RESUMEN
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.
Asunto(s)
Ciclosporina/efectos adversos , Ciclosporina/uso terapéutico , Trasplante de Corazón/inmunología , Inmunosupresores/uso terapéutico , Ácido Micofenólico/análogos & derivados , Sirolimus/análogos & derivados , Trasplante , Anciano , Creatinina/orina , Ciclosporina/farmacología , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Everolimus , Femenino , Estudios de Seguimiento , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Humanos , Riñón/efectos de los fármacos , Riñón/fisiopatología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Ácido Micofenólico/uso terapéutico , Estudios Prospectivos , Sirolimus/uso terapéutico , Factores de Tiempo , Resultado del TratamientoAsunto(s)
Ciclosporina/uso terapéutico , Trasplante de Corazón/inmunología , Riñón/fisiopatología , Ácido Micofenólico/análogos & derivados , Sirolimus/análogos & derivados , Creatinina/metabolismo , Quimioterapia Combinada , Everolimus , Estudios de Seguimiento , Humanos , Inmunosupresores/uso terapéutico , Riñón/efectos de los fármacos , Pruebas de Función Renal , Ácido Micofenólico/uso terapéutico , Seguridad , Sirolimus/uso terapéuticoRESUMEN
BACKGROUND: Folic acid therapy reduces homocysteine plasma levels, which seem to influence occurrence of cardiac allograft vasculopathy, but its effect on medium- or long-term prognosis after heart transplantation is unknown. METHODS: We analyzed 7-year outcome of 51 recipients randomized to receive 15 mg/day of methyltertrahydrofolate for 1 year after heart transplantation or standard therapy alone (originally, for intravascular ultrasound study of short-term cardiac allograft vasculopathy progression); recipients were observed for a further 5 to 6 years. RESULTS: Overall, 13 deaths occurred (six oncologic, five cardiovascular, two infective). Estimated 7-year survival was better in recipients randomized to folate (88%+/-6% vs. 61%+/-9%, P=0.04). After adjusting for age, pretransplant coronary artery disease, and hyperhomocysteinemia, posttransplant folic acid therapy was associated with lower mortality (relative risk [RR] 0.53, 95% confidence interval [CI] 0.25-0.97; P=0.036), apparently driven by reductions in both cancer-related and cardiovascular causes. Reduced mortality was marked in a high-risk subgroup comprising older recipients and patients transplanted because of coronary artery disease (RR 0.43, 95% CI 0.17-0.85) but not in the lower-risk subgroup (RR 1.11, 95% CI 0.22-5.61). CONCLUSIONS: Although further studies are needed, it seems reasonable to suggest folate therapy to heart transplant recipients. It is possible that properties other than homocysteine reduction may provide antitumoral benefits.