BACKGROUND: Immunosuppression for immunologically high-risk kidney transplant patients usually involves antithymocyte globulin induction with triple drug maintenance therapy. Alemtuzumab, a humanized anti-CD52 antibody, was expected to be a promising induction therapy agent for kidney transplantation. However, currently no consensus is available about its efficacy and safety. This study aimed to evaluate the efficacy and safety of alemtuzumab as immune induction therapy in highly sensitized kidney transplant recipients.
METHODS: In this prospective, open-label, randomized, controlled trial, we enrolled 23 highly immunological risk patients (panel reactive antibody > 20%). They were divided into two groups: alemtuzumab group (trial group) and anti-thymocyte globulin (ATG) group (control group). Patients in the alemtuzumab group received intravenous alemtuzumab (15 mg) as a single dose before reperfusion. At the 24th hour post-operation, another dosage of alemtuzumab (15 mg) was given. The control group received a bolus of rabbit ATG (9 mg/kg), which was given 2 hours before kidney transplantation and lasted until the removal of vascular clamps when the anastomoses were completed. Maintenance immunosuppression in both groups comprised standard triple therapy consisting of tacrolimus, prednisone, and mycophenolate mofetil (MMF). Acute rejection (AR) and infection episodes were recorded, and kidney function was monitored during a 2-year follow-up. χ(2) test, t test and Kaplan-Meier analysis were performed with SPSS17.0 software.
RESULTS: Median follow-up was 338 days. In both the alemtuzumab group and ATG group, creatinine and blood urea nitrogen values in surviving recipients were similar (P > 0.05). White blood cell counts were significantly reduced in the alemtuzumab group for the most time points up to 6 months (P < 0.05). One patient receiving alemtuzumab died for acute myocardial infarction at the 65th day post-operation. Two ATG patients died for severe pulmonary infection or cardiac and pulmonary failure. Cumulative 2-year graft survival rate was 90.9% in the alemtuzumab group and 81.8% in ATG group (P > 0.05) respectively. There was one graft failure in the alemtuzumab group and two graft failures in ATG group, with all graft failures at tributed to rejection episodes. The alemtuzumab group had a 2-year cumulative freedom from rejection rate of 81.8%, compared with 72.7% for the ATG group (P > 0.05).
CONCLUSION: Alemtuzumab induction therapy for highly sensitized kidney transplant recipients is an effective and safe protocol yielding an acceptable acute rejection rate.
BACKGROUND: There are few comparisons of antibody induction therapy allowing early glucocorticoid withdrawal in renal-transplant recipients. The purpose of the present study was to compare induction therapy involving alemtuzumab with the most commonly used induction regimens in patient populations at either high immunologic risk or low immunologic risk.
METHODS: In this prospective study, we randomly assigned patients to receive alemtuzumab or conventional induction therapy (basiliximab or rabbit antithymocyte globulin). Patients were stratified according to acute rejection risk, with a high risk defined by a repeat transplant, a peak or current value of panel-reactive antibodies of 20% or more, or black race. The 139 high-risk patients received alemtuzumab (one dose of 30 mg, in 70 patients) or rabbit antithymocyte globulin (a total of 6 mg per kilogram of body weight given over 4 days, in 69 patients). The 335 low-risk patients received alemtuzumab (one dose of 30 mg, in 164 patients) or basiliximab (a total of 40 mg over 4 days, in 171 patients). All patients received tacrolimus and mycophenolate mofetil and underwent a 5-day glucocorticoid taper in a regimen of early steroid withdrawal. The primary end point was biopsy-confirmed acute rejection at 6 months and 12 months. Patients were followed for 3 years for safety and efficacy end points.
RESULTS: The rate of biopsy-confirmed acute rejection was significantly lower in the alemtuzumab group than in the conventional-therapy group at both 6 months (3% vs. 15%, P<0.001) and 12 months (5% vs. 17%, P<0.001). At 3 years, the rate of biopsy-confirmed acute rejection in low-risk patients was lower with alemtuzumab than with basiliximab (10% vs. 22%, P=0.003), but among high-risk patients, no significant difference was seen between alemtuzumab and rabbit antithymocyte globulin (18% vs. 15%, P=0.63). Adverse-event rates were similar among all four treatment groups.
CONCLUSIONS: By the first year after transplantation, biopsy-confirmed acute rejection was less frequent with alemtuzumab than with conventional therapy. The apparent superiority of alemtuzumab with respect to early biopsy-confirmed acute rejection was restricted to patients at low risk for transplant rejection; among high-risk patients, alemtuzumab and rabbit antithymocyte globulin had similar efficacy. (Funded by Astellas Pharma Global Development; INTAC ClinicalTrials.gov number, NCT00113269.).
