Complement activation in pauci-immune necrotizing and crescentic glomerulonephritis: results of a proteomic analysis

Sanjeev Sethi, Ladan Zand, An S. De Vriese, Ulrich Specks, Julie A. Vrana, Siddak Kanwar, Paul Kurtin, Jason D. Theis, Andrea Angioi, Lynn Cornell, Fernando C. Fervenza

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Abstract

Background: Complement activation plays an important role in the pathophysiology of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), although it remains unclear which pathway is activated. Whether pauci-immune necrotizing crescentic glomerulonephritis (pauci-immune GN) with negative ANCA serology is part of the spectrum of AAV or a different disease entity is essentially unknown.

Methods: We used proteomic analysis to delineate the complement profile in a series of 13 kidney biopsies of patients with pauci-immune GN, with either proteinase 3 (PR3) (five patients) or myeloperoxidase (MPO) antibodies (four patients) or with consistently negative ANCA serology (four patients). Immunofluorescence staining of glomeruli was essentially negative in the PR3-ANCA and MPO-ANCA groups, while a mild staining for C3 was seen in the ANCA-negative cases. No electron-dense deposits were found in the PR3-ANCA and MPO-ANCA groups, but mesangial and few subepithelial deposits were clearly present in the ANCA-negative specimens.

Results: Mass spectrometry revealed low spectra numbers for C3 and immunoglobulins in both PR3-positive and MPO-positive patients with minimal or no C4 and C9. In contrast, larger spectra numbers for C3, moderate spectra numbers for C9, complement factor H-related protein-1 and low spectra numbers for C4, C5 and immunoglobulins were found in the ANCA-negative cases.

Conclusion: While complement activation is noted in AAV, the complement activation appears to be more prominent in the ANCA-negative glomerulonephritis. The larger amount of C3 and moderate amount of C9 in the ANCA-negative glomerulonephritis implies activation of the alternate and terminal pathway of complement, suggesting that this entity may be caused or promoted by a genetic or acquired defect in the alternative pathway.

Original languageEnglish (US)
Pages (from-to)i139-i145
JournalNephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
Volume32
Issue number1
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

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Keywords

  • alternative pathway
  • anti-neutrophil cytoplasmic antibody
  • complement
  • crescentic glomerulonephritis
  • mass spectrometry
  • pauci-immune

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