Work

Functional activity of anti-endothelin type A receptor antibodies as a predictive tool of allograft injury in pediatric kidney transplantation

Year: 2026

Type: article

Abstract: Background: Antibody-mediated rejection remains the leading cause of kidney allograft failure in pediatric recipients. While non-HLA antibodies targeting G protein-coupled receptors, particularly anti-endothelin-1 type A receptor (ETAR) antibodies, have been implicated in allograft injury, their functional activity and independent pathogenic role in pediatric kidney transplantation remain poorly characterized. Methods: In this study involving 46 pediatric kidney transplant recipients, anti-ETAR antibodies were quantified and their functional activity assessed using a β-arrestin-based luminometric bioassay in ETAR-transfected CHO cells. Furthermore, IgG-induced migration of T-lymphocytes and NK-92 cells was evaluated by chemotaxis assay. Renal function was monitored longitudinally. Predictive models of eGFR decline between consecutive follow-up visits were developed using restricted cubic spline regression with bootstrap validation. Results: Patient-derived IgG exhibited concentration-dependent agonistic activity on ETAR, including samples with anti-ETAR IgG below the standard positivity threshold (17 U/mL). Moreover, IgG enhanced endothelin-1-induced receptor activation, independently of anti-ETAR antibody levels. IgG from pediatric transplant recipients with elevated anti-ETAR levels significantly increased T-lymphocyte and NK-92 cell migration, irrespective of the presence of anti-HLA antibodies. Anti-ETAR IgG levels were associated with immune cell migration and with the decline in eGFR (Spearman ρ = 0.52). In multivariable modeling, however, antibody concentration retained no validated predictive information after bootstrap optimism correction, whereas IgG-induced T-cell migration remained associated with eGFR decline after adjustment for time since transplantation and for HLA donor-specific antibodies (DSA). Conclusion: In pediatric kidney transplant recipients, anti-ETAR antibodies are functionally active irrespective of their levels, promoting receptor signaling and immune cell recruitment associated with graft function deterioration. These results suggest that functional assessment, particularly T-cell migration, may provide complementary information beyond antibody concentration and warrants further investigation as a potential approach to risk stratification.

Source: Frontiers in Immunology

DOI: 10.3389/fimmu.2026.1925567