Liver allograft antibody-mediated rejection with demonstration of sinusoidal C4d staining and circulating donor-specific antibodies

Abstract

The importance of antibody-mediated rejection (AMR) in ABO-compatible liver transplantation is controversial. Here we report a prospective series of liver recipients with a preoperative positive crossmatch. To establish the diagnosis of AMR in liver recipients, the criteria described for kidney allografts were adopted. In approximately 10% of 197 liver transplants, we observed a positive T and B cell flow crossmatch before transplantation. Fifteen of 19 patients converted to negative crossmatches early after transplantation and displayed normal liver function while they were on routine immunosuppression. Four patients maintained positive crossmatches. Three of the 4 met the criteria for AMR and showed evidence of graft dysfunction, the presence of donor-specific antibodies (DSAs), morphological tissue destruction with positive C4d linear staining on the graft sinusoidal endothelium, and improved function with attempts to eliminate DSAs. A persistently positive crossmatch after liver transplantation may lead to early, severe AMR and liver failure. C4d staining in the liver sinusoidal endothelium should alert one to the possibility of AMR. In our experience, patients with a positive crossmatch should have it repeated at 2 weeks and, if it is positive, again at 3 to 5 weeks. Recipients with an unknown preoperative crossmatch who develop early cholestasis of unclear etiology should be crossmatched or tested for the presence of DSAs to evaluate for AMR. Liver

Prevalence, Incidence and Risk Factors for Donor-Specific Anti-HLA Antibodies in Maintenance Liver Transplant Patients

“…The difference observed between Fontana et al's (15) study and ours is probably because we used a more sensitive assay. Recently, Miyagawa-Hayashino et al (16) assessed the prevalence of DSAs among stable pediatric LT patients who had survived for >5 years: they found a prevalence of 48% at 11 years (min-max: [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] posttransplantation. This high prevalence of DSAs is probably related to the very long follow-up in this Japanese study (16).…”

Complement component 4d immunohistochemistry in the assessment of liver allograft biopsy samples: Applications and pitfalls

“…We congratulate Aguilera et al for detailing the specifics of their IHC protocol, and we strongly encourage them and others who are interested in C4d staining in liver tissue to perform IF and IHC staining in parallel in order to determine whether there is a good correlation between the 2 techniques. As we stated in our previous articles, 3,4 we believe that discussions of liver transplantation using the term AMR need to include documentation of DSAs with single antigen beads, detailed histological findings, and the specifics of the observed liver graft dysfunction (eg, transaminitis, cholangitis, and tests for ruling out anatomic abnormalities) as well as any improvements in graft function with specific therapies. This follow-up should also include changes in the relative DSA levels and a careful discussion of the methodology used in the laboratory.…”

“…As Bellamy indicates, our group has documented complement component 4d (C4d) staining in ABO-compatible liver allograft recipients in 2 recent publications. 3,4 There is 1 point in Bellamy's discussion that needs to be corrected: our patients should not be described as having hyperacute rejection but rather should be classified as having acute antibody-mediated rejection (AMR). In our articles, we have been very careful to use the previously established consensus conference definition of AMR for solid organ grafts 5 : graft dysfunction, histological evidence of AMR (as defined by Demetris et al 6 for liver grafts), donor-specific alloantibodies (DSAs) in the recipient's serum, and strong staining for C4d on endothelial cells.…”

Intravenous immunoglobulins in liver transplant patients: Perspectives of clinical immune modulation

“…The implementation of immune modulation protocols including high doses of IVIg, plasmapheresis and potent immunosuppressive drugs resulted in attenuation of the humoral alloimmune response and in acceptable outcome in highly sensitized kidney and heart transplants [127][128][129][130][131][132][133] . The prognostic relevance of a positive T-lymphocytotoxic crossmatch in LT is, however, still discussed controversially [127,[134][135][136][137][138][139][140][141][142][143][144] . Originally, the liver was considered to be less susceptible to immunologic attacks.…”

“…Therefore, pretransplant T-cell crossmatch was either not required, or did not affect the indication for LT [127] . Nowadays, there is increasing evidence that a highly positive lymphocytotoxic crossmatch promotes the risk of acute and chronic allograft rejection, cholestatic liver dysfunction and impaired allograft and patient survival [141][142][143][144][145][146][147] . Direct clinical implications of the organ shortage, like pre-LT rising transfusion need, prolonged waiting times and increasing MELD scores, have shown to promote the risk of immunologic imbalance [127,134,148] .…”