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Previous Volume 352:558-569 February 10, 2005 Number 6 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Editorial by Ingelfinger, J. R. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

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-B. 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.

Source Information

From the Departments of Nephrology (D.D., L.F., M.N.-K., D.E., K.B., H.-H.N.) and Pathology (B.R.), and the Center for Cardiovascular Research (D.D., M.N.-K., U.K., T.U.), Charité University Hospital; the Franz Volhard Clinic and HELIOS Klinikum (J.H.B., R.D., I.M., F.C.L.); the Max Delbrück Center for Molecular Medicine (D.N.M., R.P., G.W.); and the HLA Laboratory (C.S.) — all in Berlin; and the Institut de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Strasbourg, France (J.H.).

Address reprint requests to Dr. Dragun at the Department of Nephrology and Transplantation, Charité University Hospital, Campus Mitte, Schumannstr. 20–21, 10117 Berlin, Germany, or at duska.dragun{at}charite.de.

Full Text of this Article

Related Letters:

Angiotensin II Type 1–Receptor Activating Antibodies in Renal-Allograft Rejection
Hilbrands L., Hoitsma A., Wetzels J., Ansari M. J., Tinckam K., Chandraker A., Dragun D., Fritsche L., Luft F. C.
Extract | Full Text | PDF  
N Engl J Med 2005; 352:2027-2028, May 12, 2005. Correspondence

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