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Long-Term Results of TPMT Activity Monitoring in Azathioprine-Treated Renal Allograft Recipients

ERIC THERVET^*,, DANY ANGLICHEAU^*,, NATHALIE TOLEDANO, ANNE-MARIE HOULLIER, LAURE-HÉLÈNE NOEL, HENRI KREIS^§, PHILIPPE BEAUNE and CHRISTOPHE LEGENDRE^*

^* Service de Néphrologie, Hôpital Saint Louis, Paris, France.
Unité INSERM U 490, Université des Saints-Pères, Paris, France.
Laboratoire de Pathologie Rénale, Hôpital Necker, Paris, France.
^§ Service de Réanimation et Transplantation Rénale, Hôpital Necker, Paris, France.

Correspondence to Dr. Eric Thervet, Service de Néphrologie, Hôpital Saint Louis 1, Avenue C, Vellefaux, 75475 Paris, Cedex 10, France. Phone: 33142499631; Fax: 33142499606; E-mail: eric.thervet{at}sls.ap-hop-paris.fr

Abstract. 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 µmol/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.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673