1 Statewide Renal Services, Royal Prince Alfred and Concord Repatriation General Hospitals, New South Wales, Australia. 2 School of Medicine, University of Queensland, Herston, Queensland, Australia. 3 School of Medicine, University of Sydney, Camperdown, New South Wales, Australia. 4 Address correspondence to: Darren M. Roberts, M.B.B.S., Ph.D., F.R.A.C.P., Statewide renal services, Royal Prince Alfred Hospital, Missenden Road, Camperdown, New South Wales, Australia, 2050.
Antibody-mediated rejection (AMR) is a recognized cause of allograft loss in kidney transplant recipients. A range of therapies targeting removal of circulating donor-specific antibodies (DSAs), blocking their effect or reducing production have been reported.
We conducted a systematic review to determine the efficacy of treatments for acute AMR in renal allografts. Electronic databases, reference lists, and conference proceedings were searched for controlled trials. Nonrandomized publications were reviewed for the purpose of discussion.
We identified 10,388 citations, including five randomized and seven nonrandomized controlled trials. The randomized studies were small (median, 13 patients/arm; range, 5-23), of which, four examined plasmapheresis (one suggested benefit) and one for immunoadsorption (also suggesting benefit). Marked heterogeneity was evident, including the definition and severity of AMR and the treatment regimen. The end point of graft survival was common to all studies. Small, nonrandomized controlled studies suggested benefit from rituximab or bortezomib. The effects of dose and regimen on the clinical response to any of the current treatments were not apparent from the available data.
Data describing the efficacy of treatments for AMR in renal allografts are of low or very low quality. Larger randomized controlled trials and dose-response studies are required.
"Major advances have been made in controlling T-cell-mediated allograft rejection (Nankivell & Alexander 2010). However, this success has revealed the presence of significant levels of humoral allograft rejection driven by pre-existing or de novo donor-specific antibodies which is poorly controlled by current therapies (Roberts et al. 2012). Thus, there is a major unmet medical need for new therapeutic options in the treatment of antibody-dependent allograft rejection. "
[Show abstract][Hide abstract] ABSTRACT: Kidney allografts induce strong T-cell and antibody responses which mediate acute rejection. Spleen tyrosine kinase (Syk) is expressed by most leucocytes, except mature T cells, and is involved in intracellular signalling following activation of the Fcγ-receptor, B-cell receptor and some integrins. A role for Syk signalling has been established in antibody-dependent native kidney disease, but little is known of Syk in acute renal allograft rejection. Sprague–Dawley rats underwent bilateral nephrectomy and received an orthotopic Wistar renal allograft. Recipient rats were treated with a Syk inhibitor (CC0482417, 30 mg/kg/bid), or vehicle, from 1 h before surgery until being killed 5 days later. Vehicle-treated recipients developed severe allograft failure with marked histologic damage in association with dense leucocyte infiltration (T cells, macrophages, neutrophils and NK cells) and deposition of IgM, IgG and C3. Immunostaining identified Syk expression by many infiltrating leucocytes. CC0482417 treatment significantly improved allograft function and reduced histologic damage, although allograft injury was still clearly evident. CC0482417 failed to prevent T-cell infiltration and activation within the allograft. However, CC0482417 significantly attenuated acute tubular necrosis, infiltration of macrophages and neutrophils and thrombosis of peritubular capillaries. In conclusion, this study identifies a role for Syk in acute renal allograft rejection. Syk inhibition may be a useful addition to T-cell-based immunotherapy in renal transplantation.
International Journal of Experimental Pathology 12/2014; 96(1). DOI:10.1111/iep.12110 · 2.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Survival post-lung transplantation remains limited to ∼ 50% at 5 years, far below survival after other solid organ transplants. Allograft rejection is a major cause of this limited survival. At least a third of lung transplant recipients experience acute rejection within 1 year posttransplantation. Acute rejection, though rarely a direct cause of death, represents the principal risk factor for chronic rejection, which is the greatest obstacle to long-term post-lung transplant survival. This article reviews in detail the two major subtypes of acute rejection: acute cellular rejection (ACR) and antibody-mediated rejection (AMR). ACR is diagnosed primarily by bronchoscopic transbronchial biopsies and is defined as perivascular or peribronchiolar lymphocytic infiltrates in the absence of infection. AMR remains poorly defined but is thought to involve anti-donor antibodies, allograft dysfunction, and pathological evidence of lung tissue injury or deposition of complement. Pathophysiological mechanisms, clinical presentation, clinical significance, known risk factors, and treatment strategies are discussed. Additionally, the limitations of current diagnostic modalities for both ACR and AMR are explained. Emerging data on the importance of donor-specific and non-donor-specific anti-human leukocyte antigen (anti-HLA) antibodies as well as non-HLA antibodies are presented. Larger cohorts have improved statistical analyses in recent years, leading to a clearer understanding of important topics related to ACR and AMR. Further collaborative studies and multicenter trials will be key in further advancing lung transplantation knowledge and improving outcomes in years to come.
Seminars in Respiratory and Critical Care Medicine 06/2013; 34(3):320-335. DOI:10.1055/s-0033-1348471 · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Antibody-mediated rejection, be it acute, subacute or chronic, is currently recognized as the major cause of graft loss in kidney transplant recipients. Anti-HLA donor-specific antibodies are deleterious to the graft fate whether they pre-exist to the transplantation or appear in the course of transplantation. The role of complement is therefore prominent in most instances. As well, the role of complement activation is crucial in the recurrence of atypical hemolytic uremic syndrome post-transplantation (aHUS) as well as following ischemia-reperfusion injury leading to delayed graft function. Eculizumab, a fully humanized monoclonal antibody directed against the C5 component of the complement cascade is efficient in chronically and safely blocking complement activation for example in paroxysmal nocturnal hemoglobinuria. In the setting of kidney transplantation, there is convincing but still limited evidence that eculizumab is efficient in preventing both acute and chronic antibody-mediated rejection in highly sensitized recipients requiring desensitization before getting a living donor kidney transplant. Studies are currently ongoing to determine its efficacy and safety in ABO incompatible transplantation, in the prevention of acute and chronic rejection either with a living or a deceased donor kidney as well as in the prevention of delayed graft function. Similar to its efficacy in aHUS on native kidneys, eculizumab prevents or treats recurrence after kidney transplantation. There is still a lot of research to be performed in order to determine precisely the exact indications and the length of treatment with this very active but also very expensive drug that will undoubtedly revolutionize the current management of patients with donor specific antibodies (DSAs) and at risk of HUS recurrence.
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