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The impact of liver transplant recipient and donor genetic variability on tacrolimus exposure and transplant outcome.

ABSTRACT: This study investigated the effect of recipient and donor genetic variability on dose-adjusted steady-state tacrolimus concentrations (Css ) and clinical outcomes 3 and 6 months after liver transplant. Twenty-nine recipients and matched donor blood samples were genotyped for 27 single nucleotide polymorphisms including CYP3A5*3 (rs776746), ABCB1 haplotype and immune genes. Associations between genetic variability and clinical parameters and Css and the occurrence of rejection and nephrotoxicity were analysed by multivariate and multinomial logistic regression modelling and Jonckheere-Terpstra tests examined the impact of combined donor/recipient CYP3A5 expression on Css . At 3 months post-transplant modelling revealed an association between tacrolimus Css and recipient CASP1 rs580523 genotype (P = 0.005), accounting for 52% Css variance. Jonckheere-Terpstra tests revealed that as combined donor/recipient CYP3A5 expression increased, Css decreased (P = 0.010 [3 months], 0.018 [6 months]). As this is the first report of CASP1 genetic variability influencing tacrolimus Css , further validation in larger cohorts is required.

SUBMITTER: Coller JK

PROVIDER: S-EPMC6710513 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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The impact of liver transplant recipient and donor genetic variability on tacrolimus exposure and transplant outcome.

Coller Janet K JK Ramachandran Jeyamani J John Libby L Tuke Jonathan J Wigg Alan A Doogue Matthew M

British journal of clinical pharmacology 20190724 9

This study investigated the effect of recipient and donor genetic variability on dose-adjusted steady-state tacrolimus concentrations (C<sub>ss</sub> ) and clinical outcomes 3 and 6 months after liver transplant. Twenty-nine recipients and matched donor blood samples were genotyped for 27 single nucleotide polymorphisms including CYP3A5*3 (rs776746), ABCB1 haplotype and immune genes. Associations between genetic variability and clinical parameters and C<sub>ss</sub> and the occurrence of rejecti ...[more]

PMID: 31219197

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Project description:Despite early reports of an impact of complement C3 polymorphism on liver transplant patient and graft survival, subsequent evidence has been conflicting. Our aim was to clarify the contributions of donor and recipient C3 genotype, separately and together, on patient and graft outcomes and acute rejection incidence in liver transplant recipients. Eight donor/recipient groups were analyzed according to their genotype and presence or absence of C3 F allele (FFFS, FFSS, FSFF, FSFS, FSSS, SSFF, SSFS, and SSSS) and correlated with clinical outcomes of patient survival, graft survival, and rejection. The further impact of brain death vs. circulatory death during liver donation was also considered. Over a median 5.3 y follow-up of 506 patients with clinical information and matching donor and recipient tissue, five-year patient and graft survival (95% confidence interval) were 90(81-91)% and 77(73-85)%, respectively, and 72(69-94)% were rejection-free. Early disadvantages to patient survival were associated with donor C3 F variant, especially in brain-death donors. Recipient C3 genotype was an independent determinant of graft survival by Cox proportional hazards analysis (hazard ratio 0.26, P = 0.04), and the C3 F donor variant was again associated with worse liver graft survival, particularly in brain-death donors. C3 genotype did not independently determine rejection incidence, but a greater proportion of recipient C3 F carriers were rejection-free in the circulatory death, but not the brain-death cohort. Cox proportional hazards analysis revealed significant effects of acute rejection on patient survival (hazard ratio 0.24, P = 0.018), of retransplantation on rejection risk (hazard ratio 6.3, P = 0.009), and of donor type (circulatory-death vs. brain-death) on rejection incidence (hazard ratio 4.9, P = 0.005). We conclude that both donor and recipient complement C3 genotype may influence patient and graft outcomes after liver transplantation but that the type of liver donor is additionally influential, possibly via the inflammatory environment of the transplant.

Project description:AIMS:Tacrolimus has been associated with notable extrarenal adverse effects (AEs), which are unpredictable and impact patient morbidity. The association between model-predicted tacrolimus exposure metrics and standardized extrarenal AEs in stable renal transplant recipients was investigated and a limited sampling strategy (LSS) was developed to predict steady-state tacrolimus area under the curve over a 12-h dosing period (AUCss,0-12h ). METHODS:All recipients receiving tacrolimus and mycophenolic acid ?6 months completed a 12-h cross-sectional observational pharmacokinetic-pharmacodynamic study. Patients were evaluated for the presence of individual and composite gastrointestinal, neurological, and aesthetic AEs during the study visit. The associations between AEs and tacrolimus exposure metrics generated from a published population pharmacokinetic model were investigated using a logistic regression analysis in NONMEM 7.3. An LSS was determined using a Bayesian estimation method with the same patients. RESULTS:Dose-normalized tacrolimus AUCss,0-12h and apparent clearance were independently associated with diarrhoea, dyspepsia, insomnia and neurological AE ratio. Dose-normalized tacrolimus maximum concentration was significantly correlated with skin changes and acne. No AE associations were found with trough concentrations. Using limited sampling at 0, 2h; 0, 1, 4h; and 0, 1, 2, 4h provided a precise and unbiased prediction of tacrolimus AUC (root mean squared prediction error < 10%), which was not well characterized using trough concentrations only (root mean squared prediction error >15%). CONCLUSIONS:Several AEs (i.e. diarrhoea, dyspepsia, insomnia and neurological AE ratio) were associated with tacrolimus dose normalized AUCss,0-12h and clearance. Skin changes and acne were associated with dose-normalized maximum concentrations. To facilitate clinical implementation, a LSS was developed to predict AUCss,0-12h values using sparse patient data to efficiently assess projected immunosuppressive exposure and potentially minimize AE manifestations.

Dataset Information

The impact of liver transplant recipient and donor genetic variability on tacrolimus exposure and transplant outcome.

Publications

The impact of liver transplant recipient and donor genetic variability on tacrolimus exposure and transplant outcome.

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