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* Centre de Recherche des Cordeliers, Université Pierre et Marie Curie-Paris 6, Unité Mixte de Recherche S 872, Université Paris Descartes, Unité Mixte de Recherche S 872, Institut National de la Santé et de la Recherche Médicale, Unité 872, Paris;
Service d’anatomopathologie, Hôpital Necker, Assistance Publique-Hôpitaux de Paris, Paris;
Service de Transplantation Rénale et de Soins Intensifs, Hôpital Necker, Assistance Publique-Hôpitaux de Paris, and Université René Descartes, Paris;
Unité 770, Institut National de la Santé et de la Recherche Médicale, Université Paris-Sud, Le Kremlin-Bicêtre;
¶ Centre National de la Recherche Scientifique Unité Mixte de Recherche 6022, Compiègne Technological University, Compiègne; and
|| Service de Transplantation Rénale et d’Immunologie Clinique, Hôpital Edouard Herriot, and Université Claude Bernard Lyon I, Lyon, France
Chronic allograft nephropathy (CAN), a major cause of late allograft failure, is characterized by a progressive decline in graft function correlated with tissue destruction. Uncontrolled activation of the coagulation cascade by the stressed endothelium of the graft is thought to play an important role in the pathophysiology of CAN. In this study, we demonstrate that circulating IgG from renal-transplanted patients are endowed with hydrolytic properties toward coagulation factors VIII and IX, but fail to hydrolyze factor VII and prothrombin. The hydrolytic activity of IgG was reliably quantified by the measure of the hydrolysis of a fluorescent synthetic substrate for serine proteases: proline-phenylalanine-arginine-methylcoumarinamide (PFR-MCA). A retrospective case-control study indicated that an elevated hydrolysis rate of PFR-MCA by circulating IgG correlated with the absence of CAN lesions on protocol graft biopsy performed 2 years posttransplantation. We propose that circulating hydrolytic IgG may counterbalance the procoagulation state conferred by the activated endothelium by disrupting the amplification loop of thrombin generation which is dependent on factors VIII and IX. Interestingly, low rates of PFR-MCA hydrolysis, measured 3 mo posttransplantation, were predictive of CAN at 2 years down the lane. These data suggest that PFR-MCA hydrolysis may be used as a prognosis marker for CAN in renal-transplanted patients.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Université Pierre et Marie Curie, and Agence Nationale de la Recherche (ANR-05-MRAR-012). O.T. is supported by the Fondation pour la Recherche Médicale and the Fondation du Rein; B.W. is the recipient of a fellowship from Laboratoire Français du Fractionnement et des Biotechnologies (Les Ulis, France).
2 Address correspondence and reprint requests to Dr. Olivier Thaunat, Service de Transplantation Rénale et d’Immunologie Clinique, Hôpital Edouard Herriot, 5 place d’arsonval, 69437 Lyon, Cedex 03, France. E-mail address: olivier.thaunatpastu{at}free.fr
3 Abbreviations used in this paper: CAN, chronic allograft nephropathy; IVIg, intravenous Ig; FVIII, factor VIII; FIX, factor IX; FVII, factor VII; PFR-MCA, proline-phenylalanine-arginine-methylcoumarinamide; ROC, receiver operating characteristic; wCAN, without CAN.
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