This retrospective multicenter cohort study across 31 liver transplant centers in 15 countries evaluated long-term outcomes — including histological graft injury, rejection, and mortality — in 287 adult and pediatric patients (223 adults, 64 children) who achieved complete immunosuppression withdrawal (ISW) for ≥12 months after liver transplantation.
ISW was achieved in only 0.46% of the reference LT population; median time from LT to ISW was 9.4 years, with 7.8 years of post-withdrawal follow-up. Metabolic benefits were notable: diabetes dropped from 34.1% to 19.7% and hypertension from 58.7% to 31.4%. Among 108 patients with paired biopsies, 43.5% achieved operational tolerance, but 30.5% had worsening fibrosis and 22.2% had new-onset inflammation. Five-year overall survival was 93%; no patient lost their graft to immune-mediated causes, and histological changes did not significantly impact mortality (fibrosis HR=1.77 [95%CI 0.63–4.96]; inflammation HR=1.46 [95%CI 0.39–5.49]).
- Paired biopsies were available in only 37.6% of patients, limiting histological conclusions. - Retrospective design with inherent selection bias — ISW was far more common in clinical trial participants (53%), so findings may not generalize to routine practice. - ISW represented only 0.46% of the reference LT population, suggesting heavy selection and possible survivor bias.
Complete ISW after liver transplant appears safe in highly selected patients, with meaningful metabolic gains and no immune-mediated graft loss, though mild histological changes occur in roughly one-third. Clinicians should consider ISW primarily in structured trial or protocol settings until broader eligibility criteria are defined.
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