New step towards the deployment of personalized and precision medicine in kidney transplantation

Many patients who receive a kidney transplant are treated with the drug tacrolimus (Tac), a medication that decreases the activity of the immune system to prevent the body from rejecting the transplanted organ. Until recently, the starting dose of this drug was decided based only on the person’s body weight. Once steady state is reached, subsequent doses are adjusted according to the physician’s empirical experience, by trial and error, and based on blood Tac values.

Administering the correct dose of Tac is crucial: if patients treated with this drug are exposed too much or too little during the first days after a kidney transplant, the risk of complications, such as toxicity or rejection, increases. Furthermore, Tac is a drug with a very narrow therapeutic range, which is why good monitoring of its blood levels is necessary.

Now, researchers from the nephrology and kidney transplant group of the Bellvitge Biomedical Research Institute (IDIBELL) and the Bellvitge University Hospital, both institutions in Hospitalet de Llobregat, Barcelona, ​​have faced the challenge of finding the therapeutic dose of Tac that is adapt to the individual characteristics of the patients in order to achieve a good balance between efficacy and toxicity.

To do this, this team, led by Dr. Núria Lloberas, has studied in detail the metabolic process of the drug, which the body carries out through the enzymatic action of cytochrome P450 3A (CYP3A for short). CYP3A4 and CYP3A5 are enzymes located mainly in the liver and intestine, which oxidize small foreign molecules, such as toxins or drugs, so that they can be eliminated from the body.

On the other hand, Tac is also characterized by showing great variability, both within and between patients, which is a risk factor for a greater probability of rejection and side effects. In the new study, a total of 425 kidney transplant patients have been analyzed, in whom, on the one hand, the genetic polymorphisms of CYP3A (CYP3A4 and CYP3A5) that affect the metabolism of Tac have been determined, and on the other, the concentration/dose (C/D) relationship of the drug (i.e., its pharmacokinetics). The participants were classified into three phenotypes, extensive, intermediate and slow metabolizers, and it was analyzed whether the stratification of patients according to the C/D ratio coincided with the classification according to CYP3A4/5 polymorphisms.

According to Dr. Anna Vidal-Alabro, first signatory of the study and researcher in the nephrology and kidney transplant research group at IDIBELL and Bellvitge Hospital, “both strategies are proposed as an additional tool to individualize the dose of Tac in transplant patients. ”. This study has shown that being able to know what type of metabolizer the patient is, both according to the CYP polymorphisms (important for the starting dose) and by determining the C/D ratio (important in the follow-up doses), allows us to differentiate the exposure to Tac and, consequently, individualize their doses. Probably, the combination of both classification criteria would be a good tool to personalize Tac doses in transplant patients.

Members of the research team. (Photo: IDIBELL)

In summary, maintaining a good immunosuppressive regimen, especially in the early stages after kidney transplantation, is essential to ensure a good long-term transplant prognosis. The high intra- and interindividual variability in response to Tac makes correct dose adjustment a challenge, so knowing the metabolizing phenotype of the transplant patient can be very useful.

The study is titled “Tools for a personalized tacrolimus dose adjustment in the follow-up of renal transplant recipients. “Metabolizing phenotype according to CYP3A genetic polymorphisms versus concentration-dose ratio.” And it has been published in the academic journal Nefrología. (Source: IDIBELL)