Toward personalized medicine in renal transplantation.

BACKGROUND: The pharmacokinetics of tacrolimus (TRL) are clearly affected by genetic polymorphisms in drug-metabolizing enzymes, which lead to large interindividual differences in dose-response relations. In addition, TRL has a narrow therapeutic index requiring monitoring of blood levels. The objective of the present observational, retrospective study was to associate maintenance TRL doses with various genetic markers seeking to guide optimization of the initial dose. METHODS: Results of DNA samples from 15 kidney transplant patients were correlated retrospectively with clinical information from medical records. Samples were genotyped using PHARMAchip. Association studies were performed with χ2 and Pearson tests and by analysis of variance. The study was carried out in accordance with international ethical standards of the Helsinki Declaration and approved by our ethics committee. RESULTS: Two patient groups were identified to show a difference in TRL dose requirements: a control (0.014-0.10 mg/kg/per day) and an high-dose group (0.14-0.15 mg/kg/per day). The presence of CYP3A5*1 and the null allele in GSTM1 were significantly associated (P=.01 and P=.04) with the need for higher immunosuppressive doses (>0.10 mg/kg/per day). There were no differences in plasma levels of TRL or other clinical variables between the patient groups. CONCLUSION: Determination of the CYP3A5 genotype might be used to predict initial TRL requirements, although other genetic variants also provide important information to adjust the drug dose.

The intricate relationship between evidence and clinical practice in kidney transplantation.

Clinical practice is supposed to be evidence-based but it always conveys underlying values, judgements, moral principles or axioms. We explore the evidence-based nature of clinical practice in the fast-changing field of kidney transplantation and its relationship with values in five different interventions: those well supported on evidence, focussed on the use of immunosuppressant drugs like cyclosporine, mycophenolate mofetil and tacrolimus, and the elective withdrawal of cyclosporine or steroids; disputable interventions where evidence, focussed on anti-lymphocyte antibodies, is strong but not strong enough to be applied on the majority of occasions; interventions not supported by randomised controlled trials with focus on primary treatment of vascular graft rejection and rescue treatment for acute graft rejection; interventions not widely applied despite strong evidence from sources other than randomised controlled trials, with focus on HLA-matched kidney transplants in cadaver donor and living donor transplants; and finally, a variety of interventions when evidence is lacking. Being aware of the factors influencing every clinical decision we can make the strength of evidence and the nature of the values underlying them explicit and we will find it easier to improve the process of transferring evidence into practice and openly face and acknowledge the values involved.