title: Early Conversion to Prednisolone/Everolimus as an Alternative Weaning Regimen Associates With Beneficial Renal Transplant Histology and Function: The Randomized-Controlled MECANO Trial.
abstract: In renal transplantation, use of calcineurin inhibitors (CNIs) is associated with nephrotoxicity and immunosuppression with malignancies and infections. This trial aimed to minimize CNI exposure and total immunosuppression while maintaining efficacy. We performed a randomized controlled, open-label multicenter trial with early cyclosporine A (CsA) elimination. Patients started with basiliximab, prednisolone (P), mycophenolate sodium (MPS), and CsA. At 6 months, immunosuppression was tapered to P/CsA, P/MPS, or P/everolimus (EVL). Primary outcomes were renal fibrosis and inflammation. Secondary outcomes were estimated glomerular filtration rate (eGFR) and incidence of rejection at 24 months. The P/MPS arm was prematurely halted. The trial continued with P/CsA (N = 89) and P/EVL (N = 96). Interstitial fibrosis and inflammation were significantly decreased and the eGFR was significantly higher in the P/EVL arm. Cumulative rejection rates were 13% (P/EVL) and 19% (P/CsA), (p = 0.08). A post hoc analysis of HLA and donor-specific antibodies at 1 year after transplantation revealed no differences. An individualized immunosuppressive strategy of early CNI elimination to dual therapy with everolimus was associated with decreased allograft fibrosis, preserved allograft function, and good efficacy, but also with more serious adverse events and discontinuation. This can be a valuable alternative regimen in patients suffering from CNI toxicity.
authors.affiliation: Renal Transplant Unit, Amsterdam, the Netherlands.
authors.forename: F J
authors.initials: FJ
authors.lastname: Bemelman
authors.affiliation: Renal Transplant Unit, Department of Nephrology, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: J W
authors.initials: JW
authors.lastname: de Fijter
authors.affiliation: Department of Pathology, Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Kers
authors.affiliation: University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Meyer
authors.affiliation: Renal Transplant Unit, Amsterdam, the Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Peters-Sengers
authors.affiliation: Department of Nephrology, Groningen University Hospital, Groningen, the Netherlands.
authors.forename: E F
authors.initials: EF
authors.lastname: de Maar
authors.affiliation: Renal Transplant Unit, Amsterdam, the Netherlands.
authors.forename: K A M I
authors.initials: KA
authors.lastname: van der Pant
authors.affiliation: Renal Transplant Unit, Department of Nephrology, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: A P J
authors.initials: AP
authors.lastname: de Vries
authors.affiliation: Department of Nephrology, Groningen University Hospital, Groningen, the Netherlands.
authors.forename: J-S
authors.initials: JS
authors.lastname: Sanders
authors.affiliation: Department of Epidemiology and Biostatistics, Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Zwinderman
authors.affiliation: Department of Surgery, Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: M M
authors.initials: MM
authors.lastname: Idu
authors.affiliation: Department of Nephrology, Groningen University Hospital, Groningen, the Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Berger
authors.affiliation: Renal Transplant Unit, Department of Nephrology, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: M E J
authors.initials: ME
authors.lastname: Reinders
authors.affiliation: Department of Surgery, Groningen University Hospital, Groningen, the Netherlands.
authors.forename: C
authors.initials: C
authors.lastname: Krikke
authors.affiliation: Department of Pathology, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: I M
authors.initials: IM
authors.lastname: Bajema
authors.affiliation: Department of Pathology, Groningen University Hospital, Groningen, the Netherlands.
authors.forename: M C
authors.initials: MC
authors.lastname: van Dijk
authors.affiliation: Renal Transplant Unit, Amsterdam, the Netherlands.
authors.forename: I J M
authors.initials: IJ
authors.lastname: Ten Berge
authors.affiliation: Department of Surgery, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Ringers
authors.affiliation: Sanquin Diagnostic Services, Amsterdam, the Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Lardy
authors.affiliation: Department of Immunogenetics and Transplantation Immunology, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: Roelen
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, the Netherlands.
authors.forename: D-J
authors.initials: DJ
authors.lastname: Moes
authors.affiliation: Department of Pathology, Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Florquin
authors.affiliation: Department of Nephrology, Groningen University Hospital, Groningen, the Netherlands.
authors.forename: J J
authors.initials: JJ
authors.lastname: Homan van der Heide
mesh_terms: D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D000068338:Everolimus / Q000627:therapeutic use*; D005260:Female; D005355:Fibrosis / Q000188:drug therapy* / Q000209:etiology; D006084:Graft Rejection / Q000188:drug therapy* / Q000209:etiology; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D011239:Prednisolone / Q000627:therapeutic use*; D011446:Prospective Studies; D013997:Time Factors; D014886:Weaning
chemical_list: D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D000068338:Everolimus; D011239:Prednisolone
keywords: calcineurin inhibitor (CNI); clinical research/practice; clinical trial; immunosuppressant; immunosuppression/immune modulation; kidney transplantation/nephrology