M2 macrophage infiltrates in the early stages of ANCA-associated pauci-immune necrotizing GN

Abstract

Background and objectives This study examined kidney biopsies with focal segmental glomerular fibrinoid necrosis to identify early features of pauci-immune necrotizing GN and the primary effector cells mediating initial capillary injury. Design, setting, participants, & measurements Seventeen consecutive kidney biopsies with focal pauci-immune necrotizing GN, obtained over a 6-year period (2007–2012), were studied. Neutrophils and CD68+, CD163+, CD3+, CD56+, and CD20+ cellswere scored in paraffin sections counterstainedwith periodic acid–Schiff. Electron microscopywas performed in 15 of 17 biopsies and additional examples of pauci-immune necrotizing GN(n=25). Biopsies with thin basement membrane nephropathy (n=5) served as immunohistologic normal controls. Results Biopsies with pauci-immune necrotizing GN had a mean of 10 (range=3–25) normal-appearing glomeruli, a mean of 2 (range=1–5) glomeruli with segmental fibrinoid necrosis, and a mean of 2 (range=1–11) glomeruli with cellular crescents. CD68+ and CD163+ macrophages predominated at sites of fibrinoid necrosis in pauci-immune necrotizing GN, exceeding the quantity of neutrophils and T cells (mean scores [SD]=2.5 [0.7] and 2.2 [0.75] versus 0.6 [0.5] and 0.1 [0.3], respectively; P˂0.001). B and natural killer cells were rare.Normal-appearing glomeruli in pauciimmune necrotizing GN had significantly more CD68+ and CD163+ macrophages than the controls (CD68+, 0.9 [0.3] versus 0.4 [0.3]; CD163+, 1 [0.4] versus 0.4 [0.3]; P˂0.001). The quantity of other glomerular infiltrates did not differ fromcontrols. The serum creatinine level at biopsy correlated with the glomerular CD68 and neutrophil scores (r=0.74 and r=0.71, respectively; P=0.001) but did not correlatewith the extent of fibrinoid necrosis (r=0.36).Macrophages were localized at minute perforations and attenuations of the capillary basement membrane by electron microscopy. Conclusions Early pauci-immune necrotizing GN is characterized by a selective localization of CD163+ M2 macrophages at sites of glomerular fibrinoid necrosis and in normal-appearing glomeruli. These observations indicate that alternatively activated macrophages are positioned as potential effectors of glomerular injury in the early stages of pauci-immune necrotizing GN and may be potential targets for therapeutic intervention.