RESUMEN
From a prospective and multicentric French cohort, we proposed an external validation study for the expanded criteria donor (ECD), based on 4833 kidney recipients transplanted for the first time between 2000 and 2014. We estimated the subject-specific effect from a multivariable Cox model. We confirmed a 1.75-fold (95% confidence interval [CI] 1.53-2.00, P < .0001) increase in graft failure risk if a given patient received an ECD graft compared to a graft from a donor with standard criteria (standard criteria donor [SCD]). Complementarily, we estimated the population-average effect using propensity scores. We estimated a 1.34-fold (95% CI 1.09-1.64, P = .0049) increase in graft failure risk among ECD patients receiving an ECD graft compared to receiving a SCD graft. With a 10-year follow-up, it corresponded to a decrease of 8 months of the mean time to graft failure due to ECD transplantation (95% CI 2-14 months). The population-average relative risk due to ECD transplantation and the corresponding absolute effect seem finally not so high. Regarding the increase of quality of life in transplantation, our study constitutes an argument to extend the definition of marginality by considering more grafts at high risk and thereby enlarging the pool of kidney grafts.
Asunto(s)
Rechazo de Injerto/mortalidad , Fallo Renal Crónico/cirugía , Trasplante de Riñón/mortalidad , Puntaje de Propensión , Donantes de Tejidos/provisión & distribución , Obtención de Tejidos y Órganos/métodos , Obtención de Tejidos y Órganos/estadística & datos numéricos , Adulto , Anciano , Selección de Donante , Femenino , Estudios de Seguimiento , Rechazo de Injerto/etiología , Rechazo de Injerto/patología , Supervivencia de Injerto , Humanos , Trasplante de Riñón/efectos adversos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Calidad de Vida , Factores de Riesgo , Tasa de Supervivencia , Factores de Tiempo , Obtención de Tejidos y Órganos/normas , Receptores de TrasplantesRESUMEN
BACKGROUND: Anti-glomerular basement-membrane (anti-GBM) disease (or Goodpasture disease) is characterized by severe kidney and lung involvement. Prognoses have improved with treatments that combine plasma exchange and immunosuppressive drugs. However, patients with severe renal involvement can have poor renal outcomes and cyclophosphamide can cause significant complications. Anti-GBM antibodies have a direct pathogenic effect on the disease: thus, therapeutics that can decrease their production, such as rituximab, could be a good alternative. METHODS: The medical files of five patients that had received rituximab as a first-line therapy (instead of cyclophosphamide), plus plasma exchange and steroids, were reviewed. All patients had severe disease manifestations. RESULTS: Four patients required dialysis at diagnosis and remained dialysis-dependent over the mean follow-up of 15 months. Three patients had pulmonary involvement, but recovered even though mechanical ventilation was required. Anti-GBM antibodies became rapidly undetectable in all patients. One infectious and two hematological complications were observed. CONCLUSIONS: We report the outcomes of five patients with Goodpasture disease and treated with rituximab as a first-line treatment. This strategy was effective at treating pulmonary manifestations and was associated with a good biological response with no major serious adverse events. However, renal outcomes were not significantly improved.
Asunto(s)
Enfermedad por Anticuerpos Antimembrana Basal Glomerular/diagnóstico , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/tratamiento farmacológico , Antineoplásicos Inmunológicos/uso terapéutico , Rituximab/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad por Anticuerpos Antimembrana Basal Glomerular/sangre , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Intercambio Plasmático/métodos , Inducción de Remisión/métodos , Diálisis Renal/métodos , Estudios Retrospectivos , Adulto JovenRESUMEN
The aim of this study (ClinicalTrials.gov, NCT01744470) was to determine the efficacy and safety of two different doses of extended-release tacrolimus (TacER) in kidney transplant recipients (KTRs) between 4 and 12 mo after transplantation. Stable steroid-free KTRs were randomized (1:1) after 4 mo: Group A had a 50% reduction in TacER dose with a targeted TacER trough level (C0 ) >3 µg/L; group B had no change in TacER dose (TacER C0 7-12 µg/L). The primary outcome was estimated GFR at 1 year. Of 300 patients, the intent-to-treat analysis included 186 patients (group A, n = 87; group B, n = 99). TacER C0 was lower in group A than in group B at 6 mo (4.1 ± 2.7 vs. 6.7 ± 3.9 µg/L, p < 0.0001) and 12 mo (5.6 ± 2.0 vs. 7.4 ± 2.1 µg/L, p < 0.0001). Estimated GFR was similar in both groups at 12 mo (group A, 56.0 ± 17.5 mL/min per 1.73 m²; group B, 56.0 ± 22.1 mL/min per 1.73 m²). More rejection episodes occurred in group A than group B (11 vs. 3; p = 0.016). At 1 year, subclinical inflammation occurred more frequently in group A than group B (inflammation score [i] >0: 21.4% vs. 8.8%, p = 0.047; tubulitis score [t] >0: 19.6% vs. 8.7%, p = 0.076; i + t: 1.14 ± 1.21 vs. 0.72 ± 1.01, p = 0.038). Anti-HLA donor-specific antibodies appeared only in group A (6 vs. 0 patients, p = 0.008). TacER C0 should be maintained >7 µg/L during the first year after transplantation in low-immunological-risk, steroid-free KTRs receiving a moderate dose of mycophenolic acid.
