Chronic liver allograft rejection in a population treated primarily with tacrolimus as baseline immunosuppression: Long-term follow-up and evaluation of features for histopathological staging

Background: Predisposing factors, long-term occurrence, and histopathological changes associated with recovery or progression to allograft failure from chronic rejection (CR) were studied in adult patients treated primarily with tacrolimus. Methods: CR cases were identified using stringent criteria applied to a retrospective review of computerized clinicopathological data and slides. Results: After 1973 days median follow- up, 35 (3.3%) of 1049 primary liver allograft recipients first developed CR between 16 and 2532 (median 242) days. The most significant risk factors for CR were the number (P<0.001) and histological severity (P<0.005) of acute rejection episodes and donor age >40 years (P<0.03). Other demographic and matching parameters were not associated with CR in this cohort. Ten patients died with, but not of, CR. Eight required retransplantation because of CR at a median of 268 days. Ten resolved either histologically or by normalization of liver injury tests over a median of 548 days. CR persisted for 340 to 2116 days in the remaining seven patients. More extensive bile duct loss (P<0.01), small arterial loss (p<0.03), foam cell clusters (P<0.01) and higher total bilirubin (p<0.02) and aspartate aminotransferase (p<0.03) were associated with allograft failure from CR. Conclusions: Early chronic liver allograft rejection is potentially reversible and a combination of histological, clinical and laboratory data can be use to stage CR. Unique immunological and generative properties of liver allografts, which lead to low incidence and reversibility of early CR, can provide insights into transplantation biology.