Immediate and Catastrophic Antibody-Mediated Rejection in a Lung Transplant Recipient With Anti–Angiotensin II Receptor Type 1 and Anti–Endothelin-1 Receptor Type A Antibodies

Abstract

Preexisting donor-specific anti-HLA antibodies (DSAs) have been associated with reduced survival of lung allografts. However, antibodies with specificities other than HLA may have a detrimental role on the lung transplant outcome. A young man with cystic fibrosis underwent lung transplantation with organs from a suitable deceased donor. At the time of transplantation, there were no anti-HLA DSAs. During surgery, the patient developed a severe and intractable pulmonary hypertension associated with right ventriular dysfunction, which required arteriovenous extracorporeal membrane oxygenation. After a brief period of clinical improvement, a rapid deterioration in hemodynamics led to the patient's death on postoperative day 5. Postmortem studies showed that lung specimens taken at the end of surgery were compatible with antibody-mediated rejection (AMR), while terminal samples evidenced diffuse capillaritis, blood extravasation, edema, and microthrombi, with foci of acute cellular rejection (A3). Immunological investigations demonstrated the presence of preexisting antibodies against the endothelin-1 receptor type A (ETA R) and the angiotensin II receptor type 1 (AT1 R), two of the most potent vasoconstrictors reported to date, whose levels slightly rose after transplantation. These data suggest that preexisting anti-ETA R and anti-AT1 R antibodies may have contributed to the onset of AMR and to the catastrophic clinical course of this patient

Could pulmonary arterial hypertension patients be at a lower risk from severe COVID‐19?

“…3 There is also evidence that donor-specific ETa and anti-angiotensin II antibodies may lead to antibody-mediated rejection in renal, cardiac, and most recently, a fulminant post-lung transplant-associated capillaritis. 4 We speculate that there be a favorable interaction of ERAs or Ang II receptor blockade with such antibodies should they exist. Last, in models of acute inflammatory pancreatitis, ERAs are beneficial by counteracting endothelin-mediated stimulation of NFKB, IL-2 and IL-6.…”

Antibodies Against Angiotensin II Receptor Type 1 and Endothelin A Receptor Are Associated With an Unfavorable COVID19 Disease Course

“…The observed pulmonary vascular damage in COVID19 patients resembles antibody-mediated rejection (AMR) after lung transplantation. Although AMR is usually caused by the formation of antibodies directed at the donor specific human leucocyte antigen (HLA) system, it has also been associated with non-HLA auto-antibodies against the G-protein coupled receptors Angiotensin II Receptor type 1 (AT1R) and Endothelin receptor Type A (ETAR) ( 4 , 5 ). The similarity between vasculopathy in severe COVID19 and AMR after lung transplantation raised the question whether similar autoimmune mechanisms contribute to COVID19 pathogenesis.…”

Hyperacute graft dysfunction in an orthotopic heart transplant in the presence of non-HLA antibodies

“…Anti‐AT1R antibodies have been implicated in hypertension, malignant hypertension, preeclampsia, and both chronic allograft rejection and hyperacute rejection in renal transplantation . More recently, anti‐AT1R antibody was implicated in a case of hyperacute lung allograft rejection . Endothelial cell dysfunction may arise from the actions of anti‐EC or anti‐AT1R antibodies independent of the complement pathway.…”