American Journal of Transplantation 2015; 15: 407–416 Wiley Periodicals Inc.
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Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.13052
Rituximab as Induction Therapy After Renal Transplantation: A Randomized, Double-Blind, Placebo-Controlled Study of Efficacy and Safety M. W. F. van den Hoogen1,*,y, E. G. Kamburova2, M. C. Baas1, E. J. Steenbergen3, S. Florquin3, H. J. P. M. Koenen2, I. Joosten2 and L. B. Hilbrands1
Received 11 July 2014, revised 22 August 2014 and accepted for publication 07 September 2014
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With the combination of a calcineurin inhibitor, mycophenolate mofetil and prednisolone as immunosuppressive treatment, the incidence of acute rejection after renal transplantation is acceptably low. Since acute rejection is one of the main predictors of chronic transplant glomerulopathy (1), further lowering of incidence of acute rejection, for example by the additional use of IL-2 receptor antagonists or polyclonal anti-T cell antibodies, might improve long-term outcome (2,3). Increased attention for the role of B cells and antibodies in acute rejection has been elicited by the negative prognostic impact of donor-specific anti-HLA antibodies (4), the presence of B cell clusters in biopsies of patients with severe rejection (5), and the frequent finding of capillary deposition of C4d in patients with acute rejection. B cells are the progenitors of plasma cells, are effective antigen presenting cells and can secrete different cytokines to stimulate cellular immunity. Interfering with these pathways by anti-B cell therapy has been shown to be effective in diseases that were considered to be mainly T cell driven, like rheumatoid arthritis (6,7).
Department of Nephrology, Radboud University Medical Centre, Nijmegen, the Netherlands 2 Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Centre, Nijmegen, the Netherlands 3 Department of Pathology, Radboud University Medical Centre, Nijmegen, the Netherlands Corresponding author: Martijn W. F. van den Hoogen, [email protected] y Present address: Department of Internal Medicine, Renal Transplant Unit, Erasmus MC, Rotterdam We evaluated the efficacy and safety of rituximab as induction therapy in renal transplant patients. In a double-blind, placebo-controlled study, 280 adult renal transplant patients were randomized between a single dose of rituximab (375 mg/m2) or placebo during transplant surgery. Patients were stratified according to panel-reactive antibody (PRA) value and rank number of transplantation. Maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil and steroids. The primary endpoint was the incidence of biopsy proven acute rejection (BPAR) within 6 months after transplantation. The incidence of BPAR was comparable between rituximab-treated (23/138, 16.7%) and placebotreated patients (30/142, 21.2%, p ¼ 0.25). Immunologically high-risk patients (PRA >6% or re-transplant) not receiving rituximab had a significantly higher incidence of rejection (13/34, 38.2%) compared to other treatment groups (rituximab-treated immunologically high-risk patients, and rituximab- or placebo-treated immunologically low-risk (PRA 6% or first transplant) patients (17.9%, 16.4% and 15.7%, p ¼ 0.004). Neutropenia (
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Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/ajt.13052
Rituximab as Induction Therapy After Renal Transplantation: A Randomized, Double-Blind, Placebo-Controlled Study of Efficacy and Safety M. W. F. van den Hoogen1,*,y, E. G. Kamburova2, M. C. Baas1, E. J. Steenbergen3, S. Florquin3, H. J. P. M. Koenen2, I. Joosten2 and L. B. Hilbrands1
Received 11 July 2014, revised 22 August 2014 and accepted for publication 07 September 2014
1
With the combination of a calcineurin inhibitor, mycophenolate mofetil and prednisolone as immunosuppressive treatment, the incidence of acute rejection after renal transplantation is acceptably low. Since acute rejection is one of the main predictors of chronic transplant glomerulopathy (1), further lowering of incidence of acute rejection, for example by the additional use of IL-2 receptor antagonists or polyclonal anti-T cell antibodies, might improve long-term outcome (2,3). Increased attention for the role of B cells and antibodies in acute rejection has been elicited by the negative prognostic impact of donor-specific anti-HLA antibodies (4), the presence of B cell clusters in biopsies of patients with severe rejection (5), and the frequent finding of capillary deposition of C4d in patients with acute rejection. B cells are the progenitors of plasma cells, are effective antigen presenting cells and can secrete different cytokines to stimulate cellular immunity. Interfering with these pathways by anti-B cell therapy has been shown to be effective in diseases that were considered to be mainly T cell driven, like rheumatoid arthritis (6,7).
Department of Nephrology, Radboud University Medical Centre, Nijmegen, the Netherlands 2 Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud University Medical Centre, Nijmegen, the Netherlands 3 Department of Pathology, Radboud University Medical Centre, Nijmegen, the Netherlands Corresponding author: Martijn W. F. van den Hoogen, [email protected] y Present address: Department of Internal Medicine, Renal Transplant Unit, Erasmus MC, Rotterdam We evaluated the efficacy and safety of rituximab as induction therapy in renal transplant patients. In a double-blind, placebo-controlled study, 280 adult renal transplant patients were randomized between a single dose of rituximab (375 mg/m2) or placebo during transplant surgery. Patients were stratified according to panel-reactive antibody (PRA) value and rank number of transplantation. Maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil and steroids. The primary endpoint was the incidence of biopsy proven acute rejection (BPAR) within 6 months after transplantation. The incidence of BPAR was comparable between rituximab-treated (23/138, 16.7%) and placebotreated patients (30/142, 21.2%, p ¼ 0.25). Immunologically high-risk patients (PRA >6% or re-transplant) not receiving rituximab had a significantly higher incidence of rejection (13/34, 38.2%) compared to other treatment groups (rituximab-treated immunologically high-risk patients, and rituximab- or placebo-treated immunologically low-risk (PRA 6% or first transplant) patients (17.9%, 16.4% and 15.7%, p ¼ 0.004). Neutropenia (
