Review of Bortezomib Treatment of Antibody-Mediated Rejection in Renal Transplantation

Significance: Development of donor-specific antibodies (DSA) after kidney transplantation is associated with reduced allograft survival. A few strategies have been tested in controlled clinical trials for the treatment of antibody-mediated rejection (AMR), and no therapies are approved by regulatory authorities. Thus development of antihumoral therapies that provide prompt elimination of DSA and improve allograft survival is an important goal. Recent Advances: Proteasome inhibitor (PI)-based regimens provide a promising new approach for treating AMR. To date, experiences have been limited to off-label bortezomib use in AMR. Key findings with PI-based therapy are that they provide effective primary and rescue therapy for AMR by prompt reduction in immunodominant DSA and improvements in histologic and renal function. Early and late AMR differ immunologically and in response to PI therapy. Bortezomib-related toxicities in renal transplant recipients are similar to those observed in the multiple myeloma population. Critical Issues: Although preliminary evidence with PI therapy for AMR is encouraging, the evidence is limited. Larger, prospective, randomized controlled trials with long-term follow up are needed. Advancement in endpoints of clinical trial designs and rigorous clinical trials with more standardized adjunct therapies are also required to explore the risks and benefits of AMR treatment modalities. Future Directions: In the next few years, new PIs are likely to be introduced and new approaches would be developed for achieving synergy with PIs. The ultimate goal will be to develop a regimen that delivers reliable, rapid, complete, and durable elimination of DSA with an acceptable safety profile. Antioxid. Redox Signal. 21, 2401-2418.