Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection

N Engl J Med. 2005 Feb 10;352(6):558-69. doi: 10.1056/NEJMoa035717.


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

Methods: 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.

Results: 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-kappaB. 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.

Conclusions: 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.

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers / pharmacology
  • Angiotensin II Type 1 Receptor Blockers / therapeutic use
  • Animals
  • Autoantibodies / blood*
  • Combined Modality Therapy
  • Disease Models, Animal
  • Female
  • Graft Rejection / immunology*
  • Graft Rejection / pathology
  • Graft Rejection / therapy
  • HLA Antigens / immunology*
  • Humans
  • Hypertension / immunology
  • Immunoglobulin G / blood
  • Immunoglobulins, Intravenous / therapeutic use
  • Kidney / blood supply
  • Kidney / immunology
  • Kidney / pathology
  • Kidney Transplantation / immunology*
  • Losartan / pharmacology
  • Losartan / therapeutic use
  • Male
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Phosphorylation
  • Plasmapheresis
  • Rats
  • Rats, Inbred F344
  • Rats, Inbred Lew
  • Receptor, Angiotensin, Type 1 / immunology*
  • Transcription Factors / metabolism
  • Transplantation, Homologous / immunology


  • Angiotensin II Type 1 Receptor Blockers
  • Autoantibodies
  • HLA Antigens
  • Immunoglobulin G
  • Immunoglobulins, Intravenous
  • Receptor, Angiotensin, Type 1
  • Transcription Factors
  • Mitogen-Activated Protein Kinase 3
  • Losartan