Our results confirm the impact of the CYP3A4*22 allele on TAC pharmacokinetics, as a second significant genetic factor (in addition to the CYP3A5*1 allele) influencing TAC dose-adjusted blood concentrations in kidney transplant recipients.

The registry data focused new light on the epidemiology of kidney diseases in Poland. These data should be used in future follow-up and prospective studies.

PurposeNew-onset diabetes after transplantation (NODAT) is a major complication after kidney transplantation. The risk factors for NODAT include the use of calcineurin inhibitors as part of the immunosuppressive regimen, among which tacrolimus has the most pronounced diabetogenic effect. Both NODAT and type 2 diabetes mellitus (T2DM) share several risk factors. Recent studies have identified a number of common genetic variants associated with increased risk of T2DM. Here we report the results of our study on the potential effect of single nucleotide polymorphisms (SNPs) previously associated with T2DM on the risk of NODAT in kidney transplant patients medicated with tacrolimus.MethodsSeven SNPs in six genes known to increase the risk of T2DM in Caucasians were genotyped by means of TaqMan assays in 235 kidney transplant patients medicated with tacrolimus: rs4402960 and rs1470579 in IGF2BP2; rs1111875 in HHEX; rs10811661 upstream of CDKN2A/B; rs13266634 in SLC30A8; rs1801282 in PPARG; rs5215 in KCNJ11. The TCF7L2 rs7903146 SNP was also included in the multivariate analysis.ResultsNone of the analyzed SNPs was significantly associated with the risk of NODAT. However, the IGF2BP2 rs4402960 T allele was present significantly more frequently among patients diagnosed with NODAT more than 2 weeks after transplantation (p = 0.048). Mean (± standard deviation) number of the analyzed alleles tended to be lower in patients without NODAT (6.19 ± 1.71) than in NODAT patients (6.58 ± 1.1.95; p = 0.09) and significantly lower compared to late-onset NODAT patients (7.03 ± 1.88; p = 0.018). Multivariate analysis confirmed the significance of ‘diabetogenic’ allele number in late-onset NODAT development [odds ratio (OR) 1.37, 95 % confidence interval (CI) 1.05–1.78; p = 0.017]. Additionally, individuals carrying >7 of the analyzed ‘diabetogenic’ alleles were at a significantly higher risk of NODAT (OR 2.17, 95 % CI 1.18–3.99; p = 0.015).ConclusionsComplex analysis of genotypes increasing the risk of diabetes may lead to the identification of NODAT susceptibility predictors.

Thiopurine S-methyltransferase (TPMT) is an enzyme that catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine, 6-thioguanine, and azathioprine. TPMT activity exhibits an interindividual variability, mainly as a result of genetic polymorphism. Patients with intermediate or deficient TMPT activity are at risk for toxicity after receiving standard doses of thiopurine drugs. It has previously been reported that 3 variant alleles: TPMT*2, *3A, and *3C are responsible for over 95% cases of low enzyme activity. The purpose of this study was to explore the association between these polymorphisms and the occurrence of azathioprine adverse effects in 112 renal transplant recipients undergoing triple immunosuppressive therapy including azathioprine, cyclosporine, and prednisone. TPMT genetic polymorphism was determined using PCR-RFLP and allele-specific PCR methods. Azathioprine dose, leukocyte, erythrocyte, and platelet counts, graft rejection episodes, as well as cyclosporine levels were analyzed throughout the first year after organ transplantation. We found the frequency of leukopenia episodes (WBC < 4.0 x 10(9)/L) significantly higher in heterozygous patients (53.8%) compared with those with TPMT wild-type genotype (23.5%). One patient, who was a compound homozygote (3A/*3C), experienced severe azathioprine-related myelotoxicity each time after receiving the standard drug dose. Our results suggest that polymorphisms in TPMT gene may be responsible for approximately 12.5% of all leukopenia episodes in renal transplant recipients treated with azathioprine. Genotyping for the major TPMT variant alleles may be a valuable tool in preventing AZA toxicity and optimization of immunosuppressive therapy.

Our results suggest that routine genotyping of renal transplant recipients for TPMT variants may be useful in reducing the risk of AZA-related myelotoxicity, but there is not enough evidence to introduce ITPA testing into clinical practice.