title: Failure of Calcineurin Inhibitor (Tacrolimus) Weaning Randomized Trial in Long-Term Stable Kidney Transplant Recipients.
abstract: Long-term renal transplant outcome is limited by side effects of immunosuppressive drugs, particularly calcineurin inhibitor (CNI). We assumed that some patients selected for a "low immunological risk of rejection" could be eligible and benefit from a CNI weaning strategy. We designed a prospective, randomized, multicenter, double-blind placebo-controlled clinical study (Eudract: 2010-019574-33) to analyze the benefit-risk ratio of tacrolimus weaning on highly selected patients (≥4 years of transplantation, normal histology, stable graft function, no anti-HLA immunization). The primary endpoint was improvement of renal function. Fifty-two patients were scheduled in each treatment arm, placebo compared to the CNI maintenance arm. Only 10 patients were eligible and randomized. Five patients were assigned to the placebo arm and five were assigned to the tacrolimus maintenance arm. In the tacrolimus maintenance arm, all patients maintained stable graft function and no immunological events occurred. Contrastingly, in the placebo arm, all five patients had to reintroduce a full dose of tacrolimus since three of them presented an acute rejection episode (one humoral, one mixed, and one borderline) and two displayed anti-HLA antibodies without histological lesion (one donor-specific antibodies [DSA] and one non-DSA). Clearly, tacrolimus withdrawal must be avoided even in long-term highly selective stable kidney recipients.
authors.affiliation: ITUN, CHU de Nantes, INSERM, UMR 1064, Nantes, France.|Université de Nantes, Faculté de Médecine, Nantes, France.
authors.forename: E
authors.initials: E
authors.lastname: Dugast
authors.affiliation: ITUN, CHU de Nantes, INSERM, UMR 1064, Nantes, France.|Université de Nantes, Faculté de Médecine, Nantes, France.
authors.forename: J-P
authors.initials: JP
authors.lastname: Soulillou
authors.affiliation: Université de Nantes, SPHERE Laboratory EA4275, Nantes, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Foucher
authors.affiliation: ITUN, CHU de Nantes, INSERM, UMR 1064, Nantes, France.|CIC Biothérapie, Nantes, France.
authors.forename: E
authors.initials: E
authors.lastname: Papuchon
authors.affiliation: ITUN, CHU de Nantes, INSERM, UMR 1064, Nantes, France.|CIC Biothérapie, Nantes, France.
authors.forename: P
authors.initials: P
authors.lastname: Guerif
authors.affiliation: ITUN, CHU de Nantes, INSERM, UMR 1064, Nantes, France.
authors.forename: C
authors.initials: C
authors.lastname: Paul
authors.affiliation: Department of Pediatrics, Nantes University Hospital, Nantes, France.|LUNAM University, INSERM, UMR 1064 ITUN, Nantes, France.
authors.forename: D
authors.initials: D
authors.lastname: Riochet
authors.affiliation: ITUN, CHU de Nantes, INSERM, UMR 1064, Nantes, France.
authors.forename: M
authors.initials: M
authors.lastname: Chesneau
authors.affiliation: LabEx Transplantex, Nantes, France.|Etablissement Français du sang, Pays de la Loire, HLA Laboratory, Nantes, France.
authors.forename: A
authors.initials: A
authors.lastname: Cesbron
authors.affiliation: ITUN, CHU de Nantes, INSERM, UMR 1064, Nantes, France.|Université de Nantes, Faculté de Médecine, Nantes, France.
authors.forename: K
authors.initials: K
authors.lastname: Renaudin
authors.affiliation: ITUN, CHU de Nantes, INSERM, UMR 1064, Nantes, France.
authors.forename: J
authors.initials: J
authors.lastname: Dantal
authors.affiliation: ITUN, CHU de Nantes, INSERM, UMR 1064, Nantes, France. magali.giral@chu-nantes.fr.|Université de Nantes, Faculté de Médecine, Nantes, France. magali.giral@chu-nantes.fr.|LabEx Transplantex, Nantes, France. magali.giral@chu-nantes.fr.|EU consortium BIO-DrIM (www.biodrim.eu), Berlin, Germany. magali.giral@chu-nantes.fr.
authors.forename: M
authors.initials: M
authors.lastname: Giral
authors.affiliation: ITUN, CHU de Nantes, INSERM, UMR 1064, Nantes, France.|LabEx Transplantex, Nantes, France.|EU consortium BIO-DrIM (www.biodrim.eu), Berlin, Germany.|LabEx IGO "Immunotherapy Graft Oncology", Nantes, France.
authors.forename: S
authors.initials: S
authors.lastname: Brouard
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D065095:Calcineurin Inhibitors / Q000008:administration & dosage; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000188:drug therapy* / Q000209:etiology; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007676:Kidney Failure, Chronic / Q000601:surgery*; D007677:Kidney Function Tests; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications / Q000188:drug therapy; D011446:Prospective Studies; D016559:Tacrolimus / Q000008:administration & dosage*; D066027:Transplant Recipients; D017211:Treatment Failure; D014886:Weaning; D055815:Young Adult
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016559:Tacrolimus
keywords: alloantibody; biopsy; chronic allograft nephropathy; clinical research/practice; clinical trial; immunosuppressant; immunosuppression/immune modulation; kidney transplantation/nephrology