American Association for the Study of Liver Diseases (AASLD)
Boston, MA, October 29-November 2, 2010,
Background and Methods: ≥15% of selected liver transplant (tx) recipients can be w eaned from all immunosuppression (IS). Allograft acceptance (tolerance) has often been defined as normal, near normal, or stably abnormal liver function tests (LFTs) 1 yr after complete IS cessation. Studies to date have lacked either pre-weaning biopsies that might predict IS withdrawal success or failure or follow-up biopsies that might signal a need to re-initiate IS. We now describe pre-weaning and follow-up biopsy findings from 19 pediatric recipients (8 females; mean entry age 8.5 yrs; mean 7.4 yrs after tx) of parental living donor allografts enrolled in an Immune Tolerance Network-sponsored IS withdraw al trial. Histopathologic findings were prospectively scored using a combination of glass slides and whole slide digital images (WSI) and differences w ere analyzed using exact Chi-square and Wilcoxon Rank Sum tests.
Results: All but 4 recipients underw ent tx for biliary atresia; 12 recipients succeeded
(S=success) in IS w ithdraw al and are now off IS for 18-39 months; 7 failed (F=failed) IS withdraw al, 4 during and 3 after w eaning. All pre-weaning biopsies showed nodular
regenerative hyperplasia (NRH) changes of varying severity. Prospectively scored pre-weaning biopsy features significantly associated w ith F included shorter time from tx to pre-w eaning biopsy (F=5.8±1.2yrs vs S=8.3±2.5yrs; p=0.03) and increased portal inflammation (none:mild F=3:4 vs S=11:1; p=0.04). Comparison of time of failure to pre-weaning biopsies showed increased RAI scores for portal inflammation (p=0.10), bile duct damage (p=0.005) and hepatocyte apoptosis (p=0.07); 7 of 7 patients w ere clinically diagnosed with acute rejection, but only 2 met Banff criteria for mild (n=1) or moderate (n=1) acute rejection. Side-by-side WSI comparison of pre-weaning and latest follow-up biopsies (mean of 35.8 months after preweaning biopsy and 26.2 months after last IS dose) showed no statistically significant differences for the 9 patients who had reached the 2-year IS-free protocol biopsy timepoint.
Conclusions: Baseline biopsies document that long-surviving living donor liver allografts show NRH and are not normal. Shorter time after tx and portal inflammation are associated with F. Rejection that occurs during or after w eaning is portal-based and associated w ith inflammation and tissue injury - observations that will guide mechanistic studies. Importantly, all nine long-term follow-up biopsies obtained thus far showed no statistically significant increase in inflammation, fibrosis or architectural distortion over 3 yrs of study participation (1 yr of weaning+2 yrs of no IS).