Can’t Always Blame Anti-HLA Antibody: Angiotensin II Type 1 Receptor (AT1R) Antibody and Renal Allograft Vascular Rejection

The Banff 2013 classification provides a definition of antibody-mediated rejection (ABMR) based on microvascular inflammation in the absence of C4d staining. 50% of ABMR cases with severe vascular changes are C4d negative suggesting the involvement of non-HLA antibodies. Angiotensin II type 1 receptor (AT1R) is a membrane-bound receptor that is found on endothelial and immune cells. Binding of anti-AT1R antibodies (Abs) to AT1R induces similar physiological and inflammatory effects as angiotensin II including aldosterone secretion, vasoconstriction and inflammatory cytokines activation resulting in atherosclerosis and renal tissue damage. Anti-AT1R antibodies are associated with pre-eclampsia, hypertension, pulmonary arterial hypertension and biopsy-proven acute vascular rejection in the absence of donor-specific antibody (DSA). The importance of anti-AT1R Abs as an alternative mechanism for graft injury and rejection has received increased recognition recently. However, in the absence of any causal studies to determine the mechanism of anti-AT1R Abs mediated graft damage and failure, the additive value of checking anti-AT1R Abs routinely pretransplantation or at the time of graft dysfunction remains controversial, especially in the absence of more specific treatment. Based on the current evidence, antiAT1R Abs could be considered as a supplementary test where atypical pathology or graft dysfunction exists in the absence of DSA or in the presence of malignant hypertension. Further study is needed to determine if anti-AT1R Abs are an independent risk factor for graft dysfunction and loss as well as to explore the clinical utility of screening and therapeutic protocols.

Author(s): M. Khaled Shamseddin

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