Thiopurine methyltransferase activity and its relationship to the occurrence of rejection episodes in paediatric renal transplant recipients treated with azathioprine

Aims Azathioprine is a prodrug commonly used in combination therapy to prev ent allograft rejection after renal transplantation. After conversion to 6- mercaptopurine, the drug is metabolized into 6-thioguanine nucleotides (6-T GN) and catabolized by thiopurine methyltransferase (TPMT), an enzyme under monogenic control. The aim of this study was to evaluate the inter- and in traindividual variability of red blood cell thiopurine methyltransferase an d 6-TGN concentrations and their relationship to the clinical effects of az athioprine in paediatric patients. Methods In the present study, the interand intraindividual variations in re d blood cell TPMT activity and 6-TGN concentrations and their relationship to the actions of azathioprine were evaluated during the first year after r enal transplantation in 22 paediatric patients. Results 6-TGN concentration reached steady-state values after 6 months and correlated negatively with TPMT activity (P = 0.004). Initial TPMT activity (median: 20.8 nmol h(-1) ml(-1), range 7.8-34.6) and 6-TGN concentration a t steady-state (median: 80 pmol 8 x 10(8-1) cells, range not detected to 36 6) were not related to the occurrence of rejection episodes during the peri od of the study. In contrast, TPMT activity and the percentage difference i n TPMT activity from the day of transplantation determined at month 1 were higher in the patients with rejection episodes by comparison with those tha t did not reject during the first 3 months or the first year following tran splantation (P < 0.005). Conclusions We report a relationship between TPMT activity and occurrence o f rejection in paediatric kidney transplant patients undergoing azathioprin e therapy. These data suggest a link between high red blood cell TPMT activ ity and poor clinical outcome probably caused by rapid azathioprine catabol ism.