The TOMATO Study (Tacrolimus Metabolization in Kidney Transplantation): Impact of the Concentration-Dose Ratio on Death-censored Graft Survival.
Adult
Aged
Allografts
/ drug effects
Cytochrome P-450 CYP3A
/ genetics
Female
Follow-Up Studies
Glomerular Filtration Rate
Graft Rejection
/ blood
Graft Survival
/ drug effects
Humans
Immunosuppressive Agents
/ administration & dosage
Isoantibodies
/ blood
Kidney
/ drug effects
Kidney Failure, Chronic
/ mortality
Kidney Transplantation
/ adverse effects
Male
Middle Aged
Mycophenolic Acid
/ administration & dosage
Retrospective Studies
Risk Assessment
/ methods
Tacrolimus
/ administration & dosage
Journal
Transplantation
ISSN: 1534-6080
Titre abrégé: Transplantation
Pays: United States
ID NLM: 0132144
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
pubmed:
16
8
2019
medline:
7
10
2020
entrez:
16
8
2019
Statut:
ppublish
Résumé
Tacrolimus trough concentrations (mean/variability), as well as concentration-to-dose ratio (C/D ratio), affect kidney allograft outcomes. We investigated the link between the C/D ratio and death-censored kidney graft survival (DCGS). We performed a retrospective study on 1029 kidney transplant patients (2004-2016) with the following criteria: tacrolimus-based immunosuppression, >1-year graft survival, no initial use of everolimus, and available anti-human leukocyte antigen antibody data. We analyzed the impact of the time-varying C/D ratio on DCGS. Fast metabolizers were defined by a C/D ratio < 1.05. We also investigated the effect of an early (mo 3 to mo 6 post transplantation) C/D ratio below 1.05. Cox survival analyses were performed, adjusting for potential confounders (tacrolimus trough, variability of tacrolimus trough, de novo donor-specific antibody development, cytochrome P450 3A5 genotype, pregraft sensitization, mo 3 glomerular filtration rate). Time-varying C/D ratio was significantly associated with DCGS (hazard ratio [HR], 2.35; P < 0.001) in a univariate model, on the full analysis set comprising 1029 patients. In the multivariate time-varying model, based on 666 patients with available cytochrome P450 3A5 genotypes, the effect of the C/D ratio remained significant (HR, 2.26; P = 0.015); even when glomerular filtration rate at month 3 < 30 mL/min/1.73 m (HR, 2.61; P = 0.011), de novo donor-specific antibody development (HR, 4.09; P < 0.001) and continued steroid prescription (HR=2.08, P = 0.014) were taken into account (other covariates, including tacrolimus trough concentrations, were nonsignificant). In the same multivariate model, the effect of early C/D ratio (median at mo 3 and mo 6) remained significantly associated with DCGS (HR, 2.25; P = 0.041). C/D ratio is an independent and early predictor of DCGS. Identification of fast metabolizers could be a strategy to improve graft survival, for example, by optimizing tacrolimus formulation. Mechanistic studies to understand the C/D ratio effect are required.
Sections du résumé
BACKGROUND
Tacrolimus trough concentrations (mean/variability), as well as concentration-to-dose ratio (C/D ratio), affect kidney allograft outcomes. We investigated the link between the C/D ratio and death-censored kidney graft survival (DCGS).
METHODS
We performed a retrospective study on 1029 kidney transplant patients (2004-2016) with the following criteria: tacrolimus-based immunosuppression, >1-year graft survival, no initial use of everolimus, and available anti-human leukocyte antigen antibody data. We analyzed the impact of the time-varying C/D ratio on DCGS. Fast metabolizers were defined by a C/D ratio < 1.05. We also investigated the effect of an early (mo 3 to mo 6 post transplantation) C/D ratio below 1.05. Cox survival analyses were performed, adjusting for potential confounders (tacrolimus trough, variability of tacrolimus trough, de novo donor-specific antibody development, cytochrome P450 3A5 genotype, pregraft sensitization, mo 3 glomerular filtration rate).
RESULTS
Time-varying C/D ratio was significantly associated with DCGS (hazard ratio [HR], 2.35; P < 0.001) in a univariate model, on the full analysis set comprising 1029 patients. In the multivariate time-varying model, based on 666 patients with available cytochrome P450 3A5 genotypes, the effect of the C/D ratio remained significant (HR, 2.26; P = 0.015); even when glomerular filtration rate at month 3 < 30 mL/min/1.73 m (HR, 2.61; P = 0.011), de novo donor-specific antibody development (HR, 4.09; P < 0.001) and continued steroid prescription (HR=2.08, P = 0.014) were taken into account (other covariates, including tacrolimus trough concentrations, were nonsignificant). In the same multivariate model, the effect of early C/D ratio (median at mo 3 and mo 6) remained significantly associated with DCGS (HR, 2.25; P = 0.041).
CONCLUSIONS
C/D ratio is an independent and early predictor of DCGS. Identification of fast metabolizers could be a strategy to improve graft survival, for example, by optimizing tacrolimus formulation. Mechanistic studies to understand the C/D ratio effect are required.
