Alexandre Loupy1, Dewi Vernerey2, Denis Viglietti2, Olivier Aubert2, Jean-Paul Duong Van Huyen2, Jean-Philippe Empana2, Patrick Bruneval2, Denis Glotz2, Christophe Legendre2, Xavier Jouven2, Carmen Lefaucheur2. 1. From the Paris Translational Research Center for Organ Transplantation and Cardiovascular Disease, INSERM, UMR-S970, Paris, France (A.L., D. Viglietti, O.A., J.-P.D.V.H., J.-P.E., P.B., D.G., C. Legendre, X.J., C. Lefaucheur); Paris Descartes University, Sorbonne Paris Cité and Necker Hospital (A.L., J.-P.D.V.H., C. Legendre) and Department of Transplantation, Saint-Louis Hospital (D. Viglietti, D.G., C. Lefaucheur), Assistance Publique - Hôpitaux de Paris, Paris, France; Methodology Unit (EA 3181) CHRU de Besançon, Besançon, France (D. Vernerey); Department of Pathology, Necker Hospital, Paris, France (J.-P.D.V.H.); and Department of Pathology (P.B.) and Department of Cardiology (X.J.), Georges Pompidou European Hospital, Paris, France. alexandreloupy@gmail.com. 2. From the Paris Translational Research Center for Organ Transplantation and Cardiovascular Disease, INSERM, UMR-S970, Paris, France (A.L., D. Viglietti, O.A., J.-P.D.V.H., J.-P.E., P.B., D.G., C. Legendre, X.J., C. Lefaucheur); Paris Descartes University, Sorbonne Paris Cité and Necker Hospital (A.L., J.-P.D.V.H., C. Legendre) and Department of Transplantation, Saint-Louis Hospital (D. Viglietti, D.G., C. Lefaucheur), Assistance Publique - Hôpitaux de Paris, Paris, France; Methodology Unit (EA 3181) CHRU de Besançon, Besançon, France (D. Vernerey); Department of Pathology, Necker Hospital, Paris, France (J.-P.D.V.H.); and Department of Pathology (P.B.) and Department of Cardiology (X.J.), Georges Pompidou European Hospital, Paris, France.
Abstract
RATIONALE: The role of circulating antibodies in addition to traditional cardiovascular risk factors in the development of accelerated arteriosclerosis and their long-term clinical consequences have not been demonstrated. OBJECTIVE: We investigated the role of circulating antibodies in accelerated arteriosclerosis and the role of immune-associated arteriosclerosis in graft and patient survival and the occurrence of major adverse cardiovascular events. METHODS AND RESULTS: This was an observational prospective cohort study that included 1065 kidney transplant patients (principal cohort, n=744; validation cohort, n=321) between 2004 and 2010. Participants were assessed for traditional cardiovascular risk factors and circulating anti-human leukocyte antigen (HLA) antibodies. All patients underwent allograft biopsies to assess arteriosclerotic lesions and endothelial activation, endarteritis, and complement deposition. In the principal cohort, 250 (33.6%) patients had severe arteriosclerosis (luminal narrowing >25% via fibrointimal arterial thickening). Circulating donor-specific anti-HLA antibodies were significantly associated with severe allograft arteriosclerosis (hazard ratio, 2.9; P<0.0001), independently of traditional risk factors. Patients with severe arteriosclerosis and anti-HLA antibodies (n=91, 12.2%) demonstrated allograft endothelial activation, endarteritis, and complement deposition. High levels of anti-HLA antibodies and their complement binding capacity were associated with increased severity of arteriosclerosis. Patients with antibody-associated severe arteriosclerosis had decreased allograft survival and increased mortality (P<0.0001); they exhibited a 2.5- and 4.1-fold increased risk of major adverse cardiovascular events compared with patients who had severe arteriosclerosis without antibodies and patients with minimal arteriosclerosis, respectively (P<0.0005). Circulating donor-specific anti-HLA antibodies were significantly associated with occurrence of major adverse cardiovascular events (hazard ratio, 2.4; P=0.0004), independently of traditional risk factors. CONCLUSIONS: Circulating antibodies are major determinants of severe arteriosclerosis and major adverse cardiovascular events, independent of traditional cardiovascular risk factors.
RATIONALE: The role of circulating antibodies in addition to traditional cardiovascular risk factors in the development of accelerated arteriosclerosis and their long-term clinical consequences have not been demonstrated. OBJECTIVE: We investigated the role of circulating antibodies in accelerated arteriosclerosis and the role of immune-associated arteriosclerosis in graft and patient survival and the occurrence of major adverse cardiovascular events. METHODS AND RESULTS: This was an observational prospective cohort study that included 1065 kidney transplant patients (principal cohort, n=744; validation cohort, n=321) between 2004 and 2010. Participants were assessed for traditional cardiovascular risk factors and circulating anti-human leukocyte antigen (HLA) antibodies. All patients underwent allograft biopsies to assess arteriosclerotic lesions and endothelial activation, endarteritis, and complement deposition. In the principal cohort, 250 (33.6%) patients had severe arteriosclerosis (luminal narrowing >25% via fibrointimal arterial thickening). Circulating donor-specific anti-HLA antibodies were significantly associated with severe allograft arteriosclerosis (hazard ratio, 2.9; P<0.0001), independently of traditional risk factors. Patients with severe arteriosclerosis and anti-HLA antibodies (n=91, 12.2%) demonstrated allograft endothelial activation, endarteritis, and complement deposition. High levels of anti-HLA antibodies and their complement binding capacity were associated with increased severity of arteriosclerosis. Patients with antibody-associated severe arteriosclerosis had decreased allograft survival and increased mortality (P<0.0001); they exhibited a 2.5- and 4.1-fold increased risk of major adverse cardiovascular events compared with patients who had severe arteriosclerosis without antibodies and patients with minimal arteriosclerosis, respectively (P<0.0005). Circulating donor-specific anti-HLA antibodies were significantly associated with occurrence of major adverse cardiovascular events (hazard ratio, 2.4; P=0.0004), independently of traditional risk factors. CONCLUSIONS: Circulating antibodies are major determinants of severe arteriosclerosis and major adverse cardiovascular events, independent of traditional cardiovascular risk factors.
Authors: Xuedong Wei; Nicole M Valenzuela; Maura Rossetti; Rebecca A Sosa; Jessica Nevarez-Mejia; Gregory A Fishbein; Arend Mulder; Jayeeta Dhar; Karen S Keslar; William M Baldwin; Robert L Fairchild; Jianquan Hou; Elaine F Reed Journal: Am J Transplant Date: 2020-05-22 Impact factor: 8.086
Authors: Shivani Garg; Christie M Bartels; Karen E Hansen; Weixiong Zhong; Yabing Huang; Michael G Semanik; Maureen Smith; Sarah E Panzer Journal: Arthritis Care Res (Hoboken) Date: 2021-03 Impact factor: 4.794
Authors: A Loupy; M Haas; K Solez; L Racusen; D Glotz; D Seron; B J Nankivell; R B Colvin; M Afrouzian; E Akalin; N Alachkar; S Bagnasco; J U Becker; L Cornell; C Drachenberg; D Dragun; H de Kort; I W Gibson; E S Kraus; C Lefaucheur; C Legendre; H Liapis; T Muthukumar; V Nickeleit; B Orandi; W Park; M Rabant; P Randhawa; E F Reed; C Roufosse; S V Seshan; B Sis; H K Singh; C Schinstock; A Tambur; A Zeevi; M Mengel Journal: Am J Transplant Date: 2017-01 Impact factor: 8.086