Long-term results of TPMT activity monitoring in azathioprine-treated renal allograft recipients.
Thiopurine methyltransferase (TPMT) is implicated in the metabolism of azathioprine. The consequences of differential TPMT activity induction by azathioprine on the long-term results after renal transplantation were investigated. The erythrocyte TPMT activity in 82 patients on days 0, 7, and 30 was prospectively evaluated. Because various patterns of TPMT activity variation were noted, the population was subsequently divided between inductors (n = 47) and noninductors (n = 35). Data regarding patient and graft survival and acute rejection episodes were collected. Renal allograft assessment was performed at 3 mo and 2 yr to evaluate the renal function and the histologic lesions on routine biopsies. Data regarding azathioprine-related toxicity also were collected. In a subgroup of patients (n = 19), azathioprine blood levels were determined at day 7 and day 30. The graft survival censoring death was statistically improved in TPMT inductor patients when compared with non-TPMT inductors (P < 0.05). Among TPMT inductors, an acute rejection episode was observed in 34% of the patients versus 69% among non-TPMT inductors (P = 0.002). At 3 mo, serum creatinine was significantly lower among TPMT inductors when compared with non-TPMT inductors (123.1 +/- 7.6 and 161.4 +/- 13.9 micromol/L, respectively; P = 0.01). On routine allograft biopsies at 2 yr (n = 61), grade 2 or 3 chronic lesions were present in 19% versus 25%, respectively (P = NS). At days 7 and 30, the azathioprine blood levels were higher among patients who experienced acute rejection (P < 0.02). TPMT activity induction was observed in 57% of renal transplant recipients who received azathioprine. This induction was associated with better graft outcome. The appropriate conversion from azathioprine, which is a pro-drug, into 6-mercaptopurine could explain both better graft outcome and TPMT induction. Assessing the ability of azathioprine metabolism at an individualized level before transplantation may allow a more accurate choice among the different immunosuppressive treatments.
Thervet
Eric
E
Service de Néphrologie, Hôpital Saint Louis, Paris, France.|Unité INSERM U 490, Université des Saints-Pères, Paris, France.
Anglicheau
Dany
D
Service de Néphrologie, Hôpital Saint Louis, Paris, France.|Unité INSERM U 490, Université des Saints-Pères, Paris, France.
Toledano
Nathalie
N
Unité INSERM U 490, Université des Saints-Pères, Paris, France.
Houllier
Anne-Marie
AM
Unité INSERM U 490, Université des Saints-Pères, Paris, France.
Noel
Laure-Hélène
LH
Laboratoire de Pathologie Rénale, Hôpital Necker, Paris, France.
Kreis
Henri
H
Service de Réanimation et Transplantation Rénale, Hôpital Necker, Paris, France.
Beaune
Philippe
P
Unité INSERM U 490, Université des Saints-Pères, Paris, France.
Legendre
Christophe
C
Service de Néphrologie, Hôpital Saint Louis, Paris, France.
D000208:Acute Disease; D000328:Adult; D001379:Azathioprine / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use; D004790:Enzyme Induction; D004912:Erythrocytes / Q000201:enzymology; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000473:pathology / Q000502:physiology*; D008297:Male; D008780:Methyltransferases / Q000097:blood*; D011446:Prospective Studies; D012449:Safety
D007166:Immunosuppressive Agents; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine