SHOULD 6-THIOGUANINE NUCLEOTIDES BE MONITORED IN HEART-TRANSPLANT RECIPIENTS GIVEN AZATHIOPRINE

The commonly used immunosuppressive regimen after orthotopic heart tra nsplantation consists of cyclosporine (CsA), azathioprine (AZA), and s teroids. Although AZA therapy is generally regarded as unproblematic, its use can be associated with severe side effects, particularly myelo suppression. Since AZA is a prodrug, which must first be metabolized t o its active metabolites, AZA therapy, in contrast to CsA therapy, can not be controlled by measuring blood levels of this drug. Because of t he myelosuppressive properties of the AZA metabolites, the 6-thioguani ne nucleotides (6-TGN), the white blood cell count is usually monitore d in patients on AZA therapy, and AZA is discontinued if neutropenia a ppears. In a group of 20 consecutive heart recipients, 6-TGN concentra tions ranged from <30 to 2,211 pmol/8 x 10(8) red blood cells (RBCs); levels less than or equal to 450 pmol/8 x 10(8) RBCs were not associat ed with AZA-induced myelosuppression. Three cases of neutropenia were experienced, two of them with a fatal outcome. One patient died in sep ticemia owing to total myelosuppression. In this case an excessively h igh erythrocyte 6-TGN concentration (2,211 pmol/8 x 10(8) RBCs) was as sociated with a complete deficiency of thiopurine methyltransferase (T PMT), one of the main AZA detoxifying enzymes. The second patient, who had high RBC TPMT activity, developed neutropenia during rehabilitati on, and AZA was withdrawn. Coincidentally, in this case the CsA blood level was only 132 g/L, and the RBC 6-TGN level was very low (maximum 46 pmol/8 x 10(8) RBCs). This patient rapidly developed cardiogenic sh ock with clinical signs of acute rejection and was given a second tran splant on an emergency basis, but finally died from rejection of the s econd graft. Retrospectively, it was determined that neutropenia in th is patient was not related to AZA toxicity. A high 6-TGN level (698 pm ol/8 x 10(8) RBCs) was also seen in a third patient with mild neutrope nia, who required allopurinol, an inhibitor of xanthine oxidase, the o ther major detoxifying enzyme for AZA. In this patient AZA therapy cou ld be individually adapted by RBC 6-TGN monitoring. Based on our exper ience, we suggest that RBC 6-TGN monitoring allows for better individu alization of treatment with AZA and may help avoid fatal complications .