Asunto(s)
Rechazo de Injerto/etiología , Isoanticuerpos/sangre , Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Tacrolimus/farmacología , Donantes de Tejidos , Receptores de Trasplantes , Adolescente , Adulto , Anciano , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Rechazo de Injerto/sangre , Rechazo de Injerto/tratamiento farmacológico , Supervivencia de Injerto/efectos de los fármacos , Humanos , Inmunosupresores/farmacología , Isoanticuerpos/inmunología , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias , Pronóstico , Estudios Prospectivos , Factores de Riesgo , Adulto JovenRESUMEN
Little is known about the impact of posttransplant blood transfusion on the sensitization of anti-HLA antibodies and the formation of donor-specific antibodies (DSAs). The aims of our study were to determine the 1-year incidence of DSAs (assessed using a solid-phase assay) and antibody-mediated rejection (AMR) in kidney transplant patients who had or had not received a blood transfusion during the first year after transplantation. Included were 390 non-HLA-sensitized patients who had received an ABO-compatible kidney transplant and had not previously or simultaneously received a nonkidney transplant. Overall, 64% of patients received a red blood cell transfusion within the first year after transplantation, most within the first month. The overall 1-year incidence of DSAs was significantly higher in patients that had undergone transfusion (7.2% vs. 0.7% in patients with no transfusion, p < 0.0001). AMR occurred more often in the transfusion group (n = 15, 6%) compared with the nontransfusion group (n = 2, 1.4%; p = 0.04). Blood transfusion was an independent predictive factor for de novo DSA formation but not for AMR. Patients who had a transfusion and developed DSAs were more often treated with cyclosporin A (n = 10, 55.5%) rather than tacrolimus (n = 45, 19.4%; p = 0.0001). In conclusion, early posttransplant blood transfusion may increase immunological risk, especially in underimmunosuppressed patients.
Asunto(s)
Transfusión de Eritrocitos/efectos adversos , Rechazo de Injerto/epidemiología , Isoanticuerpos/sangre , Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Donantes de Tejidos , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Rechazo de Injerto/etiología , Supervivencia de Injerto , Antígenos HLA/inmunología , Humanos , Incidencia , Isoanticuerpos/inmunología , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Pronóstico , Factores de RiesgoRESUMEN
There is no approved therapy for hepatitis C virus (HCV) infection after kidney transplantation, and no data regarding the use of new-generation direct antiviral agents (DAAs) have been published so far. The aims of this pilot study were to assess the efficacy and safety of an interferon-free sofosbuvir-based regimen to treat chronic HCV infection in kidney transplant recipients. Twenty-five kidney transplant recipients with chronic HCV infection were given, for 12 (n = 19) or 24 weeks (n = 6), sofosbuvir plus ribavirin (n = 3); sofosbuvir plus daclatasvir (n = 4); sofosbuvir plus simeprevir, with (n = 1) or without ribavirin (n = 6); sofosbuvir plus ledipasvir, with (n = 1) or without ribavirin (n = 9); and sofosbuvir plus pegylated-interferon plus ribavirin (n = 1). A rapid virological response, defined by undetectable viremia at week 4 after starting DAA therapy, was observed in 22 of the 25 patients (88%). At the end of therapy, HCV RNA was undetectable in all patients. At 4 and 12 weeks after completing DAA therapy, all had a sustained virological response. The tolerance to anti-HCV therapy was excellent and no adverse event was observed. A significant decrease in calcineurin inhibitor levels was observed after HCV clearance. New-generation oral DAAs are efficient and safe to treat HCV infection after kidney transplantation.
