed by:Anders Åsberg, University of Oslo, Norway
Copyright © 2021 Thölking and Reuter. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Gerold Thölking, Gerold.Thoelking@ukmuenster.de