LAUSR

D increased utilization of paired kidney exchange and implementation in the United States of a new system for allocation of deceased donor kidneys granting waiting list priority to highly sensitized transplant candidates, those candidates with the highest levels of panelreactive antibodies continue to experience low rates of transplantation. For such patients, especially those with a potential living donor, desensitization followed by positive crossmatch (+CM) transplantation remains a viable option that is associated with better survival when compared to continuation of dialysis. However, +CM renal transplantation is associated with high rates of early active antibody-mediated rejection (AMR) that can lead to early graft loss and a higher likelihood of developing lesions of chronic AMR, most notably transplant glomerulopathy (TG, which is well documented to be associated with subsequent graft loss. Patients with TG have historically responded poorly to standard treatment for active AMR, although studies with newer agents have been more encouraging, at least for patients with TG plus active microvascular inflammation (MVI, chronic active AMR). Still, the best therapy for TG is clearly prevention of this lesion, and this involves both prevention and early aggressive treatment of active AMR, including early lesions commonly seen in recipients of +CM grafts and almost invariably leading to development of TG if not promptly treated. Complement activation via the classical pathway is involved in the pathogenesis of many cases of AMR, as manifest by C4d deposition in peritubular capillaries, although a significant fraction of even early biopsies showing active AMR are C4d-negative. To this end, investigators from the Mayo Clinic examined the efficacy of eculizumab (Ecu), a humanized monoclonal antibody against complement component C5, in preventing AMR during the first-year posttransplantation in recipients of +CM renal transplants who underwent pretransplant plasmapheresis. These investigators found that during this interval, only 2/26 (7.7%) of patients receiving Ecu during the initial 1–12 months posttransplantation (depending on levels of donor-specific antibodies [DSAs] after each 4-wk period) developed active AMR, compared with 21/51 (41.2%) historical control recipients of +CM grafts who did not receive Ecu but were otherwise similarly treated. However, by 2 years posttransplantation, there was no difference in death-censored graft survival between Ecutreated patients and historical controls, and similar findings were also seen after 5 years and 7 years, where graft survival in both +CM cohorts was significantly worse than that in recipients of negative CM grafts. All graft losses in the Ecu-treated patients were attributed to chronic AMR, and no differences in TG or histologic markers of active AMR (peritubular capillaritis, glomerulitis) were seen between Ecu-treated patients and +CM controls on biopsies performed 1, 2, and 5 years posttransplantation, despite many Ecu-treated patients having a decline in DSA levels. Noting the efficacy of Ecu in reducing early active AMR, Mayo Clinic investigators examined whether Ecu might be an effective primary treatment for active AMR associated with an abrupt increase in DSA levels within the first 30 days posttransplantation. In this issue of Transplantation, Tan et al report findings from 15 such patients who developed AMR (biopsy proven in 13) a median of 10 days posttransplantation and were treated for this with Ecu, plus plasmapheresis in 12 patients. In this cohort, active AMR was seen in only 2/12 patients with follow-up biopsies performed after 3–6 months and in 3/10 12-month biopsies, with TG seen in only 1 biopsy at each time point. There were no graft losses after a follow-up interval of 12–19 (median 13) months, and at last follow-up median estimated glomerular filtration rate was 52 mL/min, compared to 21 mL/min at the time of AMR diagnosis. What do these findings tell us about the utility of Ecu in treatment of AMR? First, timing appears to be important. All patients with active AMR in the study of Tan et al were diagnosed and had Ecu initiated during the first month posttransplantation, the majority within the first 2 weeks. Second, pathology is likely to matter. All 13 biopsies of Tan et al showing early AMR were C4d-positive, indicating complement activation. Furthermore, 7 of these biopsies showed minimal or very mild MVI, with the sum of Banff (glomerulitis + peritubular capillaritis) scores ≤1, likely reflecting an early and/or mild lesion of AMR. The hypothesis that early and mild lesions of active ISSN: 0041-1337/19/10311-2219