Asunto(s)
Antivirales/uso terapéutico , Supervivencia de Injerto/efectos de los fármacos , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Fallo Renal Crónico/complicaciones , Trasplante de Riñón/efectos adversos , Sofosbuvir/uso terapéutico , ADN Viral/genética , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Hepacivirus/genética , Hepatitis C/virología , Humanos , Fallo Renal Crónico/cirugía , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Proyectos Piloto , Pronóstico , Factores de Riesgo , Seguridad , Carga ViralRESUMEN
In the Belatacept Evaluation of Nephroprotection and Efficacy as First-Line Immunosuppression Trial-Extended Criteria Donors (BENEFIT-EXT), extended criteria donor kidney recipients were randomized to receive belatacept-based (more intense [MI] or less intense [LI]) or cyclosporine-based immunosuppression. In prior analyses, belatacept was associated with significantly better renal function compared with cyclosporine. In this prospective analysis of the intent-to-treat population, efficacy and safety were compared across regimens at 7 years after transplant. Overall, 128 of 184 belatacept MI-treated, 138 of 175 belatacept LI-treated and 108 of 184 cyclosporine-treated patients contributed data to these analyses. Hazard ratios (HRs) comparing time to death or graft loss were 0.915 (95% confidence interval [CI] 0.625-1.339; p = 0.65) for belatacept MI versus cyclosporine and 0.927 (95% CI 0.634-1.356; p = 0.70) for belatacept LI versus cyclosporine. Mean estimated GFR (eGFR) plus or minus standard error at 7 years was 53.9 ± 1.9, 54.2 ± 1.9, and 35.3 ± 2.0 mL/min per 1.73 m2 for belatacept MI, belatacept LI and cyclosporine, respectively (p < 0.001 for overall treatment effect). HRs comparing freedom from death, graft loss or eGFR <20 mL/min per 1.73 m2 were 0.754 (95% CI 0.536-1.061; p = 0.10) for belatacept MI versus cyclosporine and 0.706 (95% CI 0.499-0.998; p = 0.05) for belatacept LI versus cyclosporine. Acute rejection rates and safety profiles of belatacept- and cyclosporine-based treatment were similar. De novo donor-specific antibody incidence was lower for belatacept (p ≤ 0.0001). Relative to cyclosporine, belatacept was associated with similar death and graft loss and improved renal function at 7 years after transplant and had a safety profile consistent with previous reports.
Asunto(s)
Abatacept/uso terapéutico , Ciclosporina/uso terapéutico , Rechazo de Injerto/prevención & control , Inmunosupresores/uso terapéutico , Fallo Renal Crónico/cirugía , Trasplante de Riñón , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Supervivencia de Injerto , Humanos , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Factores de RiesgoRESUMEN
UNLABELLED: DIAMOND: multicenter, 24-week, randomized trial investigating the effect of different once-daily, prolonged-release tacrolimus dosing regimens on renal function after de novo liver transplantation. Arm 1: prolonged-release tacrolimus (initial dose 0.2mg/kg/day); Arm 2: prolonged-release tacrolimus (0.15-0.175mg/kg/day) plus basiliximab; Arm 3: prolonged-release tacrolimus (0.2mg/kg/day delayed until Day 5) plus basiliximab. All patients received MMF plus a bolus of corticosteroid (no maintenance steroids). PRIMARY ENDPOINT: eGFR (MDRD4) at Week 24. Secondary endpoints: composite efficacy failure, BCAR and AEs. Baseline characteristics were comparable. Tacrolimus trough levels were readily achieved posttransplant; initially lower in Arm 2 versus 1 with delayed initiation in Arm 3. eGFR (MDRD4) was higher in Arms 2 and 3 versus 1 (p = 0.001, p = 0.047). Kaplan-Meier estimates of composite efficacy failure-free survival were 72.0%, 77.6%, 73.9% in Arms 1-3. BCAR incidence was significantly lower in Arm 2 versus 1 and 3 (p = 0.016, p = 0.039). AEs were comparable. Prolonged-release tacrolimus (0.15-0.175mg/kg/day) immediately posttransplant plus basiliximab and MMF (without maintenance corticosteroids) was associated with lower tacrolimus exposure, and significantly reduced renal function impairment and BCAR incidence versus prolonged-release tacrolimus (0.2mg/kg/day) administered immediately posttransplant. Delayed higher-dose prolonged-release tacrolimus initiation significantly reduced renal function impairment compared with immediate posttransplant administration, but BCAR incidence was comparable.
