BACKGROUND:Cyclosporine nephrotoxicity negatively impacts long-term outcome after heart transplantation (HT). We previously reported 1-year results from a randomized study showing that cyclosporine-lowering strategies based on everolimus or mycophenolate mofetil (MMF) are equally effective for reducing progression of renal dysfunction. It is unknown whether this efficacy could be maintained over the long term. METHODS:Thirty-four recipients 1 to 4 years after HT and with 25 to 60 ml/min of creatinine clearance (CrCl) were randomized to everolimus with a very low dose (C(0): 50 to 90 ng/ml, n = 17) or MMF with low dose of cyclosporine (C(0): 100 to 150 ng/ml, n = 17). Follow-up was prolonged up to 3 years, and calculated CrCl was the main efficacy measure. RESULTS:Cyclosporine was maintained at 70% and 30% lower than baseline in the everolimus and MMF arms, respectively, throughout the 3-year study period. CrCl remained stable in the everolimus patients (+7% from baseline; p = 0.7), but improved in the MMF patients (+20% from baseline; p < 0.01), with a trend toward improved values compared with everolimus patients (46 ± 12 vs 56 ± 15 ml/min; p = 0.06). Subgroup analysis revealed that baseline proteinuria markedly influenced the renal function response to everolimus: whereas in patients with baseline proteinuria CrCl significantly worsened (-20%; p = 0.04), it improved in those without (+15%; p = 0.03). Safety was comparable between the two study arms. CONCLUSIONS:Cyclosporine nephrotoxicity improved after a prolonged dose reduction in patients receiving MMF. The everolimus-based strategy provided a similar benefit only to patients without baseline proteinuria. While raising caution against the universal use of everolimus for kidney protection, our long-term results support the need for customized approaches in the management of drug toxicities in maintenance HT recipients.
RCT Entities:
BACKGROUND:Cyclosporinenephrotoxicity negatively impacts long-term outcome after heart transplantation (HT). We previously reported 1-year results from a randomized study showing that cyclosporine-lowering strategies based on everolimus or mycophenolate mofetil (MMF) are equally effective for reducing progression of renal dysfunction. It is unknown whether this efficacy could be maintained over the long term. METHODS: Thirty-four recipients 1 to 4 years after HT and with 25 to 60 ml/min of creatinine clearance (CrCl) were randomized to everolimus with a very low dose (C(0): 50 to 90 ng/ml, n = 17) or MMF with low dose of cyclosporine (C(0): 100 to 150 ng/ml, n = 17). Follow-up was prolonged up to 3 years, and calculated CrCl was the main efficacy measure. RESULTS:Cyclosporine was maintained at 70% and 30% lower than baseline in the everolimus and MMF arms, respectively, throughout the 3-year study period. CrCl remained stable in the everolimuspatients (+7% from baseline; p = 0.7), but improved in the MMFpatients (+20% from baseline; p < 0.01), with a trend toward improved values compared with everolimuspatients (46 ± 12 vs 56 ± 15 ml/min; p = 0.06). Subgroup analysis revealed that baseline proteinuria markedly influenced the renal function response to everolimus: whereas in patients with baseline proteinuriaCrCl significantly worsened (-20%; p = 0.04), it improved in those without (+15%; p = 0.03). Safety was comparable between the two study arms. CONCLUSIONS:Cyclosporinenephrotoxicity improved after a prolonged dose reduction in patients receiving MMF. The everolimus-based strategy provided a similar benefit only to patients without baseline proteinuria. While raising caution against the universal use of everolimus for kidney protection, our long-term results support the need for customized approaches in the management of drug toxicities in maintenance HT recipients.
Authors: Nicolás Manito; Juan F Delgado; María G Crespo-Leiro; José María Arizón; Javier Segovia; Francisco González-Vílchez; Sònia Mirabet; Ernesto Lage; Domingo Pascual-Figal; Beatriz Díaz; Jesús Palomo; Gregorio Rábago; Marisa Sanz; Teresa Blasco; Eulàlia Roig Journal: World J Transplant Date: 2015-12-24
Authors: Stephan W Hirt; Christoph Bara; Markus J Barten; Tobias Deuse; Andreas O Doesch; Ingo Kaczmarek; Uwe Schulz; Jörg Stypmann; Assad Haneya; Hans B Lehmkuhl Journal: J Transplant Date: 2013-12-05
Authors: Matthias Helmschrott; Rasmus Rivinius; Thomas Bruckner; Hugo A Katus; Andreas O Doesch Journal: Drug Des Devel Ther Date: 2017-06-07 Impact factor: 4.162
Authors: Jan Van Keer; David Derthoo; Olivier Van Caenegem; Michel De Pauw; Eric Nellessen; Nathalie Duerinckx; Walter Droogne; Gábor Vörös; Bart Meyns; Ann Belmans; Stefan Janssens; Johan Van Cleemput; Johan Vanhaecke Journal: J Transplant Date: 2017-02-20
Authors: Beatriz Díaz-Molina; Paula Diaz-Bulnes; Reyes Carvajal Palao; Maria José Bernardo; Ramón M Rodriguez; Viviana Corte-Iglesias; Cesar Moris de la Tassa; Jose Luis Lambert; Beatriz Suarez-Alvarez Journal: Front Immunol Date: 2018-09-26 Impact factor: 7.561