Tacrolimus Variability: A Cause of Donor-Specific Anti-HLA Antibody Formation in Children

Aksoy G., ÇOMAK E., KOYUN M., Akbas H., AKKAYA B., AYDINLI B., ...More

EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS, vol.44, no.4, pp.539-548, 2019 (SCI-Expanded) identifier identifier identifier


Background and ObjectivesThe most important determinant of long-term graft survival in renal transplantation is adequate immunosuppression. Inadequate immunosuppression may lead to graft loss due to the presence of anti-HLA antibody. The aim of this study was to investigate the effect of variability in tacrolimus blood concentration on anti-HLA antibody development in pediatric recipients of living-donor renal transplants.MethodsPediatric recipients of living-donor renal transplants were retrospectively evaluated. Patients with a minimum of two years of follow-up who were administered tacrolimus were included in the study. Patients who had pretransplant anti-HLA antibody were excluded. Variability in tacrolimus blood concentration was assessed using the coefficient of variation (tacrolimus CV) method. Tacrolimus CV was calculated separately for the first 6months post-transplant, between 6 and 12months post-transplant, and from the end of the first year post-transplant to the last follow-up. We constructed receiver operating characteristic (ROC) curves of the tacrolimus CV for each group to find the best cutoff value.ResultsA total of 67 patients (including 48 males; 72%) with a mean age of 15.164.43years were included in the study. Anti-HLA antibody positivity was detected in 12 patients (18%). More than three HLA mismatches and the presence of acute cellular rejection correlated with the development of anti-HLA antibody (p=0.056, 0.009). Tacrolimus CVs for the three periods were 0.37 +/- 0.11, 0.31 +/- 0.18, and 0.35 +/- 0.12, respectively. The cutoff value of tacrolimus CV for anti-HLA antibody development was calculated as 0.32 with a sensitivity of 90.91% and specificity of 50.94% [AUC (area under the curve) 0.713, p = 0.023]. During the second 6-month period and after a year post-transplant, the percentage of patients with tacrolimus CV>0.32 was significantly higher in the anti-HLA antibody positive group than in the antibody negative group (67% vs 31%, p = 0.027; 83% vs 47%, p = 0.033). The eGFR (estimated glomerular filtration rate) was similar for the anti-HLA antibody negative and positive groups (78.72 +/- 2.86 vs 77.45 +/- 8.08, p>0.05).Conclusion High tacrolimus concentration variability appears to be associated with anti-HLAantibody formation in pediatric recipients of living-donor renal transplants.