Antibodies against HLA antigens cause refractory allograft rejection with vasculopathy in some, but not all, patients.

We studied 33 kidney-transplant recipients who had refractory vascular rejection. Thirteen had donor-specific anti-HLA antibodies, whereas 20 did not. Malignant hypertension was present in 16 of the patients without anti-HLA antibodies, 4 of whom had seizures. The remaining 17 patients had no malignant hypertension. We hypothesized that activating antibodies targeting the angiotensin II type 1 (AT₁) receptor might be involved.

Activating IgG antibodies targeting the AT₁ receptor were detected in serum from all 16 patients with malignant hypertension and without anti-HLA antibodies, but in no other patients. These receptor-activating antibodies are subclass IgG1 and IgG3 antibodies that bind to two different epitopes on the second extracellular loop of the AT₁ receptor. Tissue factor expression was increased in renal-biopsy specimens from patients with these antibodies. In vitro stimulation of vascular cells with an AT₁-receptor–activating antibody induced phosphorylation of ERK 1/2 kinase and increased the DNA binding activity of the transcription factors activator protein 1 (AP-1) and nuclear factor-κB. The AT₁ antagonist losartan blocked agonistic AT₁-receptor antibody–mediated effects, and passive antibody transfer induced vasculopathy and hypertension in a rat kidney-transplantation model.

A non-HLA, AT₁-receptor–mediated pathway may contribute to refractory vascular rejection, and affected patients might benefit from removal of AT₁-receptor antibodies or from pharmacologic blockade of AT₁ receptors.