title: M2 macrophage infiltrates in the early stages of ANCA-associated pauci-immune necrotizing GN.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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(+) cells were scored in paraffin sections counterstained with periodic acid-Schiff. Electron microscopy was 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 pauci-immune 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 from controls. 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 correlate with 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.
authors.affiliation: Departments of Pathology and.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Medicine, University of Chicago Medical Center, Chicago, Illinois; and.
authors.forename: Michael Z
authors.initials: MZ
authors.lastname: David
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hyjek
authors.affiliation: Departments of Pathology and.
authors.forename: Anthony
authors.initials: A
authors.lastname: Chang
authors.affiliation: Departments of Pathology and smmeehan414@gmail.com.
authors.forename: Shane M
authors.initials: SM
authors.lastname: Meehan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000097:blood / Q000276:immunology* / Q000473:pathology; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000032:analysis*; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D015415:Biomarkers / Q000032:analysis / Q000097:blood; D001706:Biopsy; D002196:Capillaries / Q000276:immunology / Q000473:pathology; D002633:Chemotaxis; D002648:Child; D002675:Child, Preschool; D003404:Creatinine / Q000097:blood; D005260:Female; D005921:Glomerulonephritis / Q000097:blood / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000276:immunology* / Q000648:ultrastructure; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000648:ultrastructure; D008297:Male; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D009336:Necrosis; D020556:Neutrophil Infiltration; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000032:analysis; D055815:Young Adult; D000098902:CD163 Antigen
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D015415:Biomarkers; D000098902:CD163 Antigen; D011956:Receptors, Cell Surface; D003404:Creatinine
keywords: ANCA; GN; macrophages; vasculitis