Acute rejection is an expected event after transplantation and has been associated with poor long-term kidney transplant outcome. The presence of B cells in the kidney graft with acute rejection is thought to be an omnious sign, as it has been associated with poor graft outcome. There is no definitive treatment for acute rejection with B cells in the graft. Rituximab, a humanized monoclonal antibody against CD20, has been used in the treatment of B cell lymphoma. We present the case of a 49-yr-old Caucasian male with early acute kidney allograft rejection that was refractory to high doses of steroids and rabbit anti-thymocyte globulin (thymoglobulin). Repeat renal biopsy revealed T cell and B cells in the kidney graft and responded to the combination of rituximab and muromonab (a mouse monoclonal antibody to CD3 receptor). Over 9 months post-transplant, the patient remains rejection free with a serum creatinine of 1.7 mg/dL.
"Compared with the control group of 10 children who received standard-of-care treatment only, rituximab-treated children had better recovery of allograft function (P = 0.026) and improved biopsy rejection scores (P <0.0001) at the follow-up biopsy after six months. Furthermore, a few case reports in adults suggest a benefit of rituximab alone or in combination with the usual anti-rejection treatment in patients with acute (therapy refractory) rejection
[Show abstract][Hide abstract] ABSTRACT: Background
Acute kidney allograft rejection is a major cause for declining graft function and has a negative impact on the long-term graft survival. The majority (90%) of acute rejections are T-cell mediated and, therefore, the anti-rejection therapy targets T-cell-mediated mechanisms of the rejection process. However, there is increasing evidence that intragraft B-cells are also important in the T-cell-mediated rejections. First, a significant proportion of patients with acute T-cell-mediated rejection have B-cells present in the infiltrates. Second, the outcome of these patients is inferior, which has been related to an inferior response to the conventional anti-rejection therapy. Third, treatment of these patients with an anti-CD20 antibody (rituximab) improves the allograft outcome as reported in single case observations and in one small study. Despite the promise of these observations, solid evidence is required before incorporating this treatment option into a general treatment recommendation.
The RIACT study is designed as a randomized, double-blind, placebo-controlled, parallel group multicenter Phase III study. The study examines whether rituximab, in addition to the standard treatment with steroid-boli, leads to an improved one-year kidney allograft function, compared to the standard treatment alone in patients with acute T-cell mediated tubulointerstitial rejection and significant B-cell infiltrates in their biopsies. A total of 180 patients will be recruited.
It is important to clarify the relevance of anti-B cell targeting in T-cell mediated rejection and answer the question whether this novel concept should be incorporated in the conventional anti-rejection therapy.
Clinical trials gov. number: NCT01117662
"Highly sensitized patients show high levels of panel reactive antibody (PRA) in serum, have a greater risk of rejection episodes, and have poorer graft survival after kidney transplantation . Rituximab has been widely used in desensitization protocols to prevent refractory antibody-mediated rejection (AMR) in these highly sensitized recipients [5-9]. In the present study, we focused on the impact of rituximab as an induction treatment for highly sensitized kidney recipients. "
[Show abstract][Hide abstract] ABSTRACT: Highly sensitized patients with a high level of panel reactive antibody (PRA) experience more episodes of antibody-mediated rejection (AMR) and poorer graft survival than non-sensitized patients. Rituximab is a well-known monoclonal anti-CD20 antibody that causes the depletion of B lymphocytes. The aim of this study was to compare a rituximab-administered and a non-administered group of highly sensitized recipients.
Forty-three kidney recipients with a PRA level of ≥50% were included. Sixteen (group R) received one dose of rituximab at 2 days prior to transplantation and 27 patients (group NR) did not.
Patients' demographics, such as age, sex, dialysis duration, and type of immunosuppressive agent were not different in the two groups. No side effects due to rituximab administration were observed in group R. Class I PRA of group R (75.6 ± 37.7%) was higher than that of group NR (45.7 ± 35.8%, P = 0.013). More acute rejection episodes occurred within 1 year after transplantation in group NR but the difference between the groups was not significant (18.8% in group R vs. 29.6% in group NR, P = 0.631). However, two AMR episodes occurred only in group NR. Renal functions were not different in the two groups. In group R, CD19 and CD20 rapidly decreased 2 days after rituximab infusion. Furthermore, the administration of rituximab was not linked to acute rejection.
