CHRONIC LIVER ALLOGRAFT REJECTION: CLINICAL FEATURES AND OUTCOME  

Index

RH Wiesner, AJ Demetris, and EC Seaberg for the NIDDK Liver Transplantation Database

Mayo Clinic, Rochester, MN, and University of Pittsburgh, Pittsburgh, PA.

Chronic liver allograft rejection (CR) remains a major cause of graft failure and indication for retransplantation.

Aim: To determine the incidence, identify clinical risk factors, and determine outcome associated with the development of CR.

Methods: The Liver Transplantation Database was used to study a cohort of 870 consecutive primary liver transplant recipients who survived 15 days or more without retransplantation (4/90 to 6/94). The group consisted of 11% children (<16 years). Patients were followed for a median of three years. CR was diagnosed using established histologic criteria; all index biopsies were reviewed by a single pathologist (AJD). Incidence rates were reported as 3-year cumulative percents.

Results: The incidence of CR was 4% (N=33), which occurred a median of 193 days posttransplantation (range 18-1,446 days). CR occurred more frequently in children <1 year of age (17%), less often in patients >60 years (1%) [p<0.001], and more often in females than males (6% vs. 3%) [p=0.04]. CR occurred more often in recipients with acute fulminant hepatitis (16%), biliary atresia (15%), autoimmune hepatitis (11%), malignancy (11%), and less often in recipients with alcoholic liver disease (1%), hepatitis C (1%), and primary biliary cirrhosis (1%) [p<0.001]. Other significant risk factors included pretransplant encephalopathy (p<0.001), negative cytomegalovirus serology (p=0.02), young donor age (p=0.02), non-Caucasian donor (19%) [p=0.004], and fewer HLA A+B+DR matches (p<0.05). Histologic severity of acute rejection and the number of episodes were significantly associated with CR (p<0.001). In patients who developed moderate-to-severe acute rejection, 61% developed CR (relative risk 72.5, p<0.0001). Immunosuppressive therapy utilized (cyclosporine vs. tacrolimus) in a double- or triple-drug regimen and the development of cytomegalovirus infection were not associated with CR. Multivariate analysis identified pretransplant encephalopathy, autoimmune hepatitis, non-Caucasian donor, fewer HLA A+DR matches, histologic severity, and number of episodes of acute rejection as independent risk factors. Of the 33 grafts with CR, 21 failed usually within one year after diagnosis; 2 partially resolved; and 10 completely resolved.

Conclusion: The overall three-year incidence of CR was 4%. Nearly two-thirds of the hepatic grafts with CR failed. Defining risk factors for the development of CR will be helpful in identifying high-risk recipients who require higher levels of immunosuppression.

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