Polimorfismo das UDP-glucuronosiltransferases e efeitos adversos em indivíduos receptores de transplante renal em terapia com micofenolato mofetil

Abstract

Pharmacogenetic studies have been performed in an attempt to demonstrate possible influences of the genetic pattern on the variable responses to the immunosuppressive medications. This finding could be another tool to tailoring individual immunosuppression. Objective: This work aimed to analyze the side effects presented by kidney transplant patients on MMF-based immunosuppression and verify their relation with the genetic polymorphism of uridine glucuronosyltransferases (UGT) enzymes, major responsible for bioavailability of mycophenolic acid (MPA), the active metabolite of MMF. Methods: In this study, we retrospectively analyzed 74 kidney transplant patients who had used MMF as part of their immunosuppression regimen. Genotyping of polymorphisms in UGT1A8 (-999C>T, codon 255A>G, codon 277G>A), UGT1A9 (-2152C>T, -275T>A, -118T9>10, codon 33T>C) and UGT2B7 (-79G>A, codon 268C>T) was performed using an automated sequencer and the chromatograms were analyzed on program StadenGap and PreGap4. The genotypes were then compared to the occurrence of eventual side effects, mainly diarrhea, blood disorders and infections. Statistical analyses used Pearson´s chi-square test. Results: Seventy-four kidney transplant patients with 56 ± 41 months post-transplant were enrolled, with mean age of 42 ± 12 years. The glomerular filtration rate was 46 ± 19 ml/min/1,73m2 and the other immunosuppressors were prednisone (98,6%), cyclosporine (39,2%), tacrolimus (35,1%) and sirolimus (28,4%). All polymorphism could be identified on the population, except the UGT2B7-79G/A. Data analysis showed that infection episodes were more frequently observed in individuals who carried the variant UGT1A8 codon 277A (p=0.03) and received 2g/day of MMF. Within individuals receiving this dosage of the medication, infection could be related to the presence of haplotype UGT1A8H5 (-999C/códon 255A/códon 277A) (p=0.02) or diplotype UGT1A8H2/H5 (-999CC/códon 255AA/códon 277GA) (p=0.02). Hematological disturbances (p<0.01) and MMF dose reduction (p<0.01) were more frequent in individuals carrying the haplotype UGT1A9H4 (-2152T/-275A/-118T9/codon 33T) and receiving 2g/day of MMF. Conclusions: The clinical and molecular data of this study suggest that UGT1A9 e UGT1A8 polymorphisms seem to be an additional factor influencing the occurrence of side effects, mainly infection and hematologic disturbances, in patients receiving 2g/day of MMF as drug transplant therapy.