A new step towards spreading personalized and precision medicine in kidney transplantation

A new step towards spreading personalized and precision medicine in kidney transplantation

Many patients undergoing a kidney transplant are treated with tacrolimus (TAC), a medication that reduces the activity of the immune system in order to prevent the body from rejecting the transplanted organ. According to reports from Bellvitge University Hospital, until recently, the initial dose of this drug was determined based on a person’s body weight only. Once a steady state is reached, subsequent doses are adjusted according to the physician’s empirical experience, by trial and error, and based on serum Tac values. “Administering the correct dose of Tac is crucial: if patients treated with this drug during the first days after a kidney transplant are exposed to too much or too little, the risk of complications such as toxicity or rejection increases.” Health professionals explain. “Tac is also a drug with a very narrow therapeutic margin, which is why good monitoring of its blood levels is essential.” a point

Now, researchers from the Nephrology and Transplantation Group at the Bellvitge Biomedical Research Institute and Bellvitge University Hospital, led by Dr. Nuria Lubras, have faced the challenge of finding the therapeutic dose of TAC that adapts to the individual characteristics of patients in order to achieve a good balance between efficacy and toxicity. To do this, they studied in detail the drug’s metabolism, which the body carries out through the enzymatic action of cytochrome P450 3A (in short, CYP3A). CYP3A4 and CYP3A5 are enzymes found mainly in the liver and intestines, which oxidize small foreign molecules, such as toxins or drugs, so that they can be eliminated from the body.

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On the other hand, Tac is also characterized by high variability, both within and between patients, which is a risk factor for increased probability of rejection and side effects. The study, recently published in the Journal of Nephrology, analyzed a total of 425 kidney transplant patients, who, on the one hand, were determined to have CYP3A genetic polymorphisms (CYP3A4 and CYP3A5) that affect Tac metabolism and, on the other hand, their concentration-to-dose ratio. (C/D) of the drug (i.e. its pharmacokinetics). Participants were classified into three phenotypes, fast, intermediate and slow, and it was analyzed whether the stratification of patients according to the C/D ratio coincided with the stratification according to the CYP3A4/5 polymorphism.

According to Dr. Ana Vidal Alabro, first signatory of the article and researcher in the Kidney Disease and Kidney Transplantation Research Group at IDIBELL and Bellvitge Hospital“Both strategies have been proposed as an additional tool to personalize Tac dose in transplant patients.” Through this study, it was shown that the fact of being able to know the type of metabolite in the patient, whether according to the CYP polymorphism (important for the starting dose) or to determine the C/D quotient (important in follow-up dosing), makes it possible to differentiate exposure to Tac, and thus Customize your doses. Combining the two classification criteria is likely to be a good tool to be able to personalize Tac dosing in transplant patients.

“In summary, maintaining a good immunosuppressive regimen, especially in the early stages after kidney transplantation, is crucial to ensuring a good long-term prognosis for kidney transplantation.” Note the same sources. The large variability in response to Tac within and between individuals makes correct dose adjustment a challenge, and for this reason, knowing the metabolic phenotype of the transplanted patient can be very useful.

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