Original ArticlesClinical Immunology and Pathology

M2 Macrophage Infiltrates in the Early Stages of ANCA-Associated Pauci-Immune Necrotizing GN

Lei Zhao, Michael Z. David, Elizabeth Hyjek, Anthony Chang and Shane M. Meehan
CJASN January 2015, 10 (1) 54-62; DOI: https://doi.org/10.2215/CJN.03230314

Article Figures & Data

Figures

  • Figure 1.
    Figure 1.

    Neutrophils, CD68+ and CD163+ macrophages, and rare CD3+ T cells are localized at sites of fibrinoid necrosis. (A) Segmental fibrinoid necrosis (FN) with capillary basement membrane perforation, fibrin thrombosis and exudation, polymorphonuclear neutrophils, mononuclear cells, and swollen extracapillary cells. (B) Segmental FN showing localization of CD68+ cells around and within the lesion. Pericapsular CD68+ cells are also evident. (C) Segmental FN showing localization of CD163+ cells in the lesion. Pericapsular CD163+ cells are prominent. (D) CD3+ cells were located primarily in the pericapsular region in glomeruli with segmental FN.

  • Figure 2.
    Figure 2.

    Macrophages are more numerous in glomeruli with FN and cellular crescents (CCs) from biopsies with pauci-immune necrotizing GN. (A) CD68+ and CD163+ macrophages are the most abundant infiltrates in glomeruli with segmental FN, exceeding polymorphonuclear neutrophils (PMNs), T cells, B cells, and natural killer cell infiltrates (data for 28 glomeruli from 14 patients; mean+SD). (B) Macrophages, PMNs, and T infiltrates are more pronounced at sites of FN and in endocapillary, extracapillary, and pericapsular sites in glomeruli with CCs. Pericapsular B cells are also more prominent in glomeruli with CCs (data for 32 glomeruli from 15 patients; mean+SD). Endo, endocapillary; Extra, extracapillary; @FN, at the site of fibrinoid necrosis; Peri, pericapsular.

  • Figure 3.
    Figure 3.

    Macrophages are the predominant infiltrates in segmental fibrinoid necrosis of all causes. Infiltrating cell populations in glomeruli with segmental FN from biopsies with (A) pauci-immune necrotizing GN compared with (B) antiglomerular basement membrane GN (10 glomeruli from five patients) and (C) immune complex–mediated GN (nine glomeruli from six patients). The distribution and phenotypes are similar in each group, suggesting common effectors of glomerular injury in FN (data presented as means+SDs). Endo, endocapillary; Extra, extracapillary; @FN, at the site of fibrinoid necrosis; Peri, pericapsular; PMN, polymorphonuclear neutrophil.

  • Figure 4.
    Figure 4.

    Macrophages are increased in normal-appearing glomeruli in PNGN compared with controls. Infiltrating cells in glomeruli of normal controls with thin basement membrane nephropathy (C N; 63 glomeruli from five patients), normal-appearing glomeruli in pauci-immune necrotizing GN (PNG N; 139 glomeruli from 17 patients), and segmental fibrinoid necrosis in pauci-immune necrotizing GN (FN; 28 glomeruli from 14 patients). There is progressive increase of (A) endocapillary, (B) extracapillary, and (C) pericapsular CD68+ and CD163+ cells with lesser infiltrates of other phenotypes (data presented as means+SDs).

  • Figure 5.
    Figure 5.

    Macrophage infiltrates in normal-appearing glomeruli from biopsies with PNGN. (A) Endocapillary and pericapsular CD68+ cells. (B) Endocapillary and pericapsular CD163+ cells. (C) Endocapillary and extracapillary CD68+ cells. (D) Endocapillary and extracapillary CD163+ cells.

  • Figure 6.
    Figure 6.

