title: Fibrosis progression according to epithelial-mesenchymal transition profile: a randomized trial of everolimus versus CsA.
abstract: Markers of epithelial-mesenchymal transition (EMT) may identify patients at high risk of graft fibrogenesis who could benefit from early calcineurin inhibitor (CNI) withdrawal. In a randomized, open-label, 12-month trial, de novo kidney transplant patients received cyclosporine, enteric-coated mycophenolate sodium (EC-MPS) and steroids to month 3. Patients were stratified as EMT+ or EMT- based on month 3 biopsy, then randomized to start everolimus with half-dose EC-MPS (720 mg/day) and cyclosporine withdrawal (CNI-free) or continue cyclosporine with standard EC-MPS (CNI). The primary endpoint was progression of graft fibrosis (interstitial fibrosis/tubular atrophy [IF/TA] grade increase ≥1 between months 3-12) in EMT+ patients. 194 patients were randomized (96 CNI-free, 98 CNI); 153 (69 CNI-free, 84 CNI) were included in histological analyses. Fibrosis progression occurred in 46.2% (12/26) CNI-free EMT+ patients versus 51.6% (16/31) CNI EMT+ patients (p = 0.68). Biopsy-proven acute rejection (BPAR, including subclinical events) occurred in 25.0% and 5.1% of CNI-free and CNI patients, respectively (p < 0.001). In conclusion, early CNI withdrawal with everolimus initiation does not prevent interstitial fibrosis. Using this CNI-free protocol, in which everolimus exposure was relatively low and administered with half-dose EC-MPS, CNI-free patients were overwhelmingly under-immunosuppressed and experienced an increased risk of BPAR.
authors: Department of Nephrology, Dialysis and Transplantation, Hôpital de Rangueil, Toulouse, France.
authors: L
authors: L
authors: Rostaing
authors: A
authors: A
authors: Hertig
authors: L
authors: L
authors: Albano
authors: D
authors: D
authors: Anglicheau
authors: A
authors: A
authors: Durrbach
authors: V
authors: V
authors: Vuiblet
authors: B
authors: B
authors: Moulin
authors: P
authors: P
authors: Merville
authors: M
authors: M
authors: Hazzan
authors: P
authors: P
authors: Lang
authors: G
authors: G
authors: Touchard
authors: B
authors: B
authors: Hurault deLigny
authors: S
authors: S
authors: Quéré
authors: F
authors: F
authors: Di Giambattista
authors: Y-C
authors: YC
authors: Dubois
authors: E
authors: E
authors: Rondeau
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001706:Biopsy; D065095:Calcineurin Inhibitors / Q000008:administration & dosage; D016572:Cyclosporine / Q000008:administration & dosage*; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D000068338:Everolimus / Q000008:administration & dosage*; D005260:Female; D005355:Fibrosis; D006085:Graft Survival; D006801:Humans; D007165:Immunosuppression Therapy; D007249:Inflammation / Q000473:pathology; D007668:Kidney / Q000473:pathology*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D051437:Renal Insufficiency / Q000601:surgery*; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D065095:Calcineurin Inhibitors; D016572:Cyclosporine; D000068338:Everolimus
keywords: calcineurin inhibitor:cyclosporine A (CsA); fibrosis; immunosuppressant