RESUMO
Sotrastaurin, a novel selective protein-kinase-C inhibitor, inhibits early T cell activation via a calcineurin-independent pathway. Efficacy and safety of sotrastaurin in a calcineurin inhibitor-free regimen were evaluated in this two-stage Phase II study of de novo kidney transplant recipients. Stage 1 randomized 131 patients (2:1) to sotrastaurin 300 mg or cyclosporine A (CsA). Stage 2 randomized 180 patients (1:1:1) to sotrastaurin 300 or 200 mg or CsA. All patients received basiliximab, everolimus (EVR) and prednisone. Primary endpoint was composite efficacy failure rate of treated biopsy-proven acute rejection, graft loss, death or lost to follow-up. Main safety assessment was estimated glomerular filtration rate (eGFR) by MDRD-4 at Month 12. Composite efficacy failure rates at 12 months were higher in sotrastaurin arms (Stage 1: 16.5% and 10.9% for sotrastaurin 300 mg and CsA; Stage 2: 27.2%, 34.5% and 19.4% for sotrastaurin 200 mg, 300 mg and CsA). eGFR was significantly better in sotrastaurin groups versus CsA at most time points, except at 12 months. Gastrointestinal and cardiac adverse events were more frequent with sotrastaurin. Higher treatment discontinuation, deaths and graft losses occurred with sotrastaurin 300 mg. Sotrastaurin combined with EVR showed higher efficacy failure rates and some improvement in renal allograft function compared to a CsA-based therapy.
Assuntos
Rejeição de Enxerto/tratamento farmacológico , Transplante de Rim , Pirróis/administração & dosagem , Quinazolinas/administração & dosagem , Sirolimo/análogos & derivados , Doença Aguda , Adulto , Antineoplásicos , Biópsia , Inibidores de Calcineurina , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Everolimo , Feminino , Seguimentos , Taxa de Filtração Glomerular , Rejeição de Enxerto/patologia , Rejeição de Enxerto/fisiopatologia , Humanos , Imunossupressores/administração & dosagem , Rim/patologia , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/administração & dosagem , Estudos Retrospectivos , Sirolimo/administração & dosagem , Transplante Homólogo , Resultado do TratamentoRESUMO
Recipients of extended-criteria donor (ECD) kidneys have poorer long-term outcomes compared to standard-criteria donor kidney recipients. We report 3-year outcomes from a randomized, phase III study in recipients of de novo ECD kidneys (n = 543) assigned (1:1:1) to either a more intensive (MI) or less intensive (LI) belatacept regimen, or cyclosporine. Three hundred twenty-three patients completed treatment by year 3. Patient survival with a functioning graft was comparable between groups (80% in MI, 82% in LI, 80% in cyclosporine). Mean calculated GFR (cGFR) was 11 mL/min higher in belatacept-treated versus cyclosporine-treated patients (42.7 in MI, 42.2 in LI, 31.5 mL/min in cyclosporine). More cyclosporine-treated patients (44%) progressed to GFR <30 mL/min (chronic kidney disease [CKD] stage 4/5) than belatacept-treated patients (27-30%). Acute rejection rates were similar between groups. Posttransplant lymphoproliferative disorder (PTLD) occurrence was higher in belatacept-treated patients (two in MI, three in LI), most of which occurred during the first 18 months; four additional cases (3 in LI, 1 in cyclosporine) occurred after 3 years. Tuberculosis was reported in two MI, four LI and no cyclosporine patients. In conclusion, at 3 years after transplantation, immunosuppression with belatacept resulted in similar patient survival, graft survival and acute rejection, with better renal function compared with cyclosporine. As previously reported, PTLD and tuberculosis were the principal safety findings associated with belatacept in this study population.
Assuntos
Rejeição de Enxerto/prevenção & controle , Imunoconjugados/uso terapêutico , Imunossupressores/uso terapêutico , Falência Renal Crônica/cirurgia , Transplante de Rim , Complicações Pós-Operatórias , Abatacepte , Adulto , Ciclosporina/uso terapêutico , Feminino , Seguimentos , Taxa de Filtração Glomerular , Sobrevivência de Enxerto , Humanos , Falência Renal Crônica/complicações , Testes de Função Renal , Transtornos Linfoproliferativos/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Taxa de SobrevidaRESUMO
We describe a patient with glutaryl-coenzyme A dehydrogenase deficiency, demonstrated by a residual enzyme activity of only 1% in cultured fibroblasts. Although the clinical presentation was typical of glutaric aciduria type I, the urine concentrations of glutaric, glutaconic, and 3-hydroxyglutaric acids remained normal, even during episodes of clinical decompensation. An increased free glutarate level was demonstrated only in cerebrospinal fluid.