Association between renal function and CYP3A5 genotype in heart transplant recipients treated with calcineurin inhibitors

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• 作者：Simon de Denus BPharm ; MSc ; PhD^a ; ^b ; ^{simon.dedenus@icm-mhi.org} ; Marcin Zakrzewski BPharm ; MSc^a ; ^c ; Amina Barhdadi PhD^b ; Marie-Hé ; lè ; ne Leblanc MD^d ; Normand Racine MD^b ; Franç ; ois Bé ; langer MSc^c ; Michel Carrier MD^b ; Anique Ducharme MD ; MSc^b ; Marie-Pierre Dubé ; PhD^b ; Jacques Turgeon BPharm ; PhD^a ; ^c ; Michel White MD^b
• 关键词：transplantation ; pharmacogenomics ; tacrolimus ; cyclosporine ; nephrotoxicity ; CYP3A5 ; ABCB1
• 刊名：The Journal of Heart and Lung Transplantation
• 出版年：2011
• 出版时间：March 2011
• 年：2011
• 卷：30
• 期：3
• 页码：326-331
• 全文大小：649 K

文摘

Background

The renal expression of the cytochrome P450 3A5 (CYP3A5) isoenzyme and of the adenosine triphosphate (ATP)-binding cassette (ABC) efflux transporter P-glycoprotein is inversely associated with calcineurin-induced nephrotoxicity. The aim of this study was to evaluate the association between polymorphisms of the genes encoding these proteins and the long-term renal function of heart transplant recipients treated with calcineurin inhibitors.

Methods

We performed a retrospective cohort study of 160 heart transplant recipients from two institutions who were discharged alive after transplant and who received a calcineurin inhibitor during follow-up. The aim of this study was to evaluate the impact of common variants of the genes encoding this isoenzyme (CYP3A5*1 and *3) and the transporter (ABCB1 G2677T/A and C3435T) on the renal function of these patients after heart transplantation. The primary end-point of the study was changes in the estimated glomerular filtration rate (eGFR) at hospital discharge; at 3, 6, 12, 18 and 24 months after heart transplant; and then every year for up to 9 years.

Results

After adjusting for independent predictors of eGFR during follow-up, CYP3A5 was significantly associated with eGFR after transplantation (p = 0.0002), with carriers of the CYP3A5*1 allele exhibiting a higher eGFR. None of the ABCB1 variants or haplotypes were associated with eGFR after transplantation.

Conclusion

The CYP3A5*1 genetic polymorphism is a promising marker to identify heart transplant recipients least likely to develop renal dysfunction during long-term treatment with a calcineurin inhibitor.