Comparative pharmacogenetic study in Brazilian and Spanish kidney transplant recipients treated with tacrolimus and mycophenolate sodium

• Grant number: 18/16212-0
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Effective date (Start): December 01, 2018
• Effective date (End): May 31, 2019
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Rosario Dominguez Crespo Hirata
• Grantee: Fabiana Dalla Vecchia Genvigir
• Supervisor: Salvador Francisco Aliño Pellicer
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Research place: Universitat de València, Spain
• Associated to the scholarship: 17/19098-1 - Biotransformation enzymes and transporters: A pharmacogenetic study in renal transplant recipients treated with tacrolimus, everolimus and mycophenolate sodium, BP.PD

Abstract

The narrow therapeutic index of the immunosuppressive drugs and the several factors influencing the pharmacological response contribute to make the patient monitoring especially complex in the organ transplantation. That is way, the individualization of treatment is an important tool that can contribute to the reduction of acute rejection events, improve efficacy and decrease the toxic or adverse effects of these drugs. This study aim to investigate the genetic determinants of the interindividual differences in clinical and laboratory parameters and therapeutic monitoring of immunosuppressive drugs in Brazilian and Spanish kidney transplant recipients. For this, 97 Brazilian and 70 Spanish adult recipients were selected and treated with an immunosuppressive regimen containing tacrolimus (TAC), corticosteroids, and mycophenolate mofetil or sodium. Blood trough concentrations of TAC and mycophenolate acid were determined by chemiluminescent microparticle immunoassay and high-performance liquid chromatography method, respectively. Polymorphisms in genes that encode biotransformation enzymes (CYP2C8*3, rs11572080 and rs10509681; CYP2J2*7, rs890293; CYP3A4*1B, rs2740574; CYP3A4*22, rs35599367; CYP3A5*3C, rs776746, and CYP3A5*1D, rs15524), membrane transporters of efflux (ABCB1 rs1128503 (c.1236C>T), rs1045642 (c.3435C>T) and rs2032582 (c.2677G>T/A); ABCC2 rs2273697 (c.1249G>A) and rs3740066 (c.3972C>T), and ABCG2 rs2231142 (c.421C>A)), and membrane transporters of uptake (SLCO1B1 rs2306283 (c.388A>G) and rs4149056 (c.521T>C), and SLCO2B1 rs2851069 (c.-71T>C)) have been identified by real-time PCR (Brazil) or MassARRAY system (Spain). Clinical and laboratory data of the kidney recipients have been recorded and they will be analyzed for up to 12 months. The results will contribute to the knowledge of pharmacogenetic mechanisms involved in the variability interindividual in metabolism of the main immunosuppressive drugs used in renal transplantation and their relationship with therapeutic outcomes. They also may provide useful information for individualized therapy in these patients, which is able to reduce side effects and improve both patient and graft survival.