MRP2 24 CT is Associated with an Increased Risk of Neoplasia and Serious Infection Among Renal Transplant Recipients
Beatriz Rodriguez-Cubillo1, Mauricio M Miranda-Cam1, Virginia V de la Orden3, Beatriz B Mediero2, Isabel I Pérez-Flores1, Natividad N Calvo-Romero1, M. Angeles MA Moreno de la Higuera1, Jose María JM Bautista-Cañas1, Marta M Calvo-Arévalo1, Ana Isabel AI Sánchez-Fructuoso1.
1Nephrology, Hospital Clinico San Carlos, Madrid, Spain; 2CTC Unit, Molecular Oncology Laboratory, Medical Oncology Service, Hospital Clinico San Carlos, Instituto de Investigación sanitaria (IdISSC), Madrid, Spain; 3cTC Unit, Molecular Oncology Laboratory, Medical Oncology Service, hospital Clinico San Carlos, Instituto de Investigación sanitaria (IdISSC).CIBERONC., Madrid, Spain
Introduction:Frequently, the use of the mycophenolic acid (MPA) meets limited by its regular digestive tolerance and serious infections.
The MPAG is a molecule proceeding from the metabolism of the MPA that is excreted in the biliary route across the carrier MRP2, essential in the entero-hepatic circulation. There is controversy over the pharmacokinetic and clinical impact that could suppose the polymorphism MRP2 24 C>T in renal transplant recipients (RTR) on treatment with MPA.
Objectives: a) Principal: to investigate if MRP2C-24T polymorphism determines a higher risk for serious infections or neoplasias in RTR treated with micophenolate (MPA). b) Secondary: to evaluate if MRP2 C-24T polymorphism associates higher levels of MPA.
Methods: The clinical data and banked DNA samples from patients transplanted between 2000 and 2005 were retrospectively studied (n=394). MPA blood concentrations were analysed to calculate the area under de curve in 118 patients. Neoplasias and serious infections episodes were investigated during the follow up in patients treated with MPA. T-student, log Rank and Cox regression were used for statistical analysis.
Results:
a) Neoplasia-free survival was lower in the group of patients carrying the MRP2 24C>T polymorphism (p=0.005)
b) Infection-free survival was lower in the group of patients carrying the MRP2 24C>T polymorphism (p=0.038).
c) Multivariate analysis showed that MRP2 C-24T polymorphism, was an independent risk factors for Neoplasia (HR: 1,817 CI 95% 0.985-3,382; p=0,056) and infections (HR: 1,625; CI95 1,017-2,597; p=0,042).
d) Higher exposition of MPA was found in MRP2 C>T polymorphism carriers (AUC12h 76,88 vs 61,85 p 0.23); (AUC6-12h 26,79 vs 20,80 p 0.028).
e) Infection free survival was lower among patients with supratherapeutics levels of MPA area under curve of 12h. (> 80 mg/L). (p 0.034)
Conclusion:
a) MRP2 C-24T polymorphism could be a risk factor for neoplasias and infections and in RTRs treated with MPA and tacrolimus.
b) Carriers of this polymorphism associate higher MPA concentrations.
