Acute liver allograft antibody-mediated rejection: An inter-institutional study of significant histopathological features

Abstract

Acute antibody-mediated rejection (AMR) occurs in a minority of sensitized liver transplant recipients. Although histopathologic characteristics have been described, a generalizable scoring system used to trigger a more in-depth analysis is needed to screen for this rare but important finding. Toward this goal, we created a training and validation cohort from 3 high volume liver transplant programs of putative acute AMR and control cases that were evaluated blindly by 4 independent transplant pathologists. The evaluations were performed on H&E sections alone without knowledge of serum DSA results nor C4d stains. Characteristics strongly correlated with acute AMR included portal eosinophilia (OR=4.37, p<0.001), portal vein endothelial cell hypertrophy (OR=2.88, p<0.001), and eosinophilic central venulitis (OR=2.48, p=0.003). These and other characteristics were incorporated into models created from the training cohort alone. The final Acute-AMR (aAMR) score exhibited a strong correlation with acute AMR in the training (OR=2.86, p<0.001) and validation cohort (OR=2.49, p<0.001). SPSS tree classification was used to select 2 cutoffs, one that optimized specificity at a score >1.75 (sensitivity = 34%, specificity = 87%) and a second that optimized sensitivity at a score >1.0 (sensitivity = 81%, specificity = 71%). In conclusion, routine histopathological features of the aAMR score can be used to screen for acute AMR on routine H&E in liver transplant biopsies, a diagnosis that requires substantiation by donor-specific HLA alloantibody testing, C4d staining, and exclusion of other insults.

Antibody-mediated rejection across solid organ transplants: manifestations, mechanisms, and therapies

“…The utility of CD68 staining in lung and liver is questionable. Rather AMR is characterized by a monocytic, neutrophilic, or eosinophilic infiltrate in these organs (31,33,95,118), again with inflammatory cells adherent to microvascular endothelial cells.…”

Advancing Transplantation

“…105,106 This resilience is facilitated by numerous mechanisms, but several are of critical importance. The liver's size, affording it a 100-fold microvasculature compared to the kidney, regenerative capacity, ability to secrete soluble class I antigen, and the existence of hypocomplementemia (secondary to liver dysfunction) serve to mollify the effects of preformed DSAs.…”

“…Key histopathologic characteristics include portal vein endothelial cell hypertrophy, portal eosinophilia and eosinophilic venulitis (Figure 10). 106 The presence of lymphocytic portal inflammation and lymphocytic venulitis without the aforementioned features favours cellular rejection as opposed to combined cellular-and AMR; acute AMR is almost never found in isolation. In 1 retrospective, multicenter study, evaluation for these key features using the acute AMR score allowed for acute AMR determination with 81% sensitivity and 71% specificity.…”

“…In 1 retrospective, multicenter study, evaluation for these key features using the acute AMR score allowed for acute AMR determination with 81% sensitivity and 71% specificity. 106 However, when acute AMR is suspected, one must also test for DSA, stain for C4d, and rule out other causes of a similar injury pattern. 107 Clinical features, such as falling platelets (secondary to consumption) or otherwise unexplained graft dysfunction, should also trigger suspicion.…”

“…172 In light of the possibly deleterious effect of the association between DSA and under immunosuppression, views regarding the role of ACR changed; ACR is now less acceptable and this new perspective is supported by published literature. 105,106,108 In a study of 493 patients, those with tacrolimus trough levels greater than 7 ng/mL, measured on the day of protocol biopsy, experienced fewer moderate/severe rejection episodes during the first 2 weeks posttransplant compared with those with tacrolimus trough levels 7 ng/mL or lower (Figure 12). 169 Data from this study indicate that trough levels of 7 to 10 ng/mL are efficacious in preventing AR and are associated with longer-term graft survival compared with patients whose trough levels are outside that window.…”