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Eculizumab as Primary Therapy for Active Antibody-mediated Rejection of Renal Allografts

A Matter of Timing, Severity, and Donor-specific Antibodies

Haas, Mark MD, PhD1

doi: 10.1097/TP.0000000000002640
Commentaries
Free

1 Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.

Received 14 January 2019. Revision received 16 January 2019.

Accepted 17 January 2019.

Correspondence: Mark Haas, MD, PhD, Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048. (mark.haas@cshs.org).

Despite 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 panel-reactive antibodies continue to experience low rates of transplantation.1 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.2

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,3 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).4 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.5

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.5 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.6 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.6 However, by 2 years posttransplantation, there was no difference in death-censored graft survival between Ecu-treated 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.7,8 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.7,8

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 al9 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.9 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.9

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 al9 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 al9 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 AMR are more amenable to primary Ecu therapy than later and more severe lesions is illustrated in Figure 1. In this figure, the early case of active AMR with mild MVI responds to Ecu with resolution of MVI; by contrast, a case of later active AMR with more severe MVI shows no response, with persistent glomerulitis and development of TG. Finally, levels and properties of DSA are likely to be vital. In +CM graft recipients who received Ecu during the first year posttransplantation, a persistently high B-cell flow cytometric crossmatch (BFCM) was associated with a higher incidence of TG at 1 year, and graft losses were only seen in those patients with a high (≥300) BFCM at transplantation.7,8 Interestingly, the presence of IgG3 DSA, which strongly activates the classical pathway of complement, was also associated with increased graft loss in +CM graft recipients treated with Ecu, although all patients with IgG3 DSA also had a high baseline BFCM. However, in a separate, multicenter study of 116 recipients of +CM renal allografts treated with either Ecu or plasma exchange plus intravenous immunoglobulin as prophylaxis against development of AMR, Ecu-treated patients had a decreased 3-month incidence of AMR; this protective effect of Ecu was observed only in patients with C1q-binding DSA at transplantation and not in those with non-C1q-binding DSA.10

FIGURE 1

FIGURE 1

In summary, the study of Tan et al9 defines a limited set of renal allograft recipients in whom Ecu is likely to be an effective primary therapy for AMR—highly sensitized patients with a negative, low, or possibly moderate baseline BFCM and early active AMR due to a rebound in DSA levels, particularly with minimal to mild MVI. Further studies are needed to determine if the efficacy of Ecu therapy in such patients is affected by the complement-activating properties of the DSA present. Ecu has also been used as one component of salvage therapy for severe early active AMR failing to respond to standard anti-AMR therapy.11 However, whether Ecu has a therapeutic role in renal transplantation beyond these limited scenarios, such as in active AMR resulting from de novo DSA or in chronic active AMR, currently remains unknown.

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