Prevalence of non-HLA antibodies and their association with FIB-4 index-based fibrosis risk in pediatric liver transplant recipients with long-term graft survival (>10 years).

BACKGROUND

While donor-specific antibodies against human leukocyte antigens (HLA-DSA) are recognized contributors to allograft injury, non-HLA antibodies are increasingly implicated in solid-organ transplant rejection. However, evidence in pediatric liver transplantation remains limited. We aimed to identify anti-HLA and non-HLA antibodies associated with liver fibrosis risk in long-term pediatric liver transplant recipients.

METHODS

This cross-sectional study included 75 pediatric liver recipients transplanted between 2006-2014 (median 13.8 years), 15 pediatric patients on liver-transplant waiting list and 22 healthy adult controls (HC). Serum samples were tested for non-HLA, anti-HLA class-I, class-II and anti-MHC class-I chain-related protein A (MICA) antibodies by multiplex microsphere-based flow cytometry (Luminex Technology). Liver fibrosis risk was assessed using the Fibrosis-4 (FIB-4) index. Univariate and multivariate logistic regression analyses evaluated associations between antibody positivity and FIB-4 index elevation.

RESULTS

Liver-transplant patients showed significantly higher frequencies of eight non-HLA specificities compared to HC: C-X-C motif chemokine ligand 9 (CXCL9), CXCL10, CXCL11, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), glial cell line-derived neurotrophic factor (GDNF), leucine-rich repeat transmembrane protein 2 (FLRT2), interferon gamma (IFNG) and vimentin (VM). Anti-HLA class-II antibody prevalence was significantly higher post-transplantation (44% vs. 0%, p=0.002). In multivariate analysis, anti-GDNF antibody positivity was independently associated with increased FIB-4 values (odds ratio [OR] 5.61, p=0.04), while female sex showed a protective effect (OR 0.23, p=0.02).

CONCLUSIONS

Eight non-HLA antibodies are prevalent in pediatric liver-transplant recipients and waitlisted candidates. Anti-GDNF antibodies were independently associated with higher FIB-4 values in long-term pediatric liver transplant recipients, suggesting a potential biomarker role in liver injury that requires validation in larger longitudinal cohorts.