Glomerular C3c deposition and intravascular macrophage accumulation in early humoral renal allograft rejection signifies a poor short‐term outcome

Abstract

C4d deposition in the walls of peritubular capillaries is considered the key phenomenon in the histopathological diagnosis of humoral, i.e. antibody-mediated, allograft rejection. We have earlier proposed that deposition of C3c in glomerular capillaries and simultaneous intravascular accumulation of macrophages in allografts with immediate or early humoral rejection indicates a potentially serious condition with very poor prognosis. The clinical outcome of 45 cadaveric grafts with this phenomenon among 1960 renal allografts transplanted at our centre during 1984-1999, and the recipients of the contralateral kidneys, was retrospectively evaluated. Graft failure occurred in 44/45 grafts within 3 weeks, with graft loss in 33/45 (77%) within 4 months and 37/45 (82%) within 1 year. From the contralateral kidneys, 5/33 (15%) were lost within 1 year. In a recent series of early biopsies, we recognised that of 13 cases showing C4d positivity in peritubular capillaries but lacking C3c in glomeruli, 10/13 (77%) were still functioning after 4 months. The mean number of CD68(+) macrophages per glomerular profile, i.e. the glomerular macrophage index, shows a significant difference between C4d(+)C3c(-) and C4d(+)C3c(+) cases (p<0.001). Our results indicate the existence of a clinically important subgroup of early humoral rejection with particular morphological features.

Is Early Complement Activation in Renal Transplantation Associated with Later Graft Outcome?

“…There are limited studies using immunohistochemistry or immunofluorescence staining for evaluation of complement mediated injury in human biopsies indicating a relevance of C3c in the pathogenesis of allograft rejection. Glomerular C3c deposition in early humoral renal allograft rejection was associated with a poor short-term outcome [34,35]. In contrast, the role of C3d on graft outcome is unclear.…”

Antibody-Mediated Renal Allograft Rejection

“…In the most comprehensive study, C3d was found only in conjunction with C4d in sensitized patients (8). Neutrophils in PTC or features of thrombotic microangiopathy correlated with C3d deposition in one study (8) but not in two others (8,29 prognosis than C4d alone (30). The interpretation of C3d is complicated by the common presence of C3d along the tubular basement membrane, commented on by Haas et al (8).…”

Glomerular macrophage index (GMI) in kidney transplant biopsies is associated with graft outcome

“…Biopsies were fixed in 4% buffered paraformaldehyde ("formalin"), transported to the laboratory, post-fixed under constant shaking for at least 1 h, embedded in paraffin, sectioned (3-4 μm), and stained with hematoxylin-eosin, periodic acid Schiff, Ag-Jones, trichrome, and elastin van Gieson. All biopsies were immunostained as previously described 20 for CD68 (Dako, N1576, Copenhagen, Denmark) and C4d…”

“…8 Glomerulitis is a well-established criterion for ABMR, [15][16][17] and a high number of glomerular macrophages has been shown to correlate with renal transplant rejection and worse prognosis, mainly in ABMR. 8,13,[18][19][20][21] The glomerular macrophage index (GMI), the average number of glomerular macrophages in a biopsy, was first investigated by Magil et al in native glomerular diseases 22 and later in transplants. 13,23 The aim of our study was to investigate the level of GMI in a large cohort of post-transplantation biopsies and to determine the impact of GMI on kidney transplant outcomes.…”