Thiopurine S-Methyltransferase Genotype Predicts Azathioprine-Induced Myelotoxicity in Kidney Transplant Recipients

Abstract

Azathioprine (AZA) is an immunosuppressive prodrug that undergoes metabolism by thiopurine Smethyltransferase (TPMT).Eighty to ninety-five percent of low or deficient TPMT enzyme activity is genetically determined by the presence of three nonfunctional mutant alleles: TPMT * 2, TPMT * 3A and TPMT * 3C. Using TPMT as a pharmacogenetic paradigm, we explored the association between these genetic mutations and development of adverse drug effects in an ethnically diverse renal transplant population receiving azathioprine. Biochemical and clinical data were retrospectively evaluated during the first four weeks after kidney transplantation. TPMT nonfunctional mutant alleles were identified by polymerase chain reaction-based methods. Of 89 patients initially consented, 36 met inclusion criteria for this retrospective study. Five patients possessing a single TPMT nonfunctional mutant allele were identified: TPMT * 3A: n = 2 Caucasians; TPMT * 3B: n = 1 Caucasian; TPMT * 3C: n = 2 African-Americans. TPMT nonfunctional mutant alleles were associated with significant reductions in hematological indices and a significant increase in cyclosporine plasma concentrations in the first month post-transplant. TPMT genotype was an independent predictor for hemoglobin, hematocrit and red blood cell changes while mean azathioprine dose (mg/kg/day), azathioprine dose (mg/kg/day) at day 30 and cyclosporinemia at day 30 were not. Prospective application of pharmacogenetic principles may assist in optimization of immunosuppressive drug therapy and minimize drug toxicities.

The Impact of Thiopurine S-Methyltransferase Polymorphism on Azathioprine-Induced Myelotoxicity in Renal Transplant Recipients

“…Similar results were reported by Fabre et al 25 However, in the recently published study, where mean AZA doses for wild-type homozygotes and TPMT variant allele carriers were comparable after 30 days of treatment (2.0 and 1.8 mg/kg per day, respectively), mean values of RBC, HCT, and Hgb were significantly lower in the latter group of patients. 28 In the current study WBC count values were slightly lower in heterozygotes, this difference was most prominent 3 months after transplantation, but even at this time point it did not reach a statistically significant level (P = 0.084).…”

Utility of Assessing Thiopurine S-methyltransferase Polymorphisms Before Azathioprine Therapy

“…African patients were assessed by McLeod and Siva [123], who reported that the frequency of allelic variants in AZA-treated patients from East and West Africa was similar to that of Caucasians, although all the allelic variants were TPMT*3C. In this sense, Formea et al [124] found that 14.3% of black kidney recipients receiving AZA had the *3C variant.…”

TPMT genotype and its clinical implication in renal transplant recipients with azathioprine treatment

“…For the purpose of this study, leukopenia was defined as white blood cell (WBC) count <3000 cells/mm 3 and thrombocytopenia as platelets (PLT) <100 000/mm 3 . A red blood cell (RBC) count <4 million/mm 3 , haemoglobin (HGB) level <11 g/dL and an haematocrit (HCT) <33% was defined as the threshold for initiating therapy for anaemia (17). Pancytopenia was defined as both RBC and WBC below normal limits.…”