Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Oct 19;13(20):6241.
doi: 10.3390/jcm13206241.

Renal Allograft Function and the Tacrolimus C/D Ratio: Insights from a Prospective Study on MeltDose Tacrolimus

Alicja Dębska-Ślizień  1 , Izabella Kuźmiuk-Glembin  1 , Roman Hożejowski  2 , Dorota Kamińska  3 , Magdalena Krajewska  3 , Anna Zawiasa-Bryszewska  4 , Ilona Kurnatowska  4 , Katarzyna Smykał-Jankowiak  5 , Maciej Głyda  5   6 , Lidia Kozioł  7 , Marek Karczewski  7 , Kazimierz Ciechanowski  8 , Ewa Kwiatkowska  8
Affiliations

Renal Allograft Function and the Tacrolimus C/D Ratio: Insights from a Prospective Study on MeltDose Tacrolimus

Alicja Dębska-Ślizień et al. J Clin Med. .

Abstract

Background: The tacrolimus concentration-to-dose (C/D) ratio is valuable for optimizing nephrotoxicity-related renal outcomes. Prospective data on the C/D ratio in kidney transplant recipients newly treated with MeltDose tacrolimus are limited. We analyzed the C/D ratio pattern of MeltDose tacrolimus and its effect on posttransplant renal function, comparing it with the literature data on immediate-release tacrolimus (IR-Tac). Methods: In total, 101 adult kidney transplant recipients on a standard immunosuppressive regimen including MeltDose tacrolimus were enrolled in this prospective, multicenter cohort study and followed for 12 months. The C/D ratio classified patients as fast, intermediate, or slow metabolizers. Renal function was assessed via the estimated glomerular filtration rate (eGFR). MeltDose tacrolimus data were compared with previous IR-Tac data by bootstrapping. Results: The cohort exhibited a right-skewed C/D ratio distribution with a mean of 2.12 ng/mL × 1/mg, which was significantly greater than the 1.29 mean for IR-Tac (p < 0.001). Compared with fast metabolizers, slow metabolizers of MeltDose tacrolimus experienced greater eGFR gains at 6 months post-transplantation (median +7.9 vs. -3.6 mL/min; p = 0.005). A Bayesian linear mixed-effects model predicting the eGFR at month 12 identified the baseline eGFR, time from transplant, body mass index, and log-transformed C/D ratio as significant variables. A one-unit increase in the log-transformed C/D ratio corresponded to an approximate increase of 4.5 mL/min in the eGFR at month 12. Conclusions: Slow metabolizers of MeltDose tacrolimus had significantly better renal function outcomes than fast metabolizers. MeltDose tacrolimus is associated with slower metabolism than is IR-Tac, as evidenced by its higher C/D ratios.

Keywords: C/D ratio; LCPT; MeltDose; glomerular filtration rate; kidney transplantation; pharmacokinetics; tacrolimus.

PubMed Disclaimer

Conflict of interest statement

A.D.-Ś. and I.K.-G. received honoraria from Chiesi Poland for lecturing and participation on advisory boards. R.H. is employed by Chiesi Poland, the sponsor of the study. The remaining co-authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Disposition of the study participants. Abbreviations: RTx = renal transplant; Tac = tacrolimus; IR-Tac = immediate-release tacrolimus; DBD = donation after brainstem death; TCMR = T-cell-mediated rejection; UTI = urinary tract infection.
Figure 2
Figure 2
Distribution of the C/D ratio for MeltDose tacrolimus (A) and comparison with the distribution for immediate-release tacrolimus (B).
Figure 3
Figure 3
Tacrolimus doses, trough concentrations, and C/D ratios over the 12-month follow-up period, stratified by metabolizer subgroups. The boxes depict interquartile ranges, with horizontal lines representing the medians and crosses representing the means. Points outside the whiskers are identified as Tukey outliers.
Figure 4
Figure 4
Renal function during the study period. Median values of CKD-EPI eGFR stratified by metabolizer group.
Figure 5
Figure 5
Predictors of the change in eGFR at month 12 (compared with baseline)—Bayesian linear mixed-effects model. The C/D ratio was logarithmically transformed to adjust for skewness in the distribution.
See this image and copyright information in PMC

References

    1. Kim H., Han A., Ahn S., Min S.K., Ha J., Min S. Association of high intra-patient variability in tacrolimus exposure with calcineurin inhibitor nephrotoxicity in kidney transplantation. Sci. Rep. 2023;13:16502. doi: 10.1038/s41598-023-43755-x. - DOI - PMC - PubMed
    1. Gijsen V.M., Madadi P., Dube M.P., Hesselink D.A., Koren G., de Wildt S.N. Tacrolimus-induced nephrotoxicity and genetic variability: A review. Ann. Transplant. 2012;17:111–121. doi: 10.12659/aot.883229. - DOI - PubMed
    1. Thölking G., Fortmann C., Koch R., Gerth H.U., Pabst D., Pavenstädt H., Kabar I., Hüsing A., Wolters H., Reuter S., et al. The tacrolimus metabolism rate influences renal function after kidney transplantation. PLoS ONE. 2014;9:e111128. doi: 10.1371/journal.pone.0111128. - DOI - PMC - PubMed
    1. Tremblay S., Nigro V., Weinberg J., Woodle E.S., Alloway R.R. A Steady-State Head-to-Head Pharmacokinetic Comparison of All FK-506 (Tacrolimus) Formulations (ASTCOFF): An Open-Label, Prospective, Randomized, Two-Arm, Three-Period Crossover Study. Am. J. Transplant. 2017;17:432–442. doi: 10.1111/ajt.13935. - DOI - PMC - PubMed
    1. Giral M., Grimbert P., Morin B., Bouvier N., Buchler M., Dantal J., Garrigue V., Bertrand D., Kamar N., Malvezzi P., et al. Impact of Switching From Immediate- or Prolonged-Release to Once-Daily Extended-Release Tacrolimus (LCPT) on Tremor in Stable Kidney Transplant Recipients: The Observational ELIT Study. Transpl. Int. 2024;37:11571. doi: 10.3389/ti.2024.11571. - DOI - PMC - PubMed

LinkOut - more resources