Congo red and thioflavine-T negative(nonamyloid) fibrillar glomerular deposition diseases

1.Data from uptodate#

• Glomerular diseases due to nonamyloid fibrillar deposits
• Fibronectin glomerulopathy

2.小心very early amyloidosis or AH amyloidosis可以congo red(-)#

• 1.Fibrillary GN/Immunotactoid glomerulopathy
  • 1% of renal biopsy
  • S/S(both disease)
    • 年齡區間大(10-80 y/o)
      • 不過大多年齡偏高?(回思immunotactoid GN多為MM related, 所以年齡偏高也合理, 不過fibrillary GN也是中老年為主)
    • Hematuria(70%)
    • Cre>1.5(50%)
    • HTN(70%)
    • Proteinuria(100%), nephrotic syndrome(70-80%)
    • 約50% 2-6 yrs會ESRD
      • 不過要看LM, sclerosing/MPGN等比較差, 而mesangial GN/membranous GN比較好...
        • 不過也有人說Mesangial GN比較像疾病早期, 之後會進展成MPGN, 所以mesangial GN當然prognosis較好一些
  • Fibrillary GN
    • 基本上只會deposit in kidney
    • Associated with
      • 可和HCV相關
      • AIR(15%)
        • most often CD, SLE, Graves' disease, ITP
        • 可和anti-GBM disease相關
      • Monoclonal gammopathy(17%)
      • Malignancy(23%)
        • 可以發生在GN前 or 後10年
    • Pathology
      • LM
        • Nonspecific, 可mesangial proliferation, endocapillary proliferative, crescent, membranous pattern(因為也可以堆積在supepithelial space)..., 可mesangial expansion with acellular amorphous material(像DM的K-W lesion or amyloidosis or MIDD, 所以需要congo red/EM來分)
          • 不過70%是mesangioproliferative/sclerosing GN, 15%是MPGN
      • Immunofluorescence
        • 多IgG(多IgG1 or IgG4(?!; Brenner(p1345):IgG4 is the dominant subclass(fibrillary GN))), C3, k, λ (polyclonal in fibrillar, monoclonal in immunotactoid)
        • [(k+λ(polyclonal) in fibrillary, k or λ(常monoclonal) in immunotactoid)]
          • 可以看起來是linear pattern like anti-GBM disease(不過Brenner(1345):The immunofluorescence staining pattern of fibrillary glomerulonephritis is relatively distinctive(Figures 32.32 and 32.33). It is neither granular nor linear; instead, it has an irregular bandlike appearance in capillary walls and an irregular shaggy appearance in the mesangium)

• DNAJB9 (DnaJ heat shock protein family member B9):
  • 【診斷革命與黃金標準】(Andeen JASN 2018; PMID 29097624 / Nasr Kidney Int Rep 2018; PMID 29866458):
    • DNAJB9 免疫組織化學染色敏感度 98%、特異度 >99%，為 Fibrillary GN 專屬特異性分子標記（沉積於繫膜區與微血管壁，正常腎臟、Amyloidosis 或 Immunotactoid 均為陰性）〔PMID 29097624〕。
    • 【陷阱突破】：約 5-10% 之 Fibrillary GN 可出現弱陽性剛果紅染色（嗜剛果紅性 congophilic FGN），極易誤診為澱粉樣變性；DNