What is the role of azathioprine in immunosuppression after solid organ transplantation?

Updated: Jan 04, 2016
  • Author: Bethany Pellegrino, MD; Chief Editor: Mary C Mancini, MD, PhD, MMM  more...
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Azathioprine was the first immunosuppressive agent used in organ transplantation and provided a share of the 1988 Nobel Prize to its developers. It is an antimetabolite prodrug that converts 6-mercaptopurine to tissue inhibitor of metalloproteinase, which is converted to thioguanine nucleotides that interfere with DNA synthesis. Other possible mechanism includes converting co-stimulation into an apoptotic signal. It is used for maintenance immunosuppression; however, it became a second-line drug after cyclosporine was introduced.

Adverse effects of azathioprine include leukopenia, thrombocytopenia, and liver toxicity. Myelosuppression becomes a serious problem when used with allopurinol. The dose of azathioprine should be decreased when administered with allopurinol and when withdrawing steroids. Complete blood cell counts and pancreatic and liver enzyme levels must be monitored. Myelosuppression can improve with drug discontinuation. Azathioprine is compatible with cyclosporine and tacrolimus. Azathioprine use in transplantation has been widely replaced by mycophenolate mofetil in North America.

Results from a study on the conversion from mycophenolate mofetil to azathioprine in high-risk renal allograft recipients on cyclosporine-based immunosuppression suggest that selective conversion from mycophenolate mofetil to azathioprine after 1 year is safe, even in high-risk kidney transplants. Normal serum creatinine and absence of proteinuria are good screening parameters to identify patients at low risk for acute rejection following such conversion.

Cost comparison suggests azathioprine to be 6-10 times cheaper than mycophenolate mofetil. In tacrolimus-based immunosuppression, azathioprine may be as good as mycophenolate mofetil as a maintenance immunosuppressive drug in living-donor kidney transplantation.

The 3-year results of a randomized, double-blind, controlled trial of mycophenolate mofetil versus azathioprine in heart transplant patients revealed no significant differences between treatments in quantitative coronary angiographic measurements of transplant coronary vasculopathy. Congestive heart failure, atrial arrhythmia, and leukopenia were more common in the azathioprine group, whereas diarrhea, esophagitis, herpes simplex infection, herpes zoster infection, and CMV infection were more common in mycophenolate mofetil–treated patients.

Consideration is increasing on whether mycophenolate acid provides survival benefits comparable to azathioprine after renal transplantation. The type of antimetabolite, azathioprine or mycophenolate acid, was not independently associated with any safety or efficacy outcome 5 years after transplantation, suggesting that azathioprine is still a viable option for low-risk kidney transplantation recipients receiving tacrolimus and steroids.

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