Thirty-year follow-up of immunosuppression modulation: Impact on graft fibrosis and anti-HLA antibodies after pediatric liver transplantation

Pediatric liver transplantation, while life-saving, poses long-term challenges in immunosuppression (IS) management. We retrospectively studied 26 pediatric recipients who underwent living donor liver transplantation between 1990 and 1994 and retained their original grafts for over 30 years. Based on IS status at the final follow-up, patients were categorized as IS-free (n=8), IS-resumption (n=9), or IS-continued (n=9). We analyzed liver allograft fibrosis score (LAFSc, range 0-9), donor-specific antibodies (DSA), and liver function tests. At the last follow-up, liver function tests showed no significant differences across groups. The IS-free group had a median IS cessation period of 22.8 years (range: 14.2-26.7) and demonstrated minimal fibrosis (median LAFSc=1) and low DSA prevalence, suggesting potential operational tolerance. The IS-resumption group resumed IS after a median cessation period of 7.9 years (range: 1.3-15.7) due to fibrosis progression and exhibited the highest fibrosis burden (median LAFSc=4) and frequent DSA positivity. Notably, some patients showed a tendency for fibrosis progression despite the restart of IS, suggesting possible subclinical antibody-mediated injury. The IS-continued group experienced fluctuating fibrosis (median LAFSc=1) and multiple late-onset T cell-mediated rejection episodes. Across all groups, high DSA positivity (mean fluorescence intensity >20,000) significantly correlated with advanced fibrosis. In conclusion, the IS-free group's favorable histology and antibody profile support the possibility of durable immune tolerance. Conversely, persistent fibrosis in the IS-resumption group highlights the limitations of conventional IS strategies. Serial histological evaluations and antibody monitoring would be helpful for long-term IS management in pediatric liver transplant recipients.