Requirement of protocol biopsy before and after complete cessation of immunosuppression after liver transplantation.

BACKGROUND: Operational tolerance is defined as long-term acceptance of a transplanted organ after complete cessation of immunosuppression (IS), but may not always protect against antigen-dependent changes in graft morphology. METHOD: IS free patients after living-donor liver transplantation (LDLT) underwent protocol biopsy (tolerance group [Gr-Tol]) and were evaluated for rejection and fibrosis. The degree of fibrosis was compared with those in the patients on maintenance IS group (Gr-IS) and the base line normal liver group (Gr-BS). When bridging fibrosis or progression of fibrosis was observed, IS was reintroduced or increased in Gr-Tol or in the patients in the weaning process. RESULTS: Neither acute nor chronic rejection was observed. The degree of fibrosis, however, was significantly greater in Gr-Tol than those in Gr-IS and Gr-BS. In Gr-Tol, the number of graft infiltrating FOXP3 cells was significantly increased, the interval between LDLT and biopsy plus the donor age was significantly longer, and recipient age at LDLT was significantly younger, compared with those in Gr-IS. However, none of these three parameters correlated with the degree of fibrosis. In 7 of 11 patients in whom IS was reintroduced or increased, the improvement of fibrosis was observed by the subsequent biopsy. CONCLUSION: Grafts of operationally tolerant patients after LDLT did not exhibit acute or chronic rejection, but they exhibited fibrosis. It remains elusive whether fibrosis observed in tolerant grafts is antigen dependent. The finding that after [corrected] the reintroduction or the increase of IS fibrosis was improved supported the possibility that fibrosis in operationally tolerant patients was antigen dependent.

Periportal edema and necrosis as diagnostic histological features of early humoral rejection in ABO-incompatible liver transplantation.

Humoral rejection caused by antidonor blood group A/B antibodies is one of the most important obstacles for successful ABO-incompatible liver transplantation. However, no specific morphologic features of liver biopsies to distinguish humoral rejection from other conditions such as ischemia or sepsis have been satisfactorily documented. To histologically clarify the early changes in humoral rejection, we studied 41 cases of living donor ABO-incompatible liver transplantation whose allograft biopsies during the first episode of suspected acute rejection were available within the first postoperative month. Postoperative isohemagglutinin IgM titers were x64 or more in 21 patients (51%; high-titer group) and less than x64 in 20 cases (49%; low-titer group). In the high-titer group, elevation of postoperative titers x64 or more occurred within postoperative days 5.7 +/- 4.1 (range: 1-17). An increase in the incidence of cholangitis was observed in the high-titer group (90% vs. 30%, P <.0001), as well as poorer overall graft survival than in the low-titer group (38% vs. 70%, P <.05). Seven biopsies obtained from the high-titer group within 3 days after the onset of elevation of the antibody titers and one biopsy obtained at the peak of the antibody titers demonstrated periportal edema and necrosis, neither of which was found in the low-titer group. All grafts of these patients caused massive hepatocyte necrosis or severe biliary complications. In conclusion, a high morbidity rate of ABO-incompatible liver transplantation is associated with high postoperative levels of antibody titers. Periportal edema and necrosis observed during elevation of antibody titers can be regarded as histological indications of early changes in severe humoral rejection.