INTRODUCCIÓN: A largo plazo ensayo prospectivo aleatorizado que evaluó el alemtuzumab, un humanizado anti-CD52 anticuerpo monoclonal, en su mayoría no-caucásica de la población aún no se ha reportado. MÉTODOS: Noventa y un donante fallecido (DD) primeros receptores de trasplante renal fueron distribuidos aleatoriamente en tres grupos diferentes de anticuerpos de inducción: grupo A, timoglobulina (Thymo), grupo B, el alemtuzumab, grupo C, daclizumab (DAC). En los grupos A y C, los niveles objetivo de valle de tacrolimus fueron 10.8 ng / ml, el micofenolato mofetil (MMF) 1 g administrado dos veces al día, y la metilprednisolona mantenimiento. En el grupo B, destino niveles valle de tacrolimus fueron 7.4 ng / ml, 500 mg de MMF administrado dos veces al día, sin metilprednisolona. Los afroamericanos y los hispanos representaron más del 50% en cada grupo. RESULTADOS: Un mínimo de seguimiento de 27 meses no mostraron diferencias entre los grupos generales de la paciente o la supervivencia del injerto (p = 0,89 y 0,66), pero una tendencia hacia la peor muerte, censura la supervivencia del injerto en el grupo B (p = 0,05). Tasas de rechazo agudo no fueron significativamente diferentes: seis (20%), siete (23%), y siete (23%) en los grupos A, B y C, respectivamente. La incidencia de nefropatía crónica del injerto fue mayor en el grupo B que en A y C (p = 0,008). La media del aclaramiento calculado de creatinina a los 24 meses fue de 81,1 + / - 5.5, 64.4 + / - 4.5, y 80.7 + / - 5,7 en los grupos A, B y C, respectivamente (p = 0,01 para B vs promedio de A y C ). CONCLUSIÓN: En este estudio aleatorizado de 27 meses de seguimiento mínimo de prueba de su mayoría no-caucásicas destinatarios DD trasplante renal con la inducción con alemtuzumab, bajas de tacrolimus de mantenimiento, MMF, y la evitación de esteroides parecen ser menos eficaz que cualquiera de Thymo o DAC con la inmunosupresión de mantenimiento mayor.
ANTECEDENTES: El citomegalovirus (CMV) es una complicación grave después del trasplante renal y está implicado en el rechazo del injerto. El anticuerpo anti-interleucina-2-receptor de daclizumab reduce la incidencia de rechazo agudo sin aumentar la incidencia de la infección por CMV. Métodos: este estudio multicéntrico, la seguridad ensayo aleatorio comparó y eficacia, en un año, de dos dosis de daclizumab (54 pacientes, grupo D) con timoglobulina (55 pacientes, el grupo T) más ciclosporina retardada (CsA), MMF (micofenolato mofetilo) y esteroides en los pacientes los primeros cadáveres de trasplante renal. Primaria criterio fue la infección por CMV / síndrome / enfermedad. D + / R-los pacientes recibieron profilaxis con ganciclovir oral durante 90 días. Resultados: El estado de CMV fue idéntico en ambos grupos. La incidencia de la infección por CMV / síndrome / enfermedad fue del 39% en el grupo D frente al 51% en el grupo T (NS). Es hora de inicio de la replicación del CMV se retrasó en el grupo D (p = 0,015) y el número medio de pp65-células positivas fue inferior a las 4 y 6 meses (p <0,001). La incidencia de sintomáticos episodios CMV no se redujo en todo el grupo D (5,6% frente a 16,4%, NS), pero menor en D + / R + y D-/ R + pacientes sin quimioprofilaxis, en comparación con el grupo T (2,8% frente a 21,6%, P = 0,028). Las supervivencias del paciente y del injerto y la incidencia de comprobada por biopsia de rechazo agudo fueron idénticos. CONCLUSIONES: El régimen de dosificación limitada de daclizumab con MMF, esteroides y la introducción de CsA retraso era seguro y eficaz. La incidencia de la infección por CMV no fue significativamente diferente, pero sin quimioprofilaxis, manifestaciones clínicas y la replicación viral se redujo con este régimen.
Immunosuppression for immunologically high-risk renal transplant patients usually involves antithymocyte globulin induction with triple drug maintenance therapy. Alemtuzumab, a humanized anti-CD52 antibody, has shown promise in tolerogenic induction protocols, requiring minimal maintenance immunosuppression. In this prospective, open-label, randomized, controlled trial, we enrolled 21 high immunological risk patients (i.e., panel reactive antibody>20% or previous transplant). Patients received either single-dose alemtuzumab given before graft reperfusion, with tacrolimus monotherapy, or four doses of Thymoglobulin with tacrolimus, mycophenolate, and steroids. Median follow-up was 377 days. One patient in the Thymoglobulin group who suffered primary graft nonfunction died. One-year cumulative graft survival was 85.7% for the alemtuzumab group and 87.5% for the Thymoglobulin group. Two alemtuzumab and three Thymoglobulin patients suffered rejection episodes. Infection rates were similar. Early results of this ongoing study indicate that a tolerogenic protocol with alemtuzumab induction and tacrolimus maintenance monotherapy is safe in immunologically high-risk renal transplant patients.
