Does low-dose allopurinol, with azathioprine, cyclosporin and prednisolone, improve renal transplant immunosuppression?

This communication reports the results of two studies aimed at improving the immunosuppressive efficacy of azathioprine in renal transplant patients. Although azathioprine has been used in transplantation for over 30 years, the mechanism of its cytotoxicity is not yet completely defined. It is generally accepted that its principal mode of action involves rapid conversion in vivo to 6-mercaptopurine (6MP), which is further metabolised via 6-thioinosinic acid to cytotoxic thioguanine nucleotides (1). The efficacy of 6MP is reduced by catabolic pathways, one of them being via xanthine oxidase (XO), which oxidises 6MP to thiouric acid. Thus the therapeutic combination of azathioprine with allopurinol, which inhibits the XO path, is usually contra-indicated, having been associated with bone marrow toxicity (2). The importance of this catabolic route is illustrated by the severe myelotoxicity reported in an XO-deficient patient treated with azathioprine (3). Azathioprine and 6MP catabolism may also occur via aldehyde oxidase (AO) and thiopurine methyltransferase (TPMT) (Figure 1).