A Banff Component Scoring-based Histologic Assessment of Bortezomib-based Antibody-mediated Rejection Therapy.

BACKGROUND: Histology remains a cornerstone for antibody-mediated rejection (AMR) diagnosis. Little data exist supporting histology for assessing therapeutic responses. This study evaluates histologic components in assessing AMR therapeutic responses. METHODS: Antibody-mediated rejection was diagnosed using Antibody Working Group criteria and Banff component scoring, and C4d staining data were analyzed. Statistics included independent and paired samples t test, χ(2), Fisher exact, or the Wilcoxon-signed rank test. Fifty-five AMR patients were analyzed. Early AMR was defined as occurring within 6 months after transplantation and treated with a single rituximab dose and 4 bortezomib doses preceded by plasmapheresis. Allograft biopsies were performed within 48 hours of treatment; repeat biopsy was performed 14 to 21 days later. RESULTS: Early AMR demonstrated histologic improvement in mean scores for acute Banff components glomerulitis (g), C4d, g+ peritubular capillaritis (ptc) and acute composite score, but showed deterioration in chronic Banff components tubular atrophy and interstitial fibrosis. Late AMR showed improved mean scores for acute Banff components tubulitis, interstitial inflammation, g, ptc, g + ptc, C4d, and acute composite score, but chronic scores did not change. Significant changes in distribution of Banff scores after treatment were observed for g, C4d, tubular atrophy, and interstitial fibrosis scores in early AMR patients and tubulitis, interstitial inflammation, g, ptc, and C4d in late AMR. CONCLUSIONS: These results show that: (1) Banff component scoring provides insights into histologic responses to AMR therapy and may provide a potential endpoint for clinical AMR trials. (2) Early and late AMR demonstrate differences in acute and chronic Banff components at the time of the AMR diagnostic biopsy, as well as differential responses to AMR therapy.

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.