Thiopurine methyltransferase activity and its relationship to the occurrence of rejection episodes in paediatric renal transplant recipients treated with azathioprine.
OBJECTIVE
Azathioprine is a prodrug commonly used in combination therapy to prevent allograft rejection after renal transplantation. After conversion to 6-mercaptopurine, the drug is metabolized into 6-thioguanine nucleotides (6-TGN) and catabolized by thiopurine methyltransferase (TPMT), an enzyme under monogenic control. The aim of this study was to evaluate the inter- and intraindividual variability of red blood cell thiopurine methyltransferase and 6-TGN concentrations and their relationship to the clinical effects of azathioprine in paediatric patients.


METHODS
In the present study, the inter- and intraindividual variations in red blood cell TPMT activity and 6-TGN concentrations and their relationship to the actions of azathioprine were evaluated during the first year after renal 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 at steady-state (median: 80 pmol 8 x 10(8-1) cells, range not detected to 366) were not related to the occurrence of rejection episodes during the period of the study. In contrast, TPMT activity and the percentage difference in TPMT activity from the day of transplantation determined at month 1 were higher in the patients with rejection episodes by comparison with those that did not reject during the first 3 months or the first year following transplantation (P<0.005).


CONCLUSIONS
We report a relationship between TPMT activity and occurrence of rejection in paediatric kidney transplant patients undergoing azathioprine therapy. These data suggest a link between high red blood cell TPMT activity and poor clinical outcome probably caused by rapid azathioprine catabolism.
Dervieux
T
T
Unité de Pharmacologie Pédiatrique, Hôpital Robert Debré, Paris, France.
Médard
Y
Y
Baudouin
V
V
Maisin
A
A
Zhang
D
D
Broly
F
F
Loirat
C
C
Jacqz-Aigrain
E
E
D000963:Antimetabolites / Q000494:pharmacology*; D001379:Azathioprine / Q000494:pharmacology*; D002648:Child; D002851:Chromatography, High Pressure Liquid; D005260:Female; D005838:Genotype; D006084:Graft Rejection / Q000378:metabolism*; D006150:Guanine Nucleotides / Q000097:blood / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016030:Kidney Transplantation / Q000502:physiology; D008297:Male; D008780:Methyltransferases / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D011355:Prodrugs / Q000494:pharmacology*; D013873:Thionucleotides / Q000097:blood / Q000378:metabolism
D000963:Antimetabolites; D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D011355:Prodrugs; D013873:Thionucleotides; C003964:6-thioguanylic acid; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine