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

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Abstract

Background and Objectives

The 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.

Methods

Pediatric 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 6 months post-transplant, between 6 and 12 months 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.

Results

A total of 67 patients (including 48 males; 72%) with a mean age of 15.16 ± 4.43 years 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-HLA antibody formation in pediatric recipients of living-donor renal transplants.

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Authors and Affiliations

  1. Department of Pediatric Nephrology, School of Medicine, Akdeniz University, 07059, Antalya, Turkey

    Gulsah Kaya Aksoy, Elif Comak, Mustafa Koyun & Sema Akman

  2. Biochemistry, Akdeniz University, Antalya, Turkey

    Halide Akbaş

  3. Pathology, Akdeniz University, Antalya, Turkey

    Bahar Akkaya

  4. General Surgery, Akdeniz University, Antalya, Turkey

    Bülent Aydınlı

  5. Medical Biology, Akdeniz University, Antalya, Turkey

    Fahri Uçar

Authors
  1. Gulsah Kaya Aksoy
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Correspondence to Gulsah Kaya Aksoy.

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Funding

No source of funding was used to conduct this study.

Conflict of interest

Gulsah Kaya Aksoy, Elif Comak, Mustafa Koyun, Halide Akbas, Bahar Akkaya, Bulent Aydınlı, Fahri Ucar, and Sema Akman declare that they have no conflict of interest.

Ethical approval

This study was approved by the review boards and ethics committees of the Akdeniz University Medical Faculty.

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Informed consent was obtained from patients, parents, or care givers.

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Kaya Aksoy, G., Comak, E., Koyun, M. et al. Tacrolimus Variability: A Cause of Donor-Specific Anti-HLA Antibody Formation in Children. Eur J Drug Metab Pharmacokinet 44, 539–548 (2019). https://doi.org/10.1007/s13318-019-00544-0

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  • DOI: https://doi.org/10.1007/s13318-019-00544-0

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