Pauline Lancia1, Tiphaine Adam de Beaumais1, Valéry Elie1, Florentine Garaix2, Marc Fila3, François Nobili4, Bruno Ranchin5, Pascale Testevuide6, Tim Ulinski7, Wei Zhao1,8,9, Georges Deschênes10, Evelyne Jacqz-Aigrain11,12,13. 1. Department of Pediatric Pharmacology and Pharmacogenetics, Robert Debré Hospital, APHP, 48 boulevard Sérurier, 75019, Paris, France. 2. Department of Pediatric Nephrology, CHU La Timone, APHM, 264 rue Saint Pierre, 13005, Marseille, France. 3. Department of Pediatric Nephrology, Arnaud de Villeneuve Hospital, 371 avenue du Doyen Gaston Giraud, 34090, Montpellier, France. 4. Department of Pediatric Nephrology, Saint Jacques Hospital, 2 Place Saint Jacques, 25000, Besançon, France. 5. Department of Pediatric Nephrology, Femme-Mère-Enfant Hospital, Hospices Civils de Lyon, 59 boulevard Pinel, 69677, Bron, France. 6. Department of Pediatric Nephrology, Territorial Hospital Center, Papeete, Polynésie Française, France. 7. Department of Pediatric Nephrology, Armand Trousseau Hospital, APHP, 26 rue du Dr Arnold Netter, 75012, Paris, France. 8. Clinical Investigation Center CIC1426, INSERM, Robert Debré Hospital, 48 boulevard Serurier, 75019, Paris, France. 9. Paris Diderot University Sorbonne Paris Cité, Paris, France. 10. Department of Pediatric Nephrology, Robert Debré Hospital, APHP, 48 boulevard Serurier, 75019, Paris, France. 11. Department of Pediatric Pharmacology and Pharmacogenetics, Robert Debré Hospital, APHP, 48 boulevard Sérurier, 75019, Paris, France. evelyne.jacqz-aigrain@aphp.fr. 12. Clinical Investigation Center CIC1426, INSERM, Robert Debré Hospital, 48 boulevard Serurier, 75019, Paris, France. evelyne.jacqz-aigrain@aphp.fr. 13. Paris Diderot University Sorbonne Paris Cité, Paris, France. evelyne.jacqz-aigrain@aphp.fr.
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.
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.
Authors: Walter L Miller; Vishal Agrawal; Duanpen Sandee; Meng Kian Tee; Ningwu Huang; Ji Ha Choi; Kari Morrissey; Kathleen M Giacomini Journal: Mol Cell Endocrinol Date: 2010-11-09 Impact factor: 4.102
Authors: Rita S Suri; William F Clark; Nick Barrowman; Jeffrey L Mahon; Heather R Thiessen-Philbrook; M Patricia Rosas-Arellano; Kelly Zarnke; Jocelyn S Garland; Amit X Garg Journal: Diabetes Care Date: 2005-10 Impact factor: 19.112
Authors: R Lorho; J Hardwigsen; J Dumortier; G-P Pageaux; F Durand; T Bizollon; A-S Blanc; F Di Giambattista; C Duvoux Journal: Clin Res Hepatol Gastroenterol Date: 2011-05-06 Impact factor: 2.947
Authors: Kathrin Klein; Maria Thomas; Stefan Winter; Andreas K Nussler; Mikko Niemi; Matthias Schwab; Ulrich M Zanger Journal: Clin Pharmacol Ther Date: 2012-06 Impact factor: 6.875
Authors: Johannes M M Boots; Maarten H L Christiaans; Elly M Van Duijnhoven; Robert-Jan Van Suylen; Johannes P Van Hooff Journal: Transplantation Date: 2002-12-27 Impact factor: 4.939
Authors: William S Oetting; Baolin Wu; David P Schladt; Weihua Guan; Jessica van Setten; Brendan J Keating; David Iklé; Rory P Remmel; Casey R Dorr; Roslyn B Mannon; Arthur J Matas; Ajay K Israni; Pamala A Jacobson Journal: Transplantation Date: 2019-06 Impact factor: 4.939
Authors: Abraham Shaked; Bao-Li Loza; Elisabet Van Loon; Kim M Olthoff; Weihua Guan; Pamala A Jacobson; Andrew Zhu; Claire E Fishman; Hui Gao; William S Oetting; Ajay K Israni; Giuliano Testa; James Trotter; Goran Klintmalm; Maarten Naesens; Sumeet K Asrani; Brendan J Keating Journal: Nat Med Date: 2022-04-07 Impact factor: 87.241