Angiotensin II Type 1 Receptor (AT1R) Antibody and Renal Allograft Vascular Rejection

Journal of Nephrology and Urology is an Open Access peer-reviewed publication that discusses current research and advancements in diagnosis and management of kidney disorders as well as related epidemiology, pathophysiology and molecular genetics.

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The expansion of sophisticated technologies and the implementation of more effective immunosuppressive regimens have resulted in more specific HLA tissue typing, anti-HLA antibody and donor-specific antibody (DSA) detection and better renal allograft survival. However, while the risk of T-Cell mediated rejection (TCMR) has decreased substantially, kidney transplant recipients continue to experience antibody-mediated rejection (ABMR) even among HLA-identical sibling grafts, suggesting involvement of non-HLA antigens.

The Banff 2007 diagnostic criteria for HLA ABMR requires pathological evidence of microvascular inflammation and injury (such as glomerulitis, peritubular capillaritis or chronic transplant glomerulopathy), deposition of the complement degradation product C4d in peritubular capillaries, and demonstration of posttransplant DSA.

Post-transplant DSA is more common in acute and chronic rejection compared to stable recipients and is frequently associated with C4d deposition in biopsies. C4d positive rejection is diagnosed in 75% of recipients with post-transplant DSA, but only in 2% in recipients with no DSA. However, DSA can be produced in the absence of clinical or pathological rejection, leaving the value of these antibodies as a diagnostic tool unclear

Diffuse C4d staining in peritubular capillaries is a specific but insensitive marker of HLA-mediated ABMR that is associated with poor graft survival. However, 40-50% of vascular rejection episodes are C4d negative, suggesting involvement of non-HLA antibodies. Many non-HLA antibodies are auto-antibodies directed against endothelial cells, tubular epithelial cells, podocytes, mesangial cells and monocytes 

he Banff 2013 classification provides a definition of ABMR based on microvascular inflammation in the absence of C4d staining. As many as 50% of ABMR cases involve severe vascular changes but are C4d negative, suggesting involvement of non-HLA antibodies. Many non-HLA antibodies are auto- antibodies directed against endothelial, tubular epithelial and inflammatory cells.

The importance of anti-AT₁R Abs has received increased recognition recently. Anti-AT₁R Abs is associated with preeclampsia, hypertension, and pulmonary hypertension. Anti-AT₁R Abs is also associated with biopsy-proven acute vascular rejection in the absence of DSA. Anti-AT₁R Abs is therefore proposed as an alternative mechanism for graft injury and rejection.

Although monitoring of pre-transplant and posttransplant anti-AT₁R Abs has been suggested in order to identify patients at increased risk of non-HLA acute rejection and graft failure, there are in fact no causal studies to determine the mechanism of anti-AT₁R Ab mediated tissue damage and graft failure. Additional prospective studies are required to confirm whether peri-transplant use of ARB/Losartan should be considered in order to reduce the risk of vascular rejection in patients with anti-AT₁R Abs.

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Journal of Nephrology and Urology