Treatment of ABMR
Acute ABMR
The primary aims of therapeutic modalities for ABMR are to remove existing antibodies and inhibit their redevelopment. The management of ABMR is challenging and is associated with poorer outcomes compared with traditional anti-T cell rejection therapy for pure cell-mediated rejection. A recent systematic review of treatments for acute ABMR in renal allografts found 10 388 citations but only five small randomized and eight non-RCTs (Table 3). Of these trials, benefit was found in five studies evaluating plasmapheresis or immunoadsorption, and small, nonrandomized controlled studies suggested benefit from rituximab or bortezomib. An evaluation of a small group of patients from a randomized trial of kidney allograft recipients suggested that immunoadsorption (received by five patients and compared with the outcomes of five controls) was effective in reversing severe C4d-positive ABMR. However, it is important to note that immunoadsorption is not practiced in the United States.
Ironically, there are no randomized controlled studies that support the benefits of IVIG in acute ABMR, despite its common use in this context. Only one randomized controlled study has found plasmapheresis to be beneficial; two controlled studies found no benefit and one found potential harm, indicating that the role of plasmapheresis for the treatment of acute ABMR remains under debate. Uncontrolled or controlled nonrandomized studies support a role for rituximab, bortezomib, plasmapheresis and IVIG. However, the relative importance of these therapies is difficult to assess because treatment strategies were not standardized, doses and frequencies were not similar, and the specific drugs were combined with other agents.
One-year results were recently reported from a phase III, multicenter, randomized, placebo-controlled trial (RITUX ERAH) that examined the effect of rituximab (combined with plasmapheresis, IVIG, corticosteroids, tacrolimus and mycophenolate mofetil) on a composite measure of graft loss or absence of improvement of renal function at day 12, in patients with biopsy-proven acute ABMR. ABMR occurred after a median of 35.5 days, with no advantage of rituximab over control for the graft loss or renal function outcome.
Eculizumab was recently used for the treatment of multidrug-resistant ABMR, but there are no randomized controlled studies to confirm the efficacy of this expensive drug. In summary, efficacy data for the treatment of acute ABMR are of very low quality, and larger RCTs and dose–response studies are needed to fully evaluate therapies in this setting. In the absence of strong evidence to support consensus guidelines for the treatment of ABMR, the Kidney Disease: Improving Global Outcomes Transplant Work Group recommends the use of corticosteroids, plasmapheresis, IVIG, anti-CD20 antibodies and lymphocyte-depleting antibodies alone or in combination (Figure 4).
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Figure 4.
Therapeutic modalities for ABMR. ABMR, antibody-mediated rejection; APC, antigen-presenting cell; IVIG, intravenous immunoglobulins.
Chronic ABMR
Chronic ABMR is a more difficult condition to treat because irreversible tissue damage has occurred in the setting of severely compromised graft survival. A small-scale retrospective study of rituximab combined with standard maintenance immunosuppression (including prednisone, mycophenolate mofetil and calcineurin inhibitors) in 31 patients with chronic ABMR had encouraging results, with partial therapeutic response and an increase in median graft survival in the rituximab-treated group compared with the control group (685 days vs. 439 days, respectively). The outcomes within the rituximab group were dichotomous, with significantly different median survival time in responders compared with nonresponders and control patients, though there were no pathologic parameters that distinguished any subset of patients.
Clinical trials of rituximab for the treatment of chronic ABMR are ongoing or recruiting patients (NCT00476164 [RituxiCAN-C4] in the United Kingdom and NCT00307125 in the United States).
New Directions and Future Perspectives
Despite the important role of ABMR in patient morbidity and mortality after renal transplantation, our current understanding of the pathogenesis and pathologic phenotypes of ABMR is limited. Evidence supports an important role for DSA in acute and chronic ABMR. However, not all DSA detected by current assays cause injury in the allograft and not all ABMR phenotypes cause rapid allograft failure. Similarly, C4d has significant limitations as a biomarker of ABMR. It will therefore be essential to determine risk stratification strategies for DSA, C4d and ABMR phenotypes to guide preventive and therapeutic approaches, including plasmapheresis, IVIG and anticomplement and anti-B/plasma cell therapies.
Treatment options for ABMR are being informed by growing awareness of the complex role played by B cells in acute ABMR and chronic allograft dysfunction and the underlying biological processes. B cell lineages are now known to have multiple negative effects on the alloimmune response, including antigen presentation to T cells, the production of cytokines supporting T cell activation, antibody production and tertiary lymphoid organ and lymphatic vessel formation. Donor-specific B cells can be detected in peripheral blood using HLA-binding tetramers, and these tetramers may also represent a potential therapeutic agent to deplete donor-specific B cells. Strategies currently used in transplantation to deplete B cells or inhibit B cell activation are rATG, alemtuzumab and rituximab. However, despite the short-term depletion of B cells, alemtuzumab is associated with altered phenotypic and functional properties of the repopulated cells, which may contribute to increased rates of ABMR. The maintenance immunosuppressant belatacept may provide indirect inhibition of B cells through costimulatory blockade of CD80 and CD86, as this disables the stimulation of CD28, a mediator of antibody production by B cells and B cell proliferation. However, belatacept is not under evaluation as a treatment for ABMR.
Limited clinical trial evidence suggests that the proteasome inhibitor bortezomib (which induces plasma cell apoptosis) may be useful in combination with plasmapheresis to reduce anti-HLA antibodies in sensitized patients and to treat ABMR following renal transplantation. Other investigational B cell-depleting therapies include potent anti-CD20 antibodies (e.g. ofatumumab and ocrelizumab) and an anti-CD22 antibody (epratuzumab). Agents targeting the BAFF pathway, which costimulates B cell survival and expansion, are also in clinical development (e.g. atacicept and belimumab). The inhibition of antibody effector function is another interesting area of research, and some promise has already been shown by eculizumab, an anti-C5 antibody, in the prevention and treatment of ABMR.
Many of the potential treatment options for ABMR have been imported from other areas of medicine, without appropriate clinical trials in kidney transplantation; hence, there is a need for well-designed clinical trials that use standardized and contemporary diagnostic, monitoring and therapeutic strategies for ABMR. There are challenges in organizing multicenter, prospective clinical trial study groups aimed at developing agents for DSA reduction and treatment of ABMR. There is also a bias toward developing B cell/antibody-targeting drugs for indications outside of transplantation (such as oncology or rheumatology), and the FDA has highly stringent requirements for the approval and labeling of new agents in the transplantation arena. Before novel and more effective treatments become available, the close monitoring of high-risk patients and an emphasis on adherence to well-tolerated maintenance immunosuppressants are recommended to minimize the risk of ABMR.