0041-1337/03/7507-1020/0 TRANSPLANTATION Vol. 75, 1020–1025, No. 7, April 15, 2003 Copyright © 2003 by Lippincott Williams & Wilkins, Inc. Printed in U.S.A. THE ABSENCE OF CHRONIC REJECTION IN PEDIATRIC PRIMARY LIVER TRANSPLANT PATIENTS WHO ARE MAINTAINED ON TACROLIMUS-BASED IMMUNOSUPPRESSION: A LONG-TERM ANALYSIS 1 ASHOK JAIN, 2 GEORGE MAZARIEGOS, 2 RENU POKHARNA, 2 MARIA PARIZHSKAYA, 3 RANDEEP KASHYAP, 2 BEVERLY KOSMACH-PARK, 2 AMY SMITH, 2 JOHN J. FUNG, 2 AND JORGE REYES 2,4 Background. Although the outcome of liver trans- plantation has improved significantly during the past two decades, graft loss caused by chronic rejec- tion after liver transplantation still occurs in 2% to 20% of recipients. The overall incidence of chronic rejection is also reported to be low in adult recipi- ents, and risk factors have been identified. Chronic rejection is associated with the inability to maintain baseline immunosuppression. Additionally, the di- agnoses of primary biliary cirrhosis, primary scle- rosing cholangitis, autoimmune hepatitis, hepatitis B virus, and hepatitis C virus, common indications for liver transplantation in adults, are associated with a higher incidence of chronic rejection. Fortu- nately, these diagnoses are rarely seen in children. Little is known about chronic rejection in long-term pediatric liver transplant survivors. The purpose of this longitudinal study was to examine the incidence of biopsy-proven chronic rejection in long-term sur- vivors of primary pediatric liver transplantation un- der tacrolimus-based immunosuppression. Methods. From October 1989 to December 1992, 166 children (boys95, girls71; mean age5.02.9 years) received a primary liver transplant. These patients were followed until March 2000 with a mean follow-up of 90.8 (range, 7.4 –10.4) years. All liver biopsy specimens and explanted grafts were evaluated for evidence of chronic rejection using the International Banff Criteria. Results. The mortality rate during the follow-up pe- riod was 15% (n25). Retransplantation was required in 11% (n18) of recipients. Actuarial patient and graft survival rates at 10 years were 84.9% and 80.1%, re- spectively. There were 535 liver biopsy samples avail- able for evaluation, including the 18 explanted allo- grafts. Biopsy specimens of three other functioning allografts showed evidence of chronic rejection. Im- munosuppression had been discontinued or drasti- cally reduced in these recipients because of life- threatening infections, noncompliance, or both. On restoring baseline immunosuppression, all three chil- dren had normalized liver function and the allografts were maintained; the liver transplant patients who are alive currently have normal liver functions. Conclusion. The findings of this study suggest that chronic rejection does not occur in pediatric liver transplant recipients receiving tacrolimus-based im- munosuppression, provided baseline immunosuppres- sion is maintained. Chronic rejection is a significant cause of graft failure after liver transplantation, with a reported incidence of 2% to 20% (1–3). The prevention and treatment of chronic rejection re- mains elusive and can lead to graft failure requiring retrans- plantation. After retransplantation for chronic rejection, a recurrence rate as high as 90% has been reported (4). Chronic rejection, occurring under cyclosporine (CsA)-based therapy, was controlled or reversed in up to 70% of cases after the initiation of tacrolimus-based therapy (5–8). Relatively little is known about the incidence of chronic rejection in long-term liver transplant survivors receiving tacrolimus-based immunosuppression. In a recent review of adult liver transplant recipients who were receiving tacroli- mus (n=1048), 5252 biopsy specimens were evaluated, with a mean follow-up of 6 years. The incidence of chronic rejection leading to graft loss or death was 1.8%. Biopsy specimens revealed chronic rejection in an additional 1.3%; however, optimizing baseline immunosuppression led to recovery in all patients. Several risk factors for the development of chronic rejection were identified including the presence of viral in- fections such as hepatitis C virus (HCV) or hepatitis B virus (HBV); autoimmune processes such as primary biliary cir- rhosis (PBC), primary sclerosing cholangitis (PSC), and au- toimmune hepatitis (AI); and the inability to maintain ther- apeutic baseline immunosuppression because of concurrent life-threatening infections, Epstein-Barr virus (EBV), post- transplant lymphoproliferative disease (PTLD), or noncom- pliance (9). Because HCV, HBV, PBC, PSC, and AI are rare indications for liver transplantation in children, little is known about the relationship between these risk factors and chronic rejection in pediatric liver transplant recipients re- ceiving tacrolimus. A recent study of 326 pediatric liver allo- grafts with a follow-up of 3 to 12 years reported that graft loss, directly related to acute or chronic rejection, was not encountered (10). The purpose of this longitudinal study was to examine the incidence of biopsy-proven chronic rejection in primary pediatric liver transplantation under tacrolimus- based immunosuppression. MATERIALS AND METHODS Cadaveric liver transplantation was performed in 166 consecutive children (boys=95, girls=71) from October 1989 through December 1992 under tacrolimus-based immunosuppression. Immunosuppres- sive protocols have been described previously (11). Mean age at 1 Data was presented at The American Transplant Congress, Washington, D.C., April 2002. 2 Thomas E. Starzl Transplantation Institute Department of Surgery, Children’s Hospital of Pittsburgh, Pittsburgh, PA. 3 Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA. 4 Address correspondence to: Jorge Reyes, M.D., Children’s Hos- pital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh PA, 15213. Received August 28, 2002. Revision Requested October 14, 2002. Accepted October 25, 2002. 1020 DOI: 10.1097/01.TP.0000056168.79903.20