Hydrolysis of coagulation factors by circulating IgG is associated with a reduced risk for chronic allograft nephropathy in renal transplanted patients.
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.
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, France.
Bharath
B
Wootla
Antonino
A
Nicoletti
Natacha
N
Patey
Jordan D
JD
Dimitrov
Christophe
C
Legendre
Olivier D
OD
Christophe
Alain
A
Friboulet
Srinivas V
SV
Kaveri
Sébastien
S
Lacroix-Desmazes
Olivier
O
Thaunat
D000328:Adult; D015415:Biomarkers / Q000097:blood; D001779:Blood Coagulation Factors / Q000276:immunology / Q000378:metabolism*; D016022:Case-Control Studies; D002908:Chronic Disease; D005164:Factor IX / Q000276:immunology / Q000378:metabolism; D005169:Factor VIII / Q000276:immunology / Q000378:metabolism; D015942:Factor VIIa / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D006868:Hydrolysis; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood*; D016030:Kidney Transplantation / Q000009:adverse effects / Q000276:immunology* / Q000473:pathology; D008297:Male; D010865:Pilot Projects; D011183:Postoperative Complications / Q000097:blood / Q000276:immunology* / Q000517:prevention & control; D011237:Predictive Value of Tests; D011516:Prothrombin / Q000276:immunology / Q000378:metabolism; D012189:Retrospective Studies; D012307:Risk Factors; D014184:Transplantation, Homologous
D015415:Biomarkers; D001779:Blood Coagulation Factors; D007074:Immunoglobulin G; D011516:Prothrombin; D005169:Factor VIII; D005164:Factor IX; D015942:Factor VIIa