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ABCB1 Genotype of the Donor but Not of the Recipient Is a Major Risk Factor for Cyclosporine-Related Nephrotoxicity after Renal Transplantation

Ingeborg A. Hauser^*, Elke Schaeffeler, Stefan Gauer^*, Ernst H. Scheuermann^*, Binytha Wegner^*, Jan Gossmann^*, Hanns Ackermann, Christian Seidl, Berthold Hocher^||, Ulrich M. Zanger, Helmut Geiger^*, Michel Eichelbaum and Matthias Schwab

^* Department of Nephrology, Medical Clinic IV, University Hospital Johann Wolfgang Goethe-University, Frankfurt am Main, Germany; Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany; Department of Biomathematics, University Hospital Johann Wolfgang Goethe-University, Frankfurt am Main, Germany; Institute of Transfusion Medicine and Immunohematology, Frankfurt am Main, Germany; and ^|| Division of Nephrology and Hypertension, Inselspital, Berne, Switzerland

Address correspondence to: Dr. Ingeborg A. Hauser, Department of Nephrology, Medical Clinic IV, University Hospital Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, D-60596 Frankfurt am Main, Germany. Phone: +49-69-6301-7864; Fax: +49-69-6301-5451; E-mail: i.hauser{at}em.uni-frankfurt.de

Dr. Matthias Schwab, Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, D-70376 Stuttgart, Germany. Phone: +49-711-8101-3728; Fax: +49-711-85-92-95; E-mail: matthias.schwab{at}ikp-stuttgart.de

Received for publication October 25, 2004. Accepted for publication January 29, 2005.

Cyclosporine (CsA) nephrotoxicity is a severe complication in organ transplantation because it leads to impaired renal function and chronic allograft nephropathy, which is a major predictor of graft loss. Animal models and in vivo studies indicate that the transmembrane efflux pump P-glycoprotein contributes substantially to CsA nephrotoxicity. It was hypothesized that the TT genotype at the ABCB1 3435CT polymorphism, which is associated with decreased expression of P-glycoprotein in renal tissue, is a risk factor for developing CsA nephrotoxicity. In a case-control study, 18 of 97 patients developed CsA nephrotoxicity and showed complete recovery of renal function in all cases when switched to a calcineurin inhibitor-free regimen. Both recipients and donors were genotyped for ABCB1 polymorphisms at the positions 3435CT and 2677GT/A. For controlling for population stratification, two additional polymorphisms, CYP2D6*4 and CYP3A5*3, with intermediate allelic frequencies were studied. The P-glycoprotein low expressor genotype 3435TT only of renal organ donors but not of the recipients was overrepresented in patients with CsA nephrotoxicity as compared with patients without toxicity (² = 10.5; P = 0.005). CsA dosage, trough levels, and the concentration per dose ratio were not different between the patient groups. In a multivariate model that included several other nongenetic covariates, only the donor’s ABCB1 3435TT genotype was strongly associated with CsA nephrotoxicity (odds ratio, 13.4; 95% confidence interval, 1.2 to 148; P = 0.034). A dominant role of the donor’s ABCB1 genotype was identified for development of CsA nephrotoxicity. This suggests that P-glycoprotein is an important factor in CsA nephrotoxicity.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673