To confirm the long-term anti-rejection and beneficial effects of rituximab, further studies should be performed with a larger cohort. In conclusion, rituximab administration 2 days prior to transplantation is both effective and safe.
[Show abstract][Hide abstract] ABSTRACT: Targeting specific limbs of the immune response known to be involved in the pathogenesis of autoimmunity or transplant rejection is a logical means of managing these conditions. For example, using agents such as anti-CD25 monoclonal antibodies or calcineurin inhibitors (CNIs) to inhibit the alloreactive effector T cells (expressing the CD25 molecule) in transplantation, or using antiproliferative agents that target both T and B lymphocytes implicated in the pathogenesis of systemic lupus erythematosus (SLE), has proved to be a highly effective treatment strategy. Recently, the use of rituximab (a chimeric monoclonal antibody) in targeting CD20-expressing B cells has gained considerable popularity in the treatment of autoimmune renal disease and in the treatment of transplant pre-conditioning and rejection. This is due to the general tolerability of the drug and the low complication rate following its administration. Interestingly, as a result of using this agent we are beginning to understand more about the pathogenesis of a number of these disorders, which in turn should lead to other significant therapeutic advances. The critical and central role B cells appear to play in immune-mediated conditions has become more obvious and the relative contributions of humoral and cellular immune effectors at different stages of disease have been emphasised. Rituximab has now been used in diverse immunological renal conditions (see Table 1), as well as in transplantation as a means of de-sensitisation or in the treatment of an antibody-mediated rejection processes. In this article I will summarise the biology of this compound, its potential utility in kidney diseases and its place in our therapeutic arsenal. It should be emphasised that, to date, no randomised clinical trials of this compound in autoimmune renal disease or transplantation have been completed and all reports regarding its efficacy in these settings have been from uncontrolled cohort studies. It has now been firmly established that it can be used in these settings as salvage therapy. However, the trial data are urgently required for us to understand how best to use it and to compare it with conventional induction or maintenance regimens. There are ongoing trials using rituximab as induction therapy in active (SLE), antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and numerous aspects of transplantation, which over the next few years should establish its true benefit. Biology of Rituximab Rituximab targets the CD20 antigen expressed on immature and mature B cells, as well as on malignant B cells (hence its original use in the treatment of non-Hodgkin's lymphoma). It is a chimeric monoclonal antibody made up of mouse heavy and light chain variable regions, directed against human CD20, on the backbone of a human immunoglobulin (Ig)G1 constant region (see Figure 1). As CD20 engagement mediates B-cell proliferation and differentiation, rituximab therapy prevents B-cell expansion and results in B-cell depletion through apoptosis and lysis by complement-dependent and -independent mechanisms. B-cell depletion generally persists for six to nine months in more than 80% of patients, 1 although the degree of depletion is highly variable and is in part dependent on FcγR polymorphisms as well as antibody concentration. 2 This is important as recent data have suggested that in certain proteinuric states the duration of B-cell depletion may be shortened, perhaps as a result of urinary antibody loss (Fervenza F, American Society of Nephrology (ASN), 2006). The ideal dosing schedules for different conditions have not been established, although data from our own co-operative studies (in ANCA vasculitis) have suggested that, at least for some autoimmune diseases, no difference in efficacy exists between the traditional (non-Hodgkin's lymphoma) protocol and the two-dose schedule used in SLE and AAV (Jones R, personal communication). Whether efficacy in proteinuric states is compromised as a result of briefer periods of B-cell depletion remains to be established. Adverse Effects Rituximab is generally well tolerated. Adverse effects are most commonly related to the infusion and are mild. Moreover, these generally disappear with repeated dosing. Infections are the next most common problem, but there does not seem to be an increased incidence of tuberculosis (TB),, completing post-doctoral research. He continues to participate in research, leading a group investigating the cause and treatment of systemic vasculitis and autoimmune glomerulonephritis. His clinical interests are pre-dialysis care, transplantation and glomerulonephritis. Dr Salama's PhD, on the immunology of antiglomerular basement membrane (GBM) disease, was completed at the Royal Postgraduate Medical School at Hammersmith Hospital. He trained in internal medicine and nephrology in London after training in medicine at Oxford University and the Royal London Hospital, graduating with honours.
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