Asunto(s)
Rechazo de Injerto/tratamiento farmacológico , Supervivencia de Injerto/fisiología , Inmunosupresores/uso terapéutico , Hepatopatías/cirugía , Trasplante de Hígado , Hígado/fisiología , Tacrolimus/uso terapéutico , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Rechazo de Injerto/patología , Humanos , Pruebas de Función Renal , Hepatopatías/fisiopatología , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias , Pronóstico , Factores de RiesgoRESUMEN
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.
Asunto(s)
Ciclosporina/administración & dosificación , Transición Epitelial-Mesenquimal/efectos de los fármacos , Everolimus/administración & dosificación , Trasplante de Riñón , Riñón/patología , Insuficiencia Renal/cirugía , Adolescente , Adulto , Anciano , Biopsia , Inhibidores de la Calcineurina/administración & dosificación , Progresión de la Enfermedad , Femenino , Fibrosis , Supervivencia de Injerto , Humanos , Terapia de Inmunosupresión , Inflamación/patología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
Pneumocystis pneumonia (PCP) in solid organ transplant (SOT) recipients becomes rare in the immediate posttransplantation period thanks to generalized prophylaxis. We aimed to identify the predictive factors for PCP in the era of universal prophylaxis and to propose a strategy for preventing PCP beyond the first year after transplantation. In a retrospective case-control study, 33 SOT cases with PCP diagnosed between 2004 and 2010 were matched with two controls each to identify risk factors for PCP by uni- and multivariate analysis. All the patients benefited from 6 months of posttransplantation trimethoprim-sulfamethoxazole prophylaxis. Most PCP in SOT patients occurred during the second year posttransplantation (33%). By univariate analysis, age, nonuse of tacrolimus, total and CD4 lymphocyte counts, gamma-globulin concentration and cytomegalovirus (CMV) infection appeared to be PCP risk factors. In the final multivariate analysis, age (adjusted odds ratio [OR] 3.7, 95% confidence interval [CI]: 1.3-10.4), CMV infection (OR: 5.2, 95% CI: 1.8-14.7) and total lymphocyte count (OR: 3.9, 95% CI: 1.4-10.7) were found to be independently associated with PCP. The second year posttransplantation appeared to be the new period of highest risk of PCP. Age, CMV viremia and lymphocytes were the most pertinent predictive criteria to evaluate the risk of PCP in clinical practice.
Asunto(s)
Profilaxis Antibiótica , Antifúngicos/uso terapéutico , Rechazo de Injerto/etiología , Trasplante de Órganos , Neumonía por Pneumocystis/etiología , Receptores de Trasplantes , Combinación Trimetoprim y Sulfametoxazol/uso terapéutico , Estudios de Casos y Controles , Citomegalovirus/patogenicidad , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/microbiología , Femenino , Estudios de Seguimiento , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/tratamiento farmacológico , Supervivencia de Injerto , Humanos , Huésped Inmunocomprometido , Masculino , Persona de Mediana Edad , Pneumocystis carinii , Neumonía por Pneumocystis/diagnóstico , Neumonía por Pneumocystis/tratamiento farmacológico , Complicaciones Posoperatorias , Estudios Retrospectivos , Factores de Riesgo , Donantes de TejidosRESUMEN
Hepatitis E virus genotype-3 (HEV3) infection can cause chronic hepatitis in immunosuppressed patients and induce extra-hepatic manifestations, such as neurological symptoms, kidney injuries, and immune-mediated thrombocytopenia. Very few cases of HEV-induced kidney manifestations have been reported. Herein, we report, for the first time, a case of de novo membranoproliferative glomerulonephritis that occurred in a kidney transplant patient who developed a chronic HEV3 infection, which was successfully treated with ribavirin.
