title: Association between renal function and CYP3A5 genotype in heart transplant recipients treated with calcineurin inhibitors.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Faculty of Pharmacy, Université de Montréal, Montreal, Quebec, Canada. simon.dedenus@icm-mhi.org
authors.forename: Simon
authors.initials: S
authors.lastname: de Denus
authors.forename: Marcin
authors.initials: M
authors.lastname: Zakrzewski
authors.forename: Amina
authors.initials: A
authors.lastname: Barhdadi
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Leblanc
authors.forename: Normand
authors.initials: N
authors.lastname: Racine
authors.forename: François
authors.initials: F
authors.lastname: Bélanger
authors.forename: Michel
authors.initials: M
authors.lastname: Carrier
authors.forename: Anique
authors.initials: A
authors.lastname: Ducharme
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Dubé
authors.forename: Jacques
authors.initials: J
authors.lastname: Turgeon
authors.forename: Michel
authors.initials: M
authors.lastname: White
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000328:Adult; D065095:Calcineurin Inhibitors; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005819:Genetic Markers; D005838:Genotype; D005919:Glomerular Filtration Rate; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007668:Kidney / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065095:Calcineurin Inhibitors; D005819:Genetic Markers; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A