Abstract and Introduction
Abstract
"New approaches examining interactions among polymorphisms of genes related to metabolizing enzymes, transporter proteins and pathophysiological or protective mechanisms – similar to the epistatic analysis of aggravating or alleviating genetic interactions for complex diseases – may help to better predict clinical outcome in kidney transplantation."
Introduction
Kidney transplantation is a complex process and despite the development of powerful immunosuppressive drugs, we seem to have reached a plateau in graft and patient outcome. One of the major challenges facing us today is the prediction of allograft rejection, drug response and clinical outcome. Multiple pharmacogenetic studies have examined the impact of genetic polymorphisms on the clinical outcome of graft recipients and on interindividual differences in response to immunosuppressive drugs. Unfortunately, however, although many reports suggest promising genotypes for predicting acute rejection, acute and chronic kidney dysfunction and immunosuppressant disposition and adverse effects, these findings have yet to be implemented in routine clinical practice.
There are several roadblocks to the successful clinical use of predictive genetic polymorphisms. First, many genetic influences are still largely unknown. In addition, other factors besides donor–recipient genetic interactions often come into play for phenotypic variation, and the relationship between a gene, its protein and its function is complex and often unstable. Furthermore, a significant number of studies have focused only on recipient genotypes and have often ignored donor genotypes that may be related to donor–recipient mismatch or graft-recipient interactions. Finally, the majority of these studies have included only a small number of patients and been limited to the assessment of specific genes in isolation without taking into account complex biological interactions between genes. For instance, while it is known that CYP3A and ABCB1 polymorphisms can affect the bioavailability of tacrolimus and cyclosporin, leading to post-transplantation kidney dysfunction, the potential combinatory effects of these polymorphisms with those in glutathione S-transferases (GSTs), with toll-like receptors or cytokine polymorphisms have not yet been examined.
Nonpharmacogenetic factors, including ethnicity and concomitant medication, are also associated with graft loss, and recently the 'ex novo' alloantibody production against the implanted graft has been attributed to medication nonadherence. The fact that donors introduce new HLA molecules in the recipient could also impact on HLA-associated drug hypersensitivity. The ability of some drugs, such as abacavir, to modify the HLA-peptide repertoire could also influence alloresponse. Nevertheless, interindividual variability in disposition and dosage requirement of immunosuppressants and in allograft rejection is to a large degree dependent on genetic diversity.