Pharmacogenetics of transplantation

he success of organ transplantation mainly depends on the appropriate use of immunosuppressant drugs. This aspect is particularly crucial for calcineurin inhibitors, cyclosporine A (CsA) and tacrolimus, both characterized by a narrow therapeutic index and high inter-individual pharmacokinetic variability. Ideally, each transplanted patient should be administered CsA or tacrolimus at a dose necessary to ensure adequate levels of immunosuppression, limiting at the same time the appearance of severe adverse effects.

In the clinical practice, immunosuppressive therapy with CsA or tacrolimus needs a careful monitoring of drug serum concentrations, especially in the first phase after transplantation, in order to verify that circulating levels of immunosuppressive drugs are in the recommended range. The use of a pharmacogenetic approach could allow to identify "slow metabolizers" (subjects with a greater accumulation of immunosuppressant blood levels and therefore at higher risk of adverse effects), and "rapid metabolizers" which have a greater probability to have not enough circulating levels of immunosuppressant drugs and therefore at higher risk of transplant rejection.

Oral bioavailability and systemic clearance of calcineurin inhibitors, CsA and tacrolimus, are mainly regulated by CYP3A4/5 enzymes and glycoprotein-P (P-gp). The inter-individual difference in CYP3A4/5 and P-gp expression is explained, at least in part, by the presence of specific polymorphisms in the corresponding genes. The pharmacogenetic study currently in progress has the main objective to determine the influence of polymorphisms on CY3A4, CYP3A5 and MDR1 genes on tacrolimus or CsA daily dose requirements, in renal transplant patients. The second aim of the study is to identify gene polymorphisms associated with the appearance of adverse reactions to immunosuppressive drugs (tremor, diabetes, gingival overgrowth, cardiovascular side effects, organ rejection). The results of this pharmacogenetic study should provide a basis towards personalization of the therapy with immunosuppresive drugs.


Project leaders: Armando Genazzani, Salvatore Terrazzino.

Clinical Centers: Nephrology and Transplantation, Department of Clinical and Experimental Medicine, Amedeo Avogadro University, Novara, Italy.


Publications

Quaglia M, Musetti C, Merlotti G, Genazzani AA, Cargnin S, Cena T, Cantaluppi V, Terrazzino S. Pilot cohort study on the potential role of TCF7L2 rs7903146 on ischemic heart disease among non-diabetic kidney transplant recipients. Clin Transplant. 2017 Mar 16. doi: 10.1111/ctr.12959.

Cargnin S, Quaglia M, Canonico PL, Piero Stratta P, Terrazzino S. Impact of recipient ACE I/D genotype on kidney function in renal transplant patients: a meta-analysis of cross-sectional and longitudinal studies. Pharmacogenomics 2015;16:1887-902.

Quaglia M, Terrazzino S, Musetti C, Cargnin S, Merlotti G, Cena T, Stratta P, Genazzani A. The Role of TCF7L2 rs7903146 in Diabetes After Kidney Transplant: Results From a Single-Center Cohort and Meta-Analysis of the Literature. Transplantation 2016;100:1750-8.

Quaglia M, Terrazzino S, Boldorini R, Stratta P, Genazzani AA. Severe acute nephrotoxicity in a kidney transplant patient despite low tacrolimus levels: a possible interaction between donor and recipient genetic polymorphisms. J Clin Pharm Ther. 2013;38:333-6.

Terrazzino S, Quaglia M, Stratta P, Canonico PL, Genazzani AA. The effect of CYP3A5 6986A>G and ABCB1 3435C>T on tacrolimus dose-adjusted trough levels and acute rejection rates in renal transplant patients: a systematic review and meta-analysis. Pharmacogenet Genomics 2012; 22(8):642-5.

Stratta P, Quaglia M, Cena T, Antoniotti R, Fenoglio R, Menegotto A, Ferrante D, Genazzani A, Terrazzino S, Magnani C. The interactions of age, sex, body mass index, genetics, and steroid weight-based doses on tacrolimus dosing requirement after adult kidney transplantation. Eur J Clin Pharmacol 2012;68(5):671-80.