Pharmacogenetics in Kidney Transplantation
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Pharmacogenetics in Kidney Transplantation Recent Updates and Potential Clinical Applications Laure Elens • Dennis A. Hesselink • Ron H. N. van Schaik • Teun van Gelder
Published online: 29 November 2012 Ó Springer International Publishing Switzerland 2012
Abstract Every month, new releases on the relationship between pharmacogenetic biomarkers and immunosuppressive drug therapy in kidney transplantation are published. However, the systematic clinical application of these discoveries occurs at a very slow pace, and the usefulness of knowing a patient’s genotype remains an important matter of debate. This can be partially ascribed to the lack of consistency when looking at the different associations reported across several studies but also the need for a broadspectrum view and a rigorous analysis of the relevance of the different associations observed to date. For that purpose, we performed a comprehensive analysis of the strength of the different reported genetic associations, and in this article we discuss their potential for clinical implementation in kidney transplantation. For tacrolimus, it is likely that a genotype-based drug dosage can benefit patient outcome, while for ciclosporin A, the data appear less convincing. For the mammalian target of rapamycin inhibitors, sirolimus L. Elens R. H. N. van Schaik Department of Clinical Chemistry, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands L. Elens Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Universite´ catholique de Louvain (UCL), Brussels, Belgium D. A. Hesselink T. van Gelder Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands T. van Gelder (&) Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3015 CE, The Netherlands e-mail: [email protected]
and everolimus – given the lack of data and the absence of large prospective studies – it is premature to implement pharmacogenetics, but some novel and promising leads have recently been reported. For mycophenolate mofetil, the complex metabolic pathways of its active moiety, mycophenolic acid, complicate analysis of the various published associations. However, at present, some interesting findings can be highlighted and offer potential value to assist clinicians in decision making.
1 Introduction Patient survival and graft outcome after kidney transplantation have drastically improved in recent decades, mainly because of major improvements in immunosuppressive therapy and in medical care. Transplant physicians have the choice between several immunosuppressive agents. The current preferred regimen is based on the combination of calcineurin inhibitors (CNIs; ciclosporin A and tacrolimus) with anti-proliferative agents (mainly mycophenolate mofetil [MMF]) and glucocorticoids. In recent years, a new class of immunosuppressants, the mammalian target of rapamycin inhibitors (mTORi; sirolimus and everolimus), has become available. Despite excellent shor
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