OBJECTIVE: Simultaneous pancreas-kidney (SPK) transplantation in type 1 diabetic patients requires immunotherapy against allo- and autoreactive T-cells. Cytomegalovirus (CMV) infection is a major cause for morbidity after transplantation and is possibly related to recurrent autoimmunity. In this study, we assessed the pattern of CMV viremia in SPK transplant recipients receiving either antithymocyte globulin (ATG) or anti-CD25 (daclizumab) immunosuppressive induction therapy.
RESEARCH DESIGN AND METHODS: We evaluated 36 SPK transplant recipients from a randomized cohort that received either ATG or daclizumab as induction therapy. Patients at risk for CMV infection received oral prophylactic ganciclovir therapy. The CMV DNA level in plasma was measured for at least 180 days using a quantitative real-time PCR. Recipient peripheral blood mononuclear cells were cross-sectionally HLA tetramer-stained for CMV-specific CD8(+) T-cells.
RESULTS: Positive CMV serostatus in donors was correlated with a higher incidence of CMV viremia than negative serostatus. In patients at risk, daclizumab induction therapy significantly prolonged CMV-free survival. CMV viremia occurred earlier and was more severe in patients with rejection episodes than in patients without rejection episodes. CMV-specific CD8(+) T-cell counts were significantly lower in patients developing CMV viremia than in those who did not.
CONCLUSIONS: Despite their comparable immunosuppressive potential, daclizumab is safer than ATG regarding CMV infection risk in SPK transplantation. ATG-treated rejection episodes are associated with earlier and more severe infection. Furthermore, high CMV-specific tetramer counts reflect antiviral immunity rather than concurrent viremia because they imply low viremic activity. These findings may prove valuable in the discussion on both safety of induction therapy and recurrent autoimmunity in SPK and islet transplantation.
Immunosuppression for immunologically high-risk kidney transplant patients usually involves antithymocyte globulin induction with triple drug maintenance therapy. Alemtuzumab, a humanized anti-CD52 antibody, was expected to be a promising induction therapy agent for kidney transplantation. However, currently no consensus is available about its efficacy and safety. This study aimed to evaluate the efficacy and safety of alemtuzumab as immune induction therapy in highly sensitized kidney transplant recipients.
METHODS:
In this prospective, open-label, randomized, controlled trial, we enrolled 23 highly immunological risk patients (panel reactive antibody > 20%). They were divided into two groups: alemtuzumab group (trial group) and anti-thymocyte globulin (ATG) group (control group). Patients in the alemtuzumab group received intravenous alemtuzumab (15 mg) as a single dose before reperfusion. At the 24th hour post-operation, another dosage of alemtuzumab (15 mg) was given. The control group received a bolus of rabbit ATG (9 mg/kg), which was given 2 hours before kidney transplantation and lasted until the removal of vascular clamps when the anastomoses were completed. Maintenance immunosuppression in both groups comprised standard triple therapy consisting of tacrolimus, prednisone, and mycophenolate mofetil (MMF). Acute rejection (AR) and infection episodes were recorded, and kidney function was monitored during a 2-year follow-up. χ(2) test, t test and Kaplan-Meier analysis were performed with SPSS17.0 software.
RESULTS:
Median follow-up was 338 days. In both the alemtuzumab group and ATG group, creatinine and blood urea nitrogen values in surviving recipients were similar (P > 0.05). White blood cell counts were significantly reduced in the alemtuzumab group for the most time points up to 6 months (P < 0.05). One patient receiving alemtuzumab died for acute myocardial infarction at the 65th day post-operation. Two ATG patients died for severe pulmonary infection or cardiac and pulmonary failure. Cumulative 2-year graft survival rate was 90.9% in the alemtuzumab group and 81.8% in ATG group (P > 0.05) respectively. There was one graft failure in the alemtuzumab group and two graft failures in ATG group, with all graft failures at tributed to rejection episodes. The alemtuzumab group had a 2-year cumulative freedom from rejection rate of 81.8%, compared with 72.7% for the ATG group (P > 0.05).
CONCLUSION:
Alemtuzumab induction therapy for highly sensitized kidney transplant recipients is an effective and safe protocol yielding an acceptable acute rejection rate.
