Fibrillary GN

on

Notes from Handbook of GN 

Font: IBM Plex Sans Arabic 

INTRODUCTION 
1. Rare
2. 1st described in 1977 by Rosenman and Eliakim
3. Recognized as a distinct entity by Duffy et al in 1983
4. Alpers coined the term 'FGN' in 1987 when describing 7 patients with non-CONGOphilic fibrillar glomerular deposits
5. Traditional definition of FGN 
  • glomerular deposition of Congo-red negative- 
  • RANDOMly oriented fibrils
  • that lack a hollow centre at magnification <30K. 
  • stain with immunoglobulins (Igs) by immunofluoroscence (IF)
6. initially thought to be idiopathic
7. recent series revelaed association in some patients with
  • Autoimmune disease
  • malignancy
  • Hepatitis C 
8. No curative treatment for FGN
9. Rituximab
  • stabilize kidney function
  • ↓ proteinuria in some patients
The conclusion = Treatment of patients with two courses of rituximab over a span of 6 months was associated with stabilization of renal function but did not result in a significant change in proteinuria and with no change in the DNAJB9 levels.



10. Pathogenesis remains unknown
11. DNAJB9 : highly sensitive and specific tissue marker for FGN

PATHOGENESIS: 
1. Difficult to interpret or understand
2. Glomerular deposits in most cases stain for IgG, kappa light chain, and Lambda light chain. 
3. Also exhibit IgG subclass restriction (usually IgG4)
4. Ultrastructural immunogold labeling studies revealed localization of IgG, Kappa and Lambda to the FGN fibrils -> immune-complex type GN (in which the IgG deposits are polymerized into fibrils due to their homogenous nature)
5. 2 research groups from Mayo Clinic and University of Washington findings 
  • Through the use of laser microdissection-assisted liquid chromatography-tandem mass spectrometry (LMD/MS-MS), identified DNAJB9 in the glomeruli of almost all tested cases of FGN but not in cases of renal amyloidosis , a large variety of non FGN glomerular diseases or in normal controls. 
  • DNAJB9 : the 4th most abundant protein identified in FGN glomeruli 
  • FGN glomeruli exhibited a 6 fold of overabundance of DNAJB9 compared to amyloidosis glomeruli. 
  • colocalization of DNAJB( and IgG in the mesangium and GBM by dual IF
  • Ultrastructural immunogold labelling revealed localization of DNAJB9 to individual FGN fibrils, but not to ITG microtubules or amyloid fibrils
  • 98% sensitivity 99% specificity
PATHOLOGY: 
LM Patterns: 
1. mesangial proliferative and sclerosing GN (MesGN) pattern: most common
  • mesangial expansion by deposits
  • mesangial hypercellularity
  • increase in mesangial matrix
2. MPGN pattern : minority. This is likely an advanced stage of disease, as a transition from MesGN to MPGN over time. 
  • GBM double contour and cellular interposition 
  • which is almost always associated with mesangial sclerosis, deposits and hypercellularity. 
3. membranous GN pattern: Rare
  • Owing to a global thickening of the GBM by subepithelial and intramembranous inflitration of fibrils with spike formation
4. Endocapillary proliferative GN 
  • leucocyte infiltration and endocapillary hypercellularity leading to occlusion of the peripheral capillaries. 
5. Focal Crescents: 17 -50% of cases

6. Diffuse Crescents: 5% of cases

LM Staining: 
1. Glomerular mesangial deposits appear glassy
2. Variable PAS positive
3. Silver negative
4. Congo red negative: although up to 4% is positive

Concurrent Glomerulopathy : 17 % of FGN cases
  • most common: Diabetic nephropathy
  • 2nd common: IgA nephropathy 
IF/IH: 

  1. Principle:

    • Immunofluorescence (IF): In IF, fluorescent dyes are used to visualize the presence of specific proteins. Antibodies labeled with fluorochromes bind to target proteins, and the emitted fluorescence is detected under a fluorescence microscope.

    • Immunohistochemistry (IHC): IHC involves the use of enzymes or chromogens to produce a visible color reaction at the site of antibody binding. Enzymes like horseradish peroxidase or alkaline phosphatase catalyze a reaction that produces a colored precipitate, allowing for visualization of the target protein.

  2. Detection:

    • IF: Detection is based on the emission of fluorescence, resulting in a visible signal under a fluorescence microscope.

    • IHC: Detection is based on the development of a visible color reaction, usually brown, at the site of antibody binding. The stained tissue can be observed under a regular light microscope.

1. Vast majority : mesangial & glomerular capillary wall positivity for IgG and C3
2. Less common (if present, it would be less intense): IgA, IgM and C1q
3. Extraglomerular deposits: 
  • 30-49% of cases
  • rare  tubular BM, peritubular capillaries or arterioles
4. The texture of glomerular deposits is typically smudgy

5. A small % of cases exhibit linear staining of the GBM and can be associated with crescents mimicking anti GBM nephritis. 

6. IgG subclass analysis in most cases of FGN exhibits exclusive or dominant staining for IgG4 whereas a minority show dominant or co-dominant staining for IgG1. 

7. Vast majority (98%) exhibit strong smudgy mesangial and glomerular capillary staining for DNAJB9. 

8. Rare cases of Ig -ve cases can be confirmed by DNAJB9 immunohistochemical staining. 

9. By standard IF on frozen tissue (IF-F)
  • roughly 90% of FGN cases exhibit polyclonal IgG deposits (i.e. positivity for both Kappa and Lambda light chains. 
  • 8-9% : show LC restriction (i.e. staining for Kappa LC or Lambda LC): 
    • These cases were traditionally considered monoclonal lesions and were included within the spectrum of pathologic lesions associated with monoclonal gammopathy of renal significance (MGRS). 
    • Most of these cases are DNAJB9 positive, similar to polytypic variant. 
    • However, 2 recent studies have questioned the inclusion of DNAJB9-associated monotypic FGN as an MGRS lesion as they showed 
      • cases with Lambda LC restriction frequently exhibit staining for both Lambda LC and Kappa  LC when IF is performed on pronase-digested, paraffin tissue
      • these cases not uncommonly exhibit staining for more than 1 IgG subcalss, excluding monoclonal deposits
      • the incidence of clinica evidence of monoclonal gammopathy in these cases (even in cases confirmed by IgG subclass staining and IF-P) is very small (comparable to polyclonal FGN)
      • Rare cases (1%) of FGN are DNAJB9-negative and associated with glomerular deposition of truncated Ig Gamma heavy chain, and these cases are associated with MRGS. 
ELECTRON MICROSCOPY:
1. Glomerular deposition of randomly oriented fibrils that measure 12-30nm in thickness 
2. FGN fibrils virtually always permeate the mesangial matrix and in most cases infiltrate the lamina densa  of the GBM, with a tendency to concentrate in the outer aspect of the GBM, occasionally associated with spike-like projections into the urinary space. 
3. Extraglomerular FGN fibrils (involving rate tubular BM, peritubular capillaries, arterioles or interstitium) are identified in up to 19% of cases if extensive ultrastructural search for them is performed. 
4. FGN fibrils have been documented in spleen but not in other organs

Comments

Post a Comment