title: Tacrolimus-induced nephrotoxicity and genetic variability: a review.
abstract: BACKGROUND
  Calcineurin inhibition (CNI) is the mainstay of immunosuppressant therapy for most solid organ transplant patients. High tacrolimus levels are related with acute nephrotoxicity, but the relationship with chronic toxicity is less clear. Variation in disposition of tacrolimus is associated with genetic variation in CYP3A5. Hence, could genetic variation in CYP3A5 or other genes involved in tacrolimus disposition and effect be associated with a risk for tacrolimus-induced nephrotoxicity? To perform a review of the literature and to identify if genetic variation in CYP3A5 or other genes involved in tacrolimus disposition or effect may be associated with tacrolimus-induced nephrotoxicity and/or renal dysfunction in solid organ transplant recipients.
  
  
  METHODS
  Pubmed/Medline, Embase and Google were searched from their inception till November 8th 2010 with the search terms 'tacrolimus', 'genetics', and 'nephrotoxicity' or 'renal dysfunction'. References of relevant articles were screened as well.
  
  
  RESULTS
  We identified 13 relevant papers. In kidney recipients, associations between donor ABCB1, recipient CCR5 genotype and tacrolimus-induced nephrotoxicity were found. CYP3A5 genotype studies in kidney recipients yielded contradictory results. In liver recipients, a possible association between recipient ACE, CYP3A5, ABCB1 and CYP2C8 genetic polymorphisms and tacrolimus-induced nephrotoxicity was suggested. In heart recipients, TGF-β genetic polymorphisms were associated with tacrolimus-induced nephrotoxicity. The quality of the studies varied considerably.
  
  
  CONCLUSIONS
  Limited evidence suggests that variation in genes involved in pharmacokinetics (ABCB1 and CYP3A5) and pharmacodynamics (TGF-β, CYP2C8, ACE, CCR5) of tacrolimus may impact a transplant recipients' risk to develop tacrolimus-induced nephrotoxicity across different transplant organ groups.
authors: Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Violette M G J
authors: VM
authors: Gijsen
authors: Parvaz
authors: P
authors: Madadi
authors: Marie-Pierre
authors: MP
authors: Dube
authors: Dennis A
authors: DA
authors: Hesselink
authors: Gideon
authors: G
authors: Koren
authors: Saskia N
authors: SN
authors: de Wildt
mesh_terms: D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D059647:Gene-Environment Interaction; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D007674:Kidney Diseases / Q000139:chemically induced* / Q000235:genetics; D016377:Organ Transplantation; D016559:Tacrolimus / Q000009:adverse effects* / Q000493:pharmacokinetics
chemical_list: D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus