Fibrosis Progression According to Epithelial‐Mesenchymal Transition Profile: A Randomized Trial of Everolimus Versus CsA |
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| Authors: | L. Rostaing A. Hertig L. Albano D. Anglicheau A. Durrbach V. Vuiblet B. Moulin P. Merville M. Hazzan P. Lang G. Touchard B. Hurault deLigny S. Quéré F. Di Giambattista Y.‐C. Dubois E. Rondeau |
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| Affiliation: | 1. Department of Nephrology, Dialysis and Transplantation, H?pital de Rangueil, Toulouse, France;2. Department of Nephrology and Transplantation, H?pital Tenon, University of Pierre and Marie Curie and INSERM, Paris, France;3. Department of Nephrology, H?pital de l'Archet, Nice, France;4. Department of Kidney Transplantation, H?pital Necker, Assistance Publique‐H?pitaux de Paris, Université Paris Descartes, Sorbonne Paris Cité, Paris, France;5. IFRNT, Department of Nephrology, H?pital du Kremlin‐Bicêtre, Le Kremlin‐Bicêtre, Université Paris Sud and INSERM UMR1014, Paris, France;6. Department of Nephrology, H?pital Maison Blanche, Reims, France;7. Department of Nephrology & Transplantation, H?pital Civil, Strasbourg, France;8. Department of Nephrology‐Transplantation‐Dialysis, H?pital Pellegrin, Bordeaux, France;9. Department of Nephrology, CHU de Lille, Lille, France;10. Department of Nephrology, CHU Henri Mondor, Créteil, France;11. Department of Nephrology, Ho? pital La Mile? trie, Poitiers, France;12. Department of Nephrology, CHU de Caen, Caen, France;13. Novartis Pharma SAS, Rueil‐Malmaison, France;14. Department of Public Health, H?pital Tenon, and INSERM. Paris, France;15. AP‐HP, H?pital Tenon, Urgences Néphrologiques et Transplantation Rénale, Sorbonne Universités, UPMC, Paris, France |
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| 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. |
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| Keywords: | calcineurin inhibitor:cyclosporine A (CsA) fibrosis immunosuppressant |
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