    Ultrastructural features of minute exudative fibrinoid necrosis, glomerular basement membrane perforations, and attenuations. (A) Exudative fibrinoid necrosis with glomerular basement membrane (GBM) perforation (arrows), fibrin thrombus attached to endothelium, and fibrin exudate and mononuclear inflammatory cells with long processes attached to fibrin sheaves and thrombus. (B) Early lesion with a minute GBM perforation (arrows), intracapillary mononuclear cells, and swollen epithelioid cells in Bowman’s space. (C) Endocapillary mononuclear cells extending processes through a minute GBM perforation (arrows). (D) Wrinkled redundant GBM at the mesangium (arrows) with cellular processes extending from the capillary lumen (lower middle) and mesangial cells with numerous processes extending toward the redundant GBM.

  • Figure 7.
    Figure 7.

    The distribution of ultrastructural lesions seen in biopsies with pauci-immune necrotizing GN (PNGN). Exudative lesions of fibrinoid necrosis (n=15) are shown in green, early lesions (n=8) are shown in red, and glomeruli without apparent diagnostic abnormalities (nonspecific [NS], n=12) are shown in blue. Endothelial injury, glomerular basement membrane attenuation and redundancy, podocyte injury, and mononuclear and polymorphonuclear neutrophil infiltrates are common accompaniments of severe glomerular injury and also present in less injured glomeruli from biopsies with PNGN. Lesions designated NS may, in fact, be the earliest recognizable lesions of PNGN in the correct clinical and pathologic context. EDD, electron dense deposit; FPE, podocyte foot process effacement; #GBM, glomerular basement membrane perforation; Mnc, mononuclear cell; PMN, polymorphonuclear neutrophil; W/R, wrinkling/redundancy.

Tables

  • Table 1.

    Clinical and histologic data for patients with pauci-immune necrotizing GN and controls

    PNGN (n=17)
     Mean age, yr (range)42.2 (3–74)
     Sex6 men, 11 women
     Race/ethnicity12 W, 3 L, 2 B
     Proteinuria16
     Hematuria17
     Mean serum creatinine, mg/dl (range)1.43 (0.5–6.6)
     Mean eGFR, ml/min per 1.73 m2 (range)81.3 (10.3–195.4)
     ANCA-positive14
      Anti-MPO8
      Anti-PR36
     ANCA negative3
     No. of glomeruli per biopsya14 (5–27)
     No. with segmental fibrinoid necrosis (range)2 (1–5)
     No. with cellular crescents (range)2 (1–11)
     No. with fibrous or fibrocellular crescents (range)0.53 (0–3)
     No. with normal appearance (range)10 (3–25)
     No. of globally sclerotic (range)0.6 (0–3)
     Interstitial inflammation scoreb1.1±0.8
     Tubulitis score0.7±1
     Interstitial fibrosis score0.4±0.5
     Tubular atrophy score0.4±0.5
     Acute tubular necrosis/injury0
     Arteriosclerosis score0.8±0.9
     Arteriolosclerosis score0.6±0.8
    Controls
     Anti-GBM GN (n=5)
      No. of glomeruli per biopsya10 (5–14)
      No. with segmental fibrinoid necrosis (range)2 (1–4)
      Immune complex GN (n=8)
       SLE4
       IgAN4
      No. of glomeruli per biopsya24.5 (10–45)
      No. with segmental fibrinoid necrosis (range)1.5 (1–4)
     TBMN (n=5)
      No. of glomeruli per biopsya13 (8–22)

    • PNGN, pauci-immune necrotizing GN; MPO, myeloperoxidase; PR3, proteinase 3; GBM, glomerular basement membrane; SLE, systemic lupus erythematosus; IgAN, IgA nephropathy; TBMN, thin basement membrane nephropathy; W, white; L, Latino; B, black.

    • ↵a Data given as mean (range) per biopsy.

    • ↵b Mean score using the Banff schema (0–3)±SD.

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M2 Macrophage Infiltrates in the Early Stages of ANCA-Associated Pauci-Immune Necrotizing GN
Lei Zhao, Michael Z. David, Elizabeth Hyjek, Anthony Chang, Shane M. Meehan
CJASN Jan 2015, 10 (1) 54-62; DOI: 10.2215/CJN.03230314
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