title: Severe acute nephrotoxicity in a kidney transplant patient despite low tacrolimus levels: a possible interaction between donor and recipient genetic polymorphisms.
abstract: OBJECTIVE
  Tacrolimus has a narrow therapeutic index and shows large interindividual variations in pharmacokinetics, which may be partly explained by genetic variability in metabolic enzymes of the cytochrome P450 (mainly CYP3A4 and CYP3A5) and transport P-glycoprotein (encoded by the ABCB1 gene). Genetic variability in the expression of biotransformation enzymes and drug transporters may also predispose individuals to tacrolimus-induced nephrotoxicity.
  
  
  METHODS
  We report a case of severe biopsy-proven Tacrolimus (TAC) nephrotoxicity that occurred 1 month after renal transplantation despite persistently low TAC levels. The donor genotype was CYP3A5*3/*3 (loss-of-function genotype), whereas that of the recipient was CYP3A5*1/*3. The donor and recipient genotypes did not differ with respect to either CYP3A4 rs35599367C>T (both were CC homozygotes) or ABCB1 gene polymorphisms (both TT homozygotes for the 1236C>T polymorphism and CT heterozygotes for the 3435C>T polymorphism).
  
  
  CONCLUSIONS
  This case study suggests that donor/recipient genetic mismatch in metabolic enzymes may have an important role in modulating tacrolimus nephrotoxicity. It provides a possible explanation for the intriguing observation that for a subset of patients, cumulative TAC doses appear to correlate better with nephrotoxicity than trough levels.
authors.affiliation: Nefrologia e Trapianto, Dipartimento di Medicina Traslazionale & Interdisciplinary Research Center Autoimmune Disease (IRCAD), Università del Piemonte Orientale A. Avogadro, Novara, Italy. marco.quaglia@gmail.com
authors.forename: M
authors.initials: M
authors.lastname: Quaglia
authors.forename: S
authors.initials: S
authors.lastname: Terrazzino
authors.forename: R
authors.initials: R
authors.lastname: Boldorini
authors.forename: P
authors.initials: P
authors.lastname: Stratta
authors.forename: A A
authors.initials: AA
authors.lastname: Genazzani
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005838:Genotype; D006801:Humans; D007668:Kidney / Q000187:drug effects*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000235:genetics*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D016559:Tacrolimus / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus
keywords: calcineurin inhibitor nephrotoxicity; genetic polymorphism; renal transplant; tacrolimus