Complement blockade with eculizumab to treat acute symptomatic humoral rejection after heart transplantation

Abstract

Antibody-mediated rejection (AMR) is a major barrier preventing successful discordant organ xenotransplantation, but it also occurs in allotransplantation due to anti-HLA antibodies. Symptomatic acute AMR is rare after heart allograft but carries a high risk of mortality, especially >1 year after transplant. As complement activation may play a major role in mediating tissue injury in acute AMR, drugs blocking the terminal complement cascade like eculizumab may be useful, particularly since "standards of care" like plasmapheresis are not based on strong evidence. Eculizumab was successfully used to treat early acute kidney AMR, a typical condition of "active AMR," but showed mitigated results in late AMR, where "chronic active" lesions are more prevalent. Here, we report the case of a heart recipient who presented with acute heart failure due to late acute AMR with eight de novo donor-specific anti-HLA antibodies (DSA), and who fully recovered allograft function and completely cleared DSA following plasmapheresis-free upfront eculizumab administration in addition to thymoglobulin, intravenous immunoglobulins (IVIG), and rituximab. Several clinical (acute onset, abrupt and severe loss of graft function), biological (sudden high-level production of DSA), and pathological features (microvascular injury, C4d deposits) of this cardiac recipient are shared with early kidney AMR and may indicate a strong role of complement in the pathogenesis of acute graft injury that may respond to drugs like eculizumab. Terminal complement blockade should be further explored to treat acute AMR in recipients of heart allografts and possibly also in recipients of discordant xenografts in the future.

Keywords: antibody-mediated rejection; complement; eculizumab; heart transplantation; xenotransplantation.

FIGURE 1

(A) Allograft function (LVEF) and donor‐specific antibodies (DSA) strength (MFI) over time. Day 1 = AMR diagnosis. Day ‐32 = time of routine evaluation 1 year after transplant. (B) C4d staining (immunochemistry) showing intense complement deposition in capillaries = immune‐pathological criterium for AMR (pAMR I+). (C) CD68 staining (immunochemistry) showing intra‐capillary macrophage deposition = immune‐pathological criterium for AMR (pAMR I+). (D) Hematoxillin‐eosin staining showing intra‐vascular activated mononuclear cells = morphologic criterium for AMR (pAMR H+) (pAMR I+ and pAMR H+ together = pAMR2). H&E, 400x. (E) Hematoxillin‐eosin staining. Control biopsy (5 months) showing complete AMR recovery. H&E, 200x (F) Coronary angiography 32 days before AMR with no CAV (G) Coronary angiography 5 months after AMR with no CAV