C5b9 Deposition in Glomerular Capillaries Is Associated With Poor Kidney Allograft Survival in Antibody-Mediated Rejection.

Valentin Goutaudier,Pierre Merville,Moglie Le Quintrec,Céline René,Simon Mucha,Sylvie Delmas,Sébastien Lepreux,Jean-Emmanuel Serre,Valérie Garrigue,Jonathan Visentin,Ilan Szwarc,Vincent Pernin,Florian Garo,Georges Mourad,Hélène Perrochia,Lionel Couzi,B Paul Morgan ,Marie-Laure Bonnet ,Véronique Fremeaux‐Bacchi ,A Ramounau-Pigot

doi:10.3389/fimmu.2019.00235

Abstract

C4d deposition in peritubular capillaries (PTC) reflects complement activation in antibody-mediated rejection (ABMR) of kidney allograft. However, its association with allograft survival is controversial. We hypothesized that capillary deposition of C5b9—indicative of complement-mediated injury—is a severity marker of ABMR. This pilot study aimed to determine the frequency, location and prognostic impact of these deposits in ABMR. We retrospectively selected patients diagnosed with ABMR in two French transplantation centers from January 2005 to December 2014 and performed C4d and C5b9 staining by immunohistochemistry. Fifty-four patients were included. Median follow-up was 52.5 (34.25–73.5) months. Thirteen patients (24%) had C5b9 deposits along glomerular capillaries (GC). Among these, seven (54%) had a global and diffuse staining pattern. Twelve of the C5b9+ patients also had deposition of C4d in GC and PTC. C4d deposits along GC and PTC were not associated with death-censored allograft survival (p = 0.42 and 0.69, respectively). However, death-censored allograft survival was significantly lower in patients with global and diffuse deposition of C5b9 in GC than those with a segmental pattern or no deposition (median survival after ABMR diagnosis, 6 months, 40.5 months and 44 months, respectively; p = 0.015). Double contour of glomerular basement membrane was diagnosed earlier after transplantation in C5b9+ ABMR than in C5b9– ABMR (median time after transplantation, 28 vs. 85 months; p = 0.058). In conclusion, we identified a new pattern of C5b9+ ABMR, associated with early onset of glomerular basement membrane duplication and poor allograft survival. Complement inhibitors might be a therapeutic option for this subgroup of patients.

Highlights

Antibody-mediated rejection (ABMR) is the most common cause of allograft failure after kidney transplantation [1]
In a cohort of 54 well-phenotyped kidney transplant recipients with ABMR from two centers, we observed that these deposits were present in a subgroup of patients, mainly located in the glomeruli and always associated with complement split product C4d (C4d) deposits
membrane attack complex (C5b9)+ ABMR seems to be associated with early onset of glomerular basement membrane duplication and accelerated development of chronic glomerular lesions

Summary

Introduction

Antibody-mediated rejection (ABMR) is the most common cause of allograft failure after kidney transplantation [1]. In active ABMR, donor-specific antibodies (DSA) bind to graft endothelium, and activate complement-dependent and -independent mechanisms that recruit natural killer (NK) cells, neutrophils and macrophages which contribute to inflammatory lesions [peritubular capillaritis (PTC), glomerulitis], cellular necrosis and thrombotic microangiopathy. In chronic active ABMR, a repetitive pattern of thrombotic events and inflammatory changes result in endothelial cell injury and allograft matrix remodeling, such as transplant glomerulopathy [2]. C4d accumulation along PTC—which reflects the ability of the DSA bound to the surface of endothelial cells to activate the classical complement pathway—is recognized as a tissue footprint marker in ABMR [3, 4]. Lefaucheur et al [7] showed that ABMR in patients with predominant DSA IgG3 subclass—which is the most able to activate the complement cascade—was associated with the poorest graft survival

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