Gene Polymorphisms and the Clinical Outcomes of Tacrolimus Postkidney Transplant: A Systematic Review

Background: The influence of gene polymorphisms on the pharmacokinetics of tacrolimus has been extensively investigated; however, no consensus has been reached in terms of clinical applicability. We aimed to carry out a systematic review of literature on the influence of gene polymorphisms on the pharmacokinetics of tacrolimus in kidney transplant patients in the postoperative period. Methods: A systematic review (PROSPERO protocol number CRD42017057535) was conducted by searching the Medline (PubMed), Latin American and Caribbean Health Sciences (LILACS), and Cochrane Central Register of Controlled Trials (CENTRAL) databases. Results: A total of 474 publications were retrieved from the electronic databases, 14 remained for methodological analysis, among which 9 were observational studies and 5 were clinical trials. Most of the reviewed studies evaluate polymorphisms in the CYP3A5 gene (rs776746), with main outcomes, although controversial, related to achieving tacrolimus trough blood concentrations; delayed graft function (DGF); and acute rejection (AR). Conclusion: This systematic review, according to the polymorphisms studied, found that personalized doses are not effective, but monitoring patients according to their metabolizer profile is an effective strategy in the case of CYP3A5. For the other polymorphisms identified, new studies are needed to indicate the relevance of the tests. To assess the clinical utility of tacrolimus pharmacogenetic testing (especially testing involving genes such as CYP3A5, CYP3A4, and ATP-binding cassette subfamily B member 1), it is necessary to go beyond pharmacokinetic associations. Hence, pharmacogenetic testing of tacrolimus cannot be recommended in postkidney transplant treatment to effectively determine genotype-guided dosing or tacrolimus trough blood concentration monitoring, as the results found in the literature are still conflicting, inconclusive, and with important methodological limitations.