Functional activity of anti-endothelin type A receptor antibodies as a predictive tool of allograft injury in pediatric kidney transplantation
8 affiliations
- 1Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova
- 2Transplant Immunology Laboratory, Institute of Pediatric Research “Città della Speranza”
- 3Unit of Biostatistics, Epidemiology and Public Health, Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova
- 4Laboratory of Immunopathology and Molecular Biology of the Kidney, Department of Women’s and Children’s Health, University of Padova
- 5Institute of Pediatric Research Città della Speranza
- 6Pediatric Nephrology, Department of Women’s and Children’s Health, Padova University Hospital
- 7Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padova
- 8Transplant Immunology Unit, Padova University Hospital
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.
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BibTeX
@article{vadori2026functional,
title = {{Functional activity of anti-endothelin type A receptor antibodies as a predictive tool of allograft injury in pediatric kidney transplantation}},
author = {Marta Vadori and Ezgi Demirkilic and Corrado Lanera and Benedetta Antoniello and Susanna Negrisolo and Emanuele Vianello and Caterina Di Bella and Elisa Benetti and Emanuele Cozzi},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1925567},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1925567/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Functional activity of anti-endothelin type A receptor antibodies as a predictive tool of allograft injury in pediatric kidney transplantation
AU - Marta Vadori
AU - Ezgi Demirkilic
AU - Corrado Lanera
AU - Benedetta Antoniello
AU - Susanna Negrisolo
AU - Emanuele Vianello
AU - Caterina Di Bella
AU - Elisa Benetti
AU - Emanuele Cozzi
PY - 2026
DA - 2026/10/22
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1925567
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1925567/full
AB - 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.
SN - 1664-3224
ER -