Donor P-gp polymorphisms strongly influence renal function and graft loss in a cohort of renal transplant recipients on cyclosporine therapy in a long-term follow-up.

Jean-Baptiste Woillard; Jean-Philippe Rerolle; Nicolas Picard; Annick Rousseau; A. Guillaudeau; Etienne Munteanu; Marie Essig; M. Drouet; Yann Le Meur; Pierre Marquet

doi:10.1038/clpt.2010.62

Donor P-gp polymorphisms strongly influence renal function and graft loss in a cohort of renal transplant recipients on cyclosporine therapy in a long-term follow-up.: Donor's P-gp polymorphisms and graft loss

Jean-Baptiste Woillard ¹ Jean-Philippe Rerolle ^{1, 2} Nicolas Picard ^{1, 3} Annick Rousseau ¹ A. Guillaudeau ⁴ Etienne Munteanu ² Marie Essig ^{1, 2} M. Drouet ⁵ Yann Le Meur ^{1, 6} Pierre Marquet ^{1, 3, *}

* Auteur correspondant

1 PIST - Pharmacologie des Immunosuppresseurs et de la Transplantation

2 Service de Néphrologie, Dialyse, Transplantations [CHU Limoges]

3 Service de Pharmacologie, toxicologie et pharmacovigilance [CHU Limoges]

4 Service d'Hématologie biologique [CHU Limoges]

5 Service d'Immunologie et immunogénétique [CHU Limoges]

6 Service de Néphrologie

Abstract : Cyclosporin A (CsA) is a substrate for cytochrome P450 3A and the efflux transporter P-glycoprotein (P-gp; ABCB1), both abundantly expressed in the kidney. In a long-term follow-up of a cohort of patients who had received kidney transplants between the years 1990 and 2005, we retrospectively investigated the effect of CYP3A4, CYP3A5, and ABCB1 polymorphisms in kidney graft donors on recipients' renal function and risk of subsequent graft loss. DNA samples from 227 donors and clinical data from the 259 respective recipients were analyzed. Graft loss was significantly associated with the presence of the ABCB1 variant haplotype 1236T/2677T/3435T in the donor (1236T/2677T/3435T vs. other haplotypes: hazard ratio = 9.346; 95% confidence interval (CI) (2.278-38.461); P = 0.0019) and with previous episodes of acute organ rejection (hazard ratio = 3.077; 95% CI (1.213-7.812); P = 0.0178). The variant haplotype was also associated with a greater decrease in renal function (homozygotes for TTT -3.047 mlxmin(-1)/year; heterozygotes for TTT -4.435 mlxmin(-1)/year; others -2.186 mlxmin(-1)/year; P = 0.0240). The study showed that the presence of ABCB1 polymorphisms in donors influences long-term graft outcome adversely with decrease in renal function and graft loss in transplant recipients receiving CsA.

Keywords : Kidney transplantation cyclosporine A pharmacogenetics graft loss P-glycoprotein CYP3As

Type de document :

Article dans une revue

Clinical Pharmacology & Therapeutics, 2010, 88 (1), pp.95-100. 〈10.1038/clpt.2010.62〉

Domaine :

Sciences du Vivant [q-bio] / Sciences pharmaceutiques

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Donor P-gp polymorphisms strongly influence renal function and graft loss in a cohort of renal transplant recipients on cyclosporine therapy in a long-term follow-up.: Donor's P-gp polymorphisms and graft loss

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Donor P-gp polymorphisms strongly influence renal function and graft loss in a cohort of renal transplant recipients on cyclosporine therapy in a long-term follow-up.: Donor's P-gp polymorphisms and graft loss

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