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

Meghan H Pearl; Lucia Chen; Rim ElChaki; David Elashoff; David W Gjertson; Maura Rossetti; Patricia L Weng; Qiuheng Zhang; Elaine F Reed; Eileen Tsai Chambers

doi:10.1016/j.ekir.2020.09.004

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

Kidney Int Rep. 2020 Sep 6;5(11):1925-1936. doi: 10.1016/j.ekir.2020.09.004. eCollection 2020 Nov.

Authors

Affiliations

¹ Division of Pediatric Nephrology, Department of Pediatrics, University of California Los Angeles, Los Angeles, California, USA.
² Department of Medicine Statistics Core, University of California Los Angeles, Los Angeles, California, USA.
³ Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California, USA.
⁴ Division of Pediatric Nephrology, Department of Pediatrics, Duke University, Durham, North Carolina, USA.
⁵ Department of Surgery, Duke University, Durham, North Carolina, USA.

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-α, IL-1β, interferon-γ, 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 = 0.024), arteritis (P = 0.016), and elevated IL-8 levels (P = 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 = 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.

Keywords: angiotensin II type 1 receptor antibody; cytokine; endothelin type A receptor antibody; human leukocyte antigen donor-specific antibody; pediatric nephrology; transplantation.

Abstract

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