Endothelin Type A Receptor Antibodies Are Associated With Angiotensin II Type 1 Receptor Antibodies, Vascular Inflammation, and Decline in Renal Function in Pediatric Kidney Transplantation

Abstract

Introduction: Autoantibody to angiotensin II type 1 receptor (AT1R-Ab) has been recognized as a non-human leukocyte antigen (HLA) antibody relevant in transplantation. Endothelin type A receptor antibody (ETAR-Ab) has been strongly associated with AT1R-Ab, but the data in kidney transplantation are scarce. Methods: We examined the relationship of ETAR-Ab and AT1R-Ab with clinical outcomes, biopsy findings, inflammatory cytokines, and HLA donor-specific antibody (DSA) in a cohort of pediatric renal transplant recipients. Sixty-five patients were longitudinally monitored for ETAR-Ab, AT1R-Ab, HLA DSA, interleukin (IL)-8, tumor necrosis factor-a, IL-1b, interferon-g, IL-17, IL-6, renal dysfunction, hypertension, rejection, and allograft loss during the first 2 years post-transplant. Results: Fifteen patients (23%) had AT1R-Ab alone, 1 (2%) had ETAR-Ab alone, 23 (35%) had both ETAR-Ab and AT1R-Ab, and 26 (40%) were negative for both antibodies at all timepoints. Having both ETAR-Ab and AT1R-Ab was associated with >30% decline in estimated glomerular filtration rate (P ¼ 0.024), arteritis (P ¼ 0.016), and elevated IL-8 levels (P ¼ 0.010), but not rejection, HLA DSA, or allograft loss. Having both antibodies resulted in greater increases in IL-8 compared with AT1R-Ab alone, even when controlled for additional clinical factors, including HLA DSA (P ¼ 0.012). Conclusion: Our study demonstrates that, in pediatric kidney transplantation, ETAR-Ab is highly associated with AT1R-Ab, but there are a subset of patients with AT1R-Ab alone. Having both antibodies is significantly associated with arteritis, elevated IL-8, and decline in renal function, and our results suggest possible interaction effects. Better understanding of this interaction may be informative in developing protocols for testing, treatment, and prevention of allograft injury.

Endothelin A Receptors Expressed in Glomeruli of Renal Transplant Patients May Be Associated with Antibody-Mediated Rejection

“…We do know that human leukocyte antigens, and, particularly, donor-specific antibodies against these antigens, play a crucial role in graft loss, but another target named non-HLA antigens (ETA receptor or AT1R receptor) may also be associated with increased incidence of antibody-mediated allograft rejection [ 34 , 35 ]. Pearl et al underlined that autoantibodies similar to the closely related G-protein‒coupled receptor, anti-ETAR, are strongly associated with anti-AT1R antibodies [ 36 ]. In our previous study in 2014, we showed that anti-ETAR antibodies are associated with worse transplant function but also with histopathological features characteristic of antibody-mediated rejection.…”

The Summarized Assessment of Endothelin A Receptor Expression in Renal Transplant Compartments Associated with Antibody-Mediated Rejection

“…It was presented that autoantibodies comparable to the closely related G-protein-coupled receptor, anti-ETAR, are correlated with anti-AT1R antibodies [ 13 ]. Furthermore, we noticed that the expression of AT1R in the tubular epithelium of the biopsy for the cause was associated with significantly higher graft loss [ 31 ].…”

“…Endothelin A receptor (ETA receptor) is now considered one of the non-HLA antigens, which may be a significant trigger in immunological response and graft loss [ 9 , 10 , 11 , 12 , 13 ].…”

The emerging field of non–human leukocyte antigen antibodies in transplant medicine and beyond

“…Displaying both antibodies elevated was significantly associated with more intimal arteritis, elevated interleukin-8, and declined kidney allograft function, suggesting synergic effects between anti-ETAR and AT1R antibodies. 51 Elevated anti-ETAR antibodies were also associated with allograft rejection and poor allograft outcome in heart, lung, liver, and composite tissue transplantation. 52 Newer non-HLA targets are exponentially emerging, including some minor histocompatibility antigens and injuryderived tissue-specific autoantigens, including Rho GDPdissociation inhibitor 2 (ARHGDIB), LIMS1, endoglin, Fmslike tyrosine kinase 3 (Flt3) ligand, intercellular adhesion molecule-4, and EGF-like repeats and discoidin I-like domain 3 (EDIL3), among numerous others.…”