Monitored high-dose azathioprine treatment reduces acute rejection episodes after renal transplantation

Transplantation. 1998 Aug 15;66(3):334-9. doi: 10.1097/00007890-199808150-00010.


Background: Azathioprine (AZA) is widely used in organ transplantation. Common practice is to adjust dose according to body weight only, despite documented pharmacokinetic variability. The purpose of this study was to investigate whether high-dose AZA treatment monitored by 6-thioguanine nucleotides (6-TGN) levels reduces the incidence of rejection episodes in renal transplantation without a corresponding increase in myelotoxicity.

Methods: Patients receiving cyclosporine, steroids, and AZA were randomized into either the low-dose AZA group (3 mg/kg on day 0, then 2 mg/kg/day the first week and 1 mg/kg/day thereafter) or the high-dose AZA group. In the latter, AZA was started at 5 mg/kg/day and then adjusted to keep 6-TGN concentrations (measured twice weekly) between 100 and 200 pmol/8 x 10(8) RBCs.

Results: A total of 360 transplant recipients were included in the final analysis. The cumulative incidence of first rejection episodes was reduced by 21%, from 62.8% in the low-dose group to 49.4% in the high-dose group (difference: 13.3%; 95% confidence interval: 3.2-23.5). Similar results were found in subgroups according to HLA-DR match. The 6-TGN concentration was significantly higher in the high-dose AZA group during the first month, and the reduction in rejection episodes was achieved in the same period. A larger proportion of patients in the high-dose group had nadir white blood cell count below 2.0 x 10(9) leukocytes/L (13.3% vs. 4.4%; difference: 8.9%; confidence interval: 3.1-14.7).

Conclusions: High-dose AZA therapy in a triple-drug regimen, monitored by 6-TGN, will keep myelotoxicity within acceptable limits with the benefit of a reduction in acute rejection episodes.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Azathioprine / administration & dosage*
  • Azathioprine / adverse effects
  • Azathioprine / pharmacokinetics
  • Bone Marrow / drug effects
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Monitoring*
  • Drug Therapy, Combination
  • Female
  • Graft Rejection / drug therapy*
  • Graft Rejection / immunology
  • Guanine Nucleotides / blood
  • Humans
  • Immunosuppressive Agents / administration & dosage*
  • Immunosuppressive Agents / adverse effects
  • Immunosuppressive Agents / pharmacokinetics
  • Kidney Transplantation* / immunology
  • Leukocyte Count
  • Male
  • Middle Aged
  • Neutrophils / drug effects
  • Neutrophils / immunology
  • Thionucleotides / blood


  • Guanine Nucleotides
  • Immunosuppressive Agents
  • Thionucleotides
  • 6-thioguanylic acid
  • Azathioprine