Multiple Hyperacute Rejections in the Absence of Detectable Complement Activation in a Patient With Endothelial Cell Reactive Antibody

Abstract

This case involves a 54-year-old patient with polycystic kidney disease and a history of hyperacute allograft rejections. Two previous compatible live donor transplants functioned immediately but failed within the first 12 h due to antibody-injury. This patient was referred for a third transplant due to decreased vascular access and progressive hypotension from uremic autonomic dysfunction. He was broadly sensitized to HLA; however, a live donor was identified through kidney paired donation for whom he had no donor-specific HLA antibody (HLA-DSA). This patient received one plasmapheresis (PP) and intravenous immunoglobulin (IVIg) treatment, anti-CD25, and anti-CD20 antibodies prior to transplant. The allograft functioned immediately but became anuric within 24 h. A biopsy revealed antibody-mediated injury in the absence of C4d. Daily PP/IVIg, a second dose of anti-CD20, and eculizumab were administered. A retrospective endothelial cell crossmatch (ECXM) was positive with serum drawn 3 days prior to transplant and these EC antibodies were enriched for IgG2 and IgG4, noncomplement activating subclasses. Postoperative day (POD) 3, HLA-DSA remained negative but a rescue splenectomy was performed. Cultured splenocytes produced antibodies that bound donor ECs but not lymphocytes. Bortezomib was initiated on POD5. Despite aggressive therapy, the allograft never regained function.

Endothelial Cell Antibodies Associated with Novel Targets and Increased Rejection

“…We and others have reported hyperacute rejections in patients positive for AECAs with no detectable HLA-DSA. 13,20 Thus, there is growing evidence that antibody-induced endothelial cell activation, independent of complement, may be sufficient for immune cell recruitment and microvascular injury. Three of the AECA targets identified in this study (endoglin, EDIL3, and FLT3) have been implicated in endothelial activation and leukocyte extravasation, and these findings are consistent with our in vitro data showing that AECA stimulation of endothelial cells results in the upregulation of adhesion and HLA molecules and the production of inflammatory chemokines and cytokines.…”

“…Subsequently, we reported that these antiendothelial cell antibodies (AECAs) are enriched for IgG2 and IgG4, which are IgG subclasses that activate complement poorly or not at all. 12,13 In contrast, identification of AECAs in recipients with broad HLA sensitization or in those undergoing HLA-incompatible transplantation was associated with an increased incidence and severity of antibody-mediated rejection (AMR).…”

Pretransplant IgG Reactivity to Apoptotic Cells Correlates With Late kidney Allograft Loss

“…However, a number of observations suggest that non-HLA reactive antibodies also contribute to pre-sensitization and may influence the overall graft outcome (7–9). Cases of early humoral rejection in the absence of detectable donor-specific antibodies (DSA) have also been reported (10, 11). In a landmark collaborative transplant study, Opelz and colleagues revealed the association between high panel reactive antibodies (PRA) before transplantation and late graft loss in recipients of kidney transplants from HLA identical siblings (12).…”

Pre-Transplant IgG Reactivity to Apoptotic Cells Correlates With Late Kidney Allograft Loss.

“…However, a number of observations suggest that non-HLA reactive antibodies also contribute to pre-sensitization and may influence the overall graft outcome (7)(8)(9). Cases of early humoral rejection in the absence of detectable donor-specific antibodies (DSA) have also been reported (10,11). In a landmark collaborative transplant study, Opelz and colleagues revealed the association between high panel reactive antibodies (PRA) before transplantation and late graft loss in recipients of kidney transplants from HLA identical siblings (12).…”