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Pharmacogenetics of post-transplant diabetes mellitus in children with renal transplantation treated with tacrolimus

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Abstract

Background

Post-transplant diabetes mellitus (PTDM) is a major complication of immunosuppressive therapy, with many risk factors reported in adults with renal transplantation. The objective of this study was to investigate potential non-genetic and genetic risk factors of PTDM in children with renal transplantation treated with tacrolimus.

Methods

A national database was screened for patients developing PTDM within 4 years following tacrolimus introduction. PTDM was defined as glucose disorder requiring anti-diabetic treatment. PTDM patients were matched to “non-PTDM” control transplanted children according to age, gender, and duration of post-transplant follow-up. Patients were genotyped for six selected genetic variants in POR*28 (rs1057868), PPARa (rs4253728), CYP3A5 (rs776746), VDR (rs2228570 and rs731236), and ABCB1 (rs1045642) genes, implicated in glucose homeostasis and tacrolimus disposition.

Results

Among the 98 children with renal transplantation enrolled in this multicentre study, 18 developed PTDM. None of the clinical and biological parameters was significant between PTDM and control patients. Homozygous carriers of POR*28 or wild-type ABCB1 (rs1045642) gene variants were more frequent in PTDM than in control patients with differences close to significance (p = 0.114 and p = 0.066 respectively). A genetic score based on these variants demonstrated that POR*28/*28 and ABCB1 CC or CT genotype carriers were at a significantly higher risk of developing PTDM after renal transplantation.

Conclusion

Identification of PTDM risk factors should allow clinicians to allocate the best immunosuppressant for each patient with renal transplantation, and improve care for patients who are at a higher risk.

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Acknowledgements

The authors thank Dr MA Macher, Biomedicine Agency and Department of Paediatric Nephrology, Robert Debré Hospital, for her help in the study organisation, Yves Medard, Department of Paediatric Pharmacology and Pharmacogenetics, Robert Debré Hospital, for technical expertise in molecular biology and Professor M Tsimaratos, Department of Paediatric Nephrology, La Timone, Marseille, for his collaboration.

Funding

Funding was partially provided by the European Union Seventh Framework Programme FP7/2007–2013-Global Research in Paediatrics Network (grant no. 261060).

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Authors and Affiliations

  1. Department of Pediatric Pharmacology and Pharmacogenetics, Robert Debré Hospital, APHP, 48 boulevard Sérurier, 75019, Paris, France

    Pauline Lancia, Tiphaine Adam de Beaumais, Valéry Elie, Wei Zhao & Evelyne Jacqz-Aigrain

  2. Department of Pediatric Nephrology, CHU La Timone, APHM, 264 rue Saint Pierre, 13005, Marseille, France

    Florentine Garaix

  3. Department of Pediatric Nephrology, Arnaud de Villeneuve Hospital, 371 avenue du Doyen Gaston Giraud, 34090, Montpellier, France

    Marc Fila

  4. Department of Pediatric Nephrology, Saint Jacques Hospital, 2 Place Saint Jacques, 25000, Besançon, France

    François Nobili

  5. Department of Pediatric Nephrology, Femme-Mère-Enfant Hospital, Hospices Civils de Lyon, 59 boulevard Pinel, 69677, Bron, France

    Bruno Ranchin

  6. Department of Pediatric Nephrology, Territorial Hospital Center, Papeete, Polynésie Française, France

    Pascale Testevuide

  7. Department of Pediatric Nephrology, Armand Trousseau Hospital, APHP, 26 rue du Dr Arnold Netter, 75012, Paris, France

    Tim Ulinski

  8. Clinical Investigation Center CIC1426, INSERM, Robert Debré Hospital, 48 boulevard Serurier, 75019, Paris, France

    Wei Zhao & Evelyne Jacqz-Aigrain

  9. Paris Diderot University Sorbonne Paris Cité, Paris, France

    Wei Zhao & Evelyne Jacqz-Aigrain

  10. Department of Pediatric Nephrology, Robert Debré Hospital, APHP, 48 boulevard Serurier, 75019, Paris, France

    Georges Deschênes

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  1. Pauline Lancia
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Correspondence to Evelyne Jacqz-Aigrain.

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The authors declare that they have no conflicts of interest.

Ethical approval

All procedures were carried out in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The project fulfils the requirement of the “Commission Nationale Informatique et Liberté” (2014), and approval was obtained from the local Ethics Committee CEERB (2016/287). Informed consent was signed by the parents.

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Lancia, P., Adam de Beaumais, T., Elie, V. et al. Pharmacogenetics of post-transplant diabetes mellitus in children with renal transplantation treated with tacrolimus. Pediatr Nephrol 33, 1045–1055 (2018). https://doi.org/10.1007/s00467-017-3881-3

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