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ABCB1 Genotypes Predict Cyclosporine-Related Adverse Events and Kidney Allograft Outcome

Dario Cattaneo^*,, Piero Ruggenenti^*,, Sara Baldelli^*,, Nicola Motterlini^*,, Eliana Gotti^*, Silvio Sandrini, Maurizio Salvadori^||, Giuseppe Segoloni^¶, Paolo Rigotti^**, Donato Donati, Norberto Perico^*,, Giuseppe Remuzzi^*, for the Mycophenolate Steroids Sparing (MYSS) Genetics Study Group

^* Department of Medicine and Transplantation, Ospedali Riuniti –Mario Negri Institute for Pharmacological Research, Bergamo, Italy; Laboratory of Biostatistics, Mario Negri Institute for Pharmacological Research, Bergamo, Italy; Center for Research on Organ Transplantation "Chiara Cucchi De Alessandri e Gilberto Crespi," Bergamo, Italy; Division of Nephrology, Dialysis and Transplantation, Azienda Ospedaliera Spedali Civili, Brescia, Italy; ^|| Unit of Nephrology and Dialysis, Azienda Ospedaliera Careggi Monna Tessa, Florence, Italy; ^¶ Unit of Nephrology, Dialysis and Transplantation, Azienda Ospedaliera S.G. Battista, Torino, Italy; ^** II Institute of General Surgery, Ospedale Giustinianeo, Padua, Italy; Unit of Nephrology and Dialysis, Azienda Ospedaliera Universitaria "Ospedale Regionale di Circolo e Fondazione Macchi," Varese, Italy

Correspondence: Giuseppe Remuzzi, M.D., FRCP, Mario Negri Institute for Pharmacological Research, Via Gavazzeni 11 –24125 Bergamo, Italy. Phone: +39.035.319888; Fax: +39.035.319.331; E-mail: gremuzzi{at}marionegri.it

Received for publication August 1, 2008. Accepted for publication January 14, 2009.

Cyclosporine A (CsA) is a substrate of P-glycoprotein, an efflux transporter encoded by the ABCB1 gene. Compared with carriers of the wild-type gene, carriers of T allelic variants in exons 21 or 26 have reduced P-glycoprotein activity and, secondarily, increased intracellular concentration of CsA; therefore, carriers of T variants might be at increased risk for CsA-related adverse events. We evaluated the associations between ABCB1 genotypes (in exons 12, 21, and 26) and CsA-related outcomes in 147 renal transplant recipients who were receiving CsA-based immunosuppression and were included in the Mycophenolate Steroids Sparing study. During a median of 65.5 mo follow-up, carriers of T allelic variants in exons 21 or 26 had a three-fold risk for delayed graft function (DGF), a trend to slower recovery of renal function and lower GFR at study end, and significantly higher incidences of new-onset diabetes and cytomegalovirus reactivation compared with carriers of the wild-type genotype. T variants in both exons 21 and 26 were independently associated with 3.8- and 3.5-fold higher risk for DGF, respectively (P = 0.022 and P = 0.034). The incidence of acute rejection and the mean CsA dose and blood levels were comparable in genotype groups. In conclusion, renal transplant recipients with T allelic variants in ABCB1 exons 21 or 26 are at increased risk for CsA-related adverse events. Genetic evaluation may help to identify patients at risk and to modulate CsA therapy to optimize graft and patient outcomes.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673