Identifiants
pubmed: 31415035
doi: 10.1097/TP.0000000000002920
pii: 00007890-202006000-00028
doi:
Substances chimiques
Immunosuppressive Agents
0
Isoantibodies
0
CYP3A5 protein, human
EC 1.14.14.1
Cytochrome P-450 CYP3A
EC 1.14.14.1
Mycophenolic Acid
HU9DX48N0T
Tacrolimus
WM0HAQ4WNM
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1263-1271Commentaires et corrections
Type : CommentIn
Références
Ekberg H, Tedesco-Silva H, Demirbas A, et al.; ELITE-Symphony StudyReduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007; 357252562–2575
Ekberg H, Bernasconi C, Tedesco-Silva H, et al. Calcineurin inhibitor minimization in the symphony study: observational results 3 years after transplantation. Am J Transplant. 2009; 981876–1885
Dugast E, Soulillou JP, Foucher Y, et al. Failure of calcineurin inhibitor (tacrolimus) weaning randomized trial in long-term stable kidney transplant recipients. Am J Transplant. 2016; 16113255–3261
Gatault P, Kamar N, Büchler M, et al. Reduction of extended-release tacrolimus dose in low-immunological-risk kidney transplant recipients increases risk of rejection and appearance of donor-specific antibodies: a randomized study. Am J Transplant. 2017; 1751370–1379
Borra LC, Roodnat JI, Kal JA, et al. High within-patient variability in the clearance of tacrolimus is a risk factor for poor long-term outcome after kidney transplantation. Nephrol Dial Transplant. 2010; 2582757–2763
O’Regan JA, Canney M, Connaughton DM, et al. Tacrolimus trough-level variability predicts long-term allograft survival following kidney transplantation. J Nephrol. 2016; 292269–276
Rodrigo E, Segundo DS, Fernández-Fresnedo G, et al. Within-patient variability in tacrolimus blood levels predicts kidney graft loss and donor-specific antibody development. Transplantation. 2016; 100112479–2485
Knight SR. Intrapatient variability in tacrolimus exposure—a useful tool for clinical practice? Transpl Int. 2016; 29111155–1157
Thölking G, Fortmann C, Koch R, et al. The tacrolimus metabolism rate influences renal function after kidney transplantation. PLOS One. 2014; 910e111128
Egeland EJ, Robertsen I, Hermann M, et al. High tacrolimus clearance is a risk factor for acute rejection in the early phase after renal transplantation. Transplantation. 2017; 1018e273–e279
Schütte-Nütgen K, Thölking G, Steinke J, et al. Fast Tac metabolizers at risk—it is time for a C/D ratio calculation. J Clin Med. 2019; 85587
Egeland EJ, Reisaeter AV, Robertsen I, et al. High tacrolimus clearance—a risk factor for development of interstitial fibrosis and tubular atrophy in the transplanted kidney: a retrospective single-center cohort study. Transpl Int. 2019; 323257–269
Sapir-Pichhadze R, Wang Y, Famure O, et al. Time-dependent variability in tacrolimus trough blood levels is a risk factor for late kidney transplant failure. Kidney Int. 2014; 8561404–1411
Janmaat CJ, van Diepen M, Tsonaka R, et al. Pitfalls of linear regression for estimating slopes over time and how to avoid them by using linear mixed-effects models. Nephrol Dial Transplant. 2019; 344561–566
R Core TeamR: A Language and Environment for Statistical Computing [computer program]. 2018Vienna, AustriaR Foundation for Statistical ComputingAvailable at https://www.R-project.org/
Rojas L, Neumann I, Herrero MJ, et al. Effect of CYP3A5*3 on kidney transplant recipients treated with tacrolimus: a systematic review and meta-analysis of observational studies. Pharmacogenomics J. 2015; 15138–48
Picard N, Bergan S, Marquet P, et al. Pharmacogenetic biomarkers predictive of the pharmacokinetics and pharmacodynamics of immunosuppressive drugs. Ther Drug Monit. 2016; 38Suppl 1S57–S69
Tron C, Lemaitre F, Verstuyft C, et al. Pharmacogenetics of membrane transporters of tacrolimus in solid organ transplantation. Clin Pharmacokinet. 2019; 585593–613
Trofe-Clark J, Brennan DC, West-Thielke P, et al. Results of ASERTAA, a randomized prospective crossover pharmacogenetic study of immediate-release versus extended-release tacrolimus in African American kidney transplant recipients. Am J Kidney Dis. 2018; 713315–326
Gonschior AK, Christians U, Winkler M, et al. Tacrolimus (FK506) metabolite patterns in blood from liver and kidney transplant patients. Clin Chem. 1996; 4291426–1432
Zegarska J, Hryniewiecka E, Zochowska D, et al. Tacrolimus metabolite M-III may have nephrotoxic and myelotoxic effects and increase the incidence of infections in kidney transplant recipients. Transplant Proc. 2016; 4851539–1542
Zegarska J, Hryniewiecka E, Zochowska D, et al. Evaluation of the relationship between concentrations of tacrolimus metabolites, 13-O-demethyl tacrolimus and 15-O-demethyl tacrolimus, and clinical and biochemical parameters in kidney transplant recipients. Transplant Proc. 2018; 5072235–2239
Vanhove T, de Jonge H, de Loor H, et al. Relationship between in vivo CYP3A4 activity, CYP3A5 genotype, and systemic tacrolimus metabolite/parent drug ratio in renal transplant recipients and healthy volunteers. Drug Metab Dispos. 2018; 46111507–1513
Jouve T, Rostaing L, Malvezzi P. New formulations of tacrolimus and prevention of acute and chronic rejections in adult kidney-transplant recipients. Expert Opin Drug Saf. 2017; 167845–855
Jouve T, Noble J, Rostaing L, et al. Tailoring tacrolimus therapy in kidney transplantation. Expert Rev Clin Pharmacol. 2018; 116581–588