Non-HLA Antibody Induced Agonism on the Angiotensin II Type 1 Receptor in Renal Allograft Vascular Injury

The rising incidence of steroid-refractory rejections is a challenging problem in renal allotransplantation. Etiological studies implicate either an overwhelming T-cell response or, more frequently, involvement of alloantibodies. Alloantibodies induce a spectrum of histologic tubulointerstitial and vascular changes paralleled with immunohistochemical positivity for C4d along peritubular capillaries. The degree of vascular involvement seems to be a more important prognostic determinant. Fibrinoid necrosis of the arteries with secondary thrombotic occlusions is C4d negative in 50% of cases and has a worst prognosis among all allograft vascular lesions. Apart from donor-specific human leukocyte antigen antibodies, non-human leukocyte antigen antibodies reacting to arterial antigens have been speculated to be responsible for rejections in some patients. We recently reported the presence of agonistic antibodies against the angiotensin II type 1 receptor (AT1R-AA) in 16 recipients of renal allografts who had severe vascular rejection and malignant hypertension, but who did not have anti-human leukocyte antigen antibodies. The AT1R-AA appear to be non-complement-fixing autoantibodies targeting the second extracellular loop of AT1R. The AT1R-AA act as allosteric activators on AT1R and induce mediators of inflammation and thrombosis. Transfer of AT1R-AA into rats with kidney allografts induced vasculitis and hypertension, supporting the notion that AT1R-AA are not an epiphenomenon. Removal of AT1R-AA by plasmapheresis in combination with pharmacologic AT1R blockade leads to improved renal function and graft survival in AT1R-AA-positive patients. We have shown that the analysis of the subtle diagnostic and mechanistic differences may help to identify patients at particular risk and improve outcome of steroid-refractory rejections with vascular pathology. (Trends in Transplant. 2007;1:113-20) Corresponding author: Duska Dragun, [email protected]