Asunto(s)
Antivirales/uso terapéutico , Crioglobulinemia/tratamiento farmacológico , Glomerulonefritis Membranoproliferativa/tratamiento farmacológico , Rechazo de Injerto/prevención & control , Hepatitis E/tratamiento farmacológico , Huésped Inmunocomprometido , Inmunosupresores/efectos adversos , Trasplante de Riñón , Ribavirina/uso terapéutico , Crioglobulinemia/etiología , Crioglobulinemia/virología , Glomerulonefritis Membranoproliferativa/etiología , Glomerulonefritis Membranoproliferativa/virología , Virus de la Hepatitis E , Humanos , Masculino , Persona de Mediana Edad , Nefritis Hereditaria/cirugía , Receptores de Trasplantes , Resultado del TratamientoRESUMEN
This Phase III randomized trial examined efficacy and safety of a novel once-daily extended-release tacrolimus formulation (LCP-Tacro [LCPT]) versus twice-daily tacrolimus in de novo kidney transplantation. Primary efficacy end point was proportion of patients with treatment failure (death, graft failure, biopsy-proven acute rejection or lost to follow-up) within 12 months. Starting doses were, LCPT: 0.17 mg/kg/day and tacrolimus twice-daily: 0.1 mg/kg/day; 543 patients were randomized, LCPT: n = 268; tacrolimus twice-daily: n = 275. At 12 months treatment failure was LCPT: 18.3% and tacrolimus twice-daily: 19.6%; the upper 95% CI of the treatment difference was +5.27%, below the predefined +10% noninferiority criteria. There were no significant differences in the incidence of individual efficacy events or adverse events. Target tacrolimus trough levels were more rapidly achieved in the LCPT group. Following initial dose, 36.6% of patients in the LCPT group had rapidly attained trough levels within 6-11 ng/mL versus 18.5% of tacrolimus twice-daily patients; majority of tacrolimus twice-daily patients (74.7%) had troughs <6 ng/mL compared with 33.5% in the LCPT group. Overall, cumulative study dose was 14% lower for LCPT. Results suggest that use of once-daily LCPT in de novo kidney transplantation is efficacious and safe. Lower LCPT dose reflects the improved absorption provided by the novel formulation.
Asunto(s)
Rechazo de Injerto/tratamiento farmacológico , Inmunosupresores/administración & dosificación , Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Complicaciones Posoperatorias , Tacrolimus/administración & dosificación , Adulto , Método Doble Ciego , Esquema de Medicación , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Rechazo de Injerto/etiología , Supervivencia de Injerto , Humanos , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Pronóstico , Factores de Riesgo , Factores de TiempoRESUMEN
One hundred ninety-seven patients received anti-T-lymphocyte globulins Fresenius, mycophenolate mofetil and delayed cyclosporine, and were randomized to ≥6-month corticosteroids (+CS; n=99) or no CS (-CS; n=98). One- and five-year actual graft survival (censored for death) was 93.2% and 86.4% in the +CS group versus 94.9% and 89.8% in the -CS group (5-year follow-up, p=0.487). Freedom from clinical rejection was 86.9% and 81.8% versus 74.5% and 74.5% (p=0.144), respectively, at 1 and 5 years; 5-year freedom from biopsy-proven rejection was 88.9% versus 83.7% (p=0.227). More late first rejections occurred in the +CS group. Significantly lower 5-year graft survival in patients experiencing rejection was observed for +CS (55.6% vs. 92.0%; p=0.005) with 8/18 versus 2/25 graft losses. Renal function at 5 years was stable and comparable (median serum creatinine, 159 vs. 145 µmol/L; creatinine clearance, 53.5 vs. 56.6 mL/min). More +CS patients developed diabetes, dyslipidemia and malignancies. Rejections in -CS patients occurred early after transplantation and did not impair long-term renal function. In patients receiving CS, rejections occurred later and with a higher risk for subsequent graft failure. A similar and not inferior 5-year efficacy profile and a reduced morbidity were observed in CS-free patients compared to patients who received CS for at least 6 months.
Asunto(s)
Trasplante de Riñón , Acondicionamiento Pretrasplante , Adolescente , Adulto , Anciano , Femenino , Supervivencia de Injerto , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
This exploratory phase II study evaluated the safety and efficacy of belatacept in de novo adult liver transplant recipients. Patients were randomized (N = 260) to one of the following immunosuppressive regimens: (i) basiliximab + belatacept high dose [HD] + mycophenolate mofetil (MMF), (ii) belatacept HD + MMF, (iii) belatacept low dose [LD] + MMF, (iv) tacrolimus + MMF, or (v) tacrolimus alone. All received corticosteroids. Demographic characteristics were similar among groups. The proportion of patients who met the primary end point (composite of acute rejection, graft loss, death by month 6) was higher in the belatacept groups (4248%) versus tacrolimus groups (1538%), with the highest number of deaths and grafts losses in the belatacept LD group. By month 12, the proportion surviving with a functioning graft was higher with tacrolimus + MMF (93%) and lower with belatacept LD (67%) versus other groups (90%: basiliximab + belatacept HD; 83%: belatacept HD; 88%: tacrolimus). Mean calculated GFR was 1534 mL/min higher in belatacept-treated patients at 1 year. Two cases of posttransplant lymphoproliferative disease and one case of progressive multifocal leukoencephalopathy occurred in belatacept-treated patients. Follow-up beyond month 12 revealed an increase in death and graft loss in another belatacept group (belatacept HD), after which the study was terminated.
Asunto(s)
Inmunoconjugados/uso terapéutico , Inmunosupresores/uso terapéutico , Trasplante de Hígado , Abatacept , Adulto , Anciano , Esquema de Medicación , Femenino , Tasa de Filtración Glomerular , Rechazo de Injerto , Supervivencia de Injerto , Hepatitis C/mortalidad , Hepatitis C/cirugía , Humanos , Inmunoconjugados/administración & dosificación , Terapia de Inmunosupresión , Inmunosupresores/administración & dosificación , Leucoencefalopatías/complicaciones , Fallo Hepático/mortalidad , Fallo Hepático/cirugía , Trastornos Linfoproliferativos/complicaciones , Masculino , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Ácido Micofenólico/análogos & derivados , Recurrencia , Tacrolimus/administración & dosificación , Resultado del TratamientoRESUMEN
Although large retrospective studies have identified the presence of donor-specific antibodies (DSAs) to be a risk factor for rejection and impaired survival after liver transplantation, the long-term predicted pathogenic potential of individual DSAs after liver transplantation remains unclear. We investigated the incidence, prevalence and consequences of DSAs in maintenance liver transplant (LT) recipients. Two hundred sixty-seven LT recipients, who had undergone transplantation at least 6 months previously and had been screened for DSAs at least twice using single-antigen bead technology, were included and tested annually for the presence of DSAs. At a median of 51 months (min-max: 6-220) after an LT, 13% of patients had DSAs. At a median of 36.5 months (min-max: 2-45) after the first screening, 9% of patients have developed de novo DSAs. The sole predictive factor for the emergence of de novo DSAs was retransplantation (OR 3.75; 95% CI 1.28-11.05, p = 0.025). Five out of 21 patients with de novo DSAs (23.8%) developed an antibody-mediated rejection. Fibrosis score was higher among patients with DSAs. In conclusion, monitoring for the development of DSAs in maintenance LT patients is useful in case of graft dysfunction and to identify patients with a high risk of developing liver fibrosis.
Asunto(s)
Rechazo de Injerto/etiología , Antígenos HLA/sangre , Isoanticuerpos/sangre , Cirrosis Hepática/etiología , Hepatopatías/cirugía , Trasplante de Hígado/efectos adversos , Adolescente , Adulto , Anciano , Femenino , Estudios de Seguimiento , Rechazo de Injerto/epidemiología , Rechazo de Injerto/mortalidad , Supervivencia de Injerto , Antígenos HLA/inmunología , Humanos , Incidencia , Isoanticuerpos/inmunología , Cirrosis Hepática/epidemiología , Cirrosis Hepática/mortalidad , Hepatopatías/complicaciones , Hepatopatías/mortalidad , Masculino , Persona de Mediana Edad , Prevalencia , Pronóstico , Estudios Prospectivos , Reoperación , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia , Adulto JovenRESUMEN
Phase III noninferiority trial examining efficacy and safety of converting stable renal transplant recipients from twice-daily tacrolimus to a novel extended-release once-daily tacrolimus formulation (LCPT) with a controlled agglomeration technology. Controls maintained tacrolimus twice daily. The primary efficacy endpoint was proportion of patients with efficacy failures (death, graft failure, locally read biopsy-proven acute rejection [BPAR], or loss to follow-up) within 12 months. Starting LCPT dose was 30% lower (15% for blacks) than preconversion tacrolimus dose; target trough levels were 4-15 ng/mL. A total of 326 patients were randomized; the mITT population (n = 162 each group) was similar demographically in the two groups. Mean daily dose of LCPT was significantly (p < 0.0001) lower than preconversion tacrolimus dose at each visit; mean trough levels between groups were similar. There were four efficacy failures in each group; safety outcomes were similar between groups. Frequency of premature study drug discontinuation was LCPT: 12% versus tacrolimus twice daily: 5% (p = 0.028). LCPT demonstrated noninferiority to tacrolimus twice daily in efficacy failure rates. LCPT may offer a safe and effective alternative for converting patients to a once-daily formulation. Compared to currently available tacrolimus formulation, LCPT requires lower doses to achieve target trough levels.
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Rechazo de Injerto/tratamiento farmacológico , Inmunosupresores/administración & dosificación , Enfermedades Renales/cirugía , Trasplante de Riñón/efectos adversos , Tacrolimus/administración & dosificación , Esquema de Medicación , Femenino , Estudios de Seguimiento , Rechazo de Injerto/etiología , Supervivencia de Injerto , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias , Pronóstico , Estudios ProspectivosRESUMEN
Memory T cells play a central role in mediating allograft rejection and are a rational target for immunosuppressive therapy. Alefacept is a recombinant LFA3/IgG1 fusion protein that reduces the number of memory T cells in both psoriatic lesions and the peripheral circulation of psoriasis patients. This study evaluated the efficacy and safety of alefacept compared with placebo when combined with tacrolimus, mycophenolate mofetil and corticosteroids in de novo renal transplant recipients. Between December 2007 and March 2009 patients were randomized in a double-blind fashion to receive alefacept (n = 105) or placebo (n = 107) for 3 months and were then followed for a further 3 months. The primary efficacy endpoint was the incidence of biopsy-confirmed acute T cell mediated rejection (Banff grade ≥ 1) through Month 6. Memory T cell counts were significantly reduced in the alefacept group from Week 3 to study end compared with placebo. However, there was no significant difference between the alefacept and placebo groups for the primary efficacy endpoint (alefacept, 11.0% vs. placebo, 7.0%, p = 0.3). Patient and graft survival as well as renal function was similar between treatment groups. Safety and tolerability were generally similar between the treatment arms. Malignancy was higher in the alefacept treatment arm.
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Rechazo de Injerto/tratamiento farmacológico , Terapia de Inmunosupresión/métodos , Trasplante de Riñón , Metilprednisolona/uso terapéutico , Ácido Micofenólico/análogos & derivados , Proteínas Recombinantes de Fusión/uso terapéutico , Tacrolimus/uso terapéutico , Adolescente , Adulto , Anciano , Alefacept , Biopsia , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Vías de Administración de Medicamentos , Quimioterapia Combinada , Estudios de Seguimiento , Glucocorticoides/administración & dosificación , Glucocorticoides/uso terapéutico , Rechazo de Injerto/inmunología , Rechazo de Injerto/patología , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/uso terapéutico , Metilprednisolona/administración & dosificación , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Ácido Micofenólico/uso terapéutico , Proteínas Recombinantes de Fusión/administración & dosificación , Estudios Retrospectivos , Tacrolimus/administración & dosificación , Donantes de Tejidos , Resultado del Tratamiento , Adulto JovenRESUMEN
Thrombotic microangiopathy (TMA) is one of the hallmark vascular lesions of antiphospholipid syndrome nephropathy (APSN). These lesions are at high risk of recurrence after kidney transplantation. The complement pathway is thought to be active in this process. We used eculizumab to treat three consecutive kidney transplant recipients with posttransplant TMA due to APSN recurrence that was resistant to plasmapheresis and explored the complement deposition and apoptotic and vascular cell markers on the sequential transplant biopsies. Treatment with eculizumab resulted in a rapid and dramatic improvement of the graft function in all three patients and in improvement of the TMA lesions within the graft. None of these patients had TMA flares after eculizumab was withdrawn. At the time of TMA diagnosis, immunofluorescence studies revealed intense C5b-9 and C4d depositions at the endothelial cell surface of the injured vessels. Moreover, C5b-9 colocalized with vessels exhibiting a high rate of apoptotic cells. Examination of sequential biopsies during eculizumab therapy showed that TMA lesions, C4d and apoptotic markers were rapidly cleared but the C5b-9 deposits persisted for several months as a footprint of the TMA. Finally, we noticed that complement inhibition did not prevent the development of the chronic vascular changes associated with APSN. Eculizumab seems to be an efficient method for treating severe forms of posttransplant TMA due to APSN recurrence. Terminal complement inhibition does not prevent the development of chronic APSN.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Síndrome Antifosfolípido/complicaciones , Apoptosis/efectos de los fármacos , Complicaciones Posoperatorias , Microangiopatías Trombóticas/prevención & control , Enfermedades Vasculares/tratamiento farmacológico , Adulto , Anticuerpos Antifosfolípidos/sangre , Síndrome Antifosfolípido/terapia , Enfermedad Crónica , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Depleción Linfocítica , Masculino , Plasmaféresis , Pronóstico , Recurrencia , Microangiopatías Trombóticas/etiología , Microangiopatías Trombóticas/patología , Enfermedades Vasculares/etiología , Enfermedades Vasculares/patologíaRESUMEN
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.
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Rechazo de Injerto/tratamiento farmacológico , Trasplante de Riñón , Pirroles/administración & dosificación , Quinazolinas/administración & dosificación , Sirolimus/análogos & derivados , Enfermedad Aguda , Adulto , Antineoplásicos , Biopsia , Inhibidores de la Calcineurina , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Everolimus , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Rechazo de Injerto/patología , Rechazo de Injerto/fisiopatología , Humanos , Inmunosupresores/administración & dosificación , Riñón/patología , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/administración & dosificación , Estudios Retrospectivos , Sirolimus/administración & dosificación , Trasplante Homólogo , Resultado del TratamientoRESUMEN
The Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial randomized patients receiving a living or standard criteria deceased donor kidney transplant to a more (MI) or less intensive (LI) regimen of belatacept or cyclosporine A (CsA). The 5-year results of the long-term extension (LTE) cohort are reported. A total of 456 (68.5% of intent-to-treat) patients entered the LTE at 36 months; 406 patients (89%) completed 60 months. Between Months 36 and 60, death occurred in 2%, 1% and 5% of belatacept MI, belatacept LI and CsA patients, respectively; graft loss occurred in 0% belatacept and 2% of CsA patients. Acute rejection between Months 36 and 60 was rare: zero belatacept MI, one belatacept LI and one CsA. Rates for infections and malignancies for Months 36-60 were generally similar across belatacept groups and CsA, respectively: fungal infections (14%, 15%, 12%), viral infections (21%, 18%, 16%) and malignancies (6%, 6%, 9%). No new posttransplant lymphoproliferative disorder cases occurred after 36 months. Mean calculated GFR (MDRD, mL/min/1.73 m(2) ) at Month 60 was 74 for belatacept MI, 76 for belatacept LI and 53 for CsA. These results show that the renal function benefit and safety profile observed in belatacept-treated patients in the early posttransplant period was sustained through 5 years.
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Ciclosporina/uso terapéutico , Rechazo de Injerto/prevención & control , Inmunoconjugados/uso terapéutico , Inmunosupresores/uso terapéutico , Fallo Renal Crónico/cirugía , Trasplante de Riñón , Abatacept , Adulto , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Humanos , Agencias Internacionales , Pruebas de Función Renal , Trastornos Linfoproliferativos/prevención & control , Masculino , Complicaciones Posoperatorias/prevención & control , Pronóstico , Seguridad , Factores de TiempoRESUMEN
Patients in the BENEFIT-EXT study received extended criteria donor kidneys and a more intensive (MI) or less intensive (LI) belatacept immunosuppression regimen, or cyclosporine A (CsA). Patients who remained on assigned therapy through year 3 were eligible to enter a long-term extension (LTE) study. Three hundred four patients entered the LTE (n = 104 MI; n = 113 LI; n = 87 CsA), and 260 continued treatment through year 5 (n = 91 MI; n = 100 LI; n = 69 CsA). Twenty patients died during the LTE (n = 5 MI; n = 9 LI; n = 6 CsA), and eight experienced graft loss (n = 2 MI; n = 1 LI; n = 5 CsA). Three patients experienced an acute rejection episode (n = 2 MI; n = 1 LI). The incidence rate of serious adverse events, viral infections and fungal infections was similar across groups during the LTE. There were four cases of posttransplant lymphoproliferative disorder (PTLD) from the beginning of the LTE to year 5 (n = 3 LI; n = 1 CsA); two of three PTLD cases in the LI group were in patients who were seronegative for Epstein-Barr virus (EBV(-)) at transplantation. Mean ± SD calculated GFR at year 5 was 55.9 ± 17.5 (MI), 59.0 ± 29.1 (LI) and 44.6 ± 16.4 (CsA) mL/min/1.73 m(2) . Continued treatment with belatacept was associated with a consistent safety profile and sustained improvement in renal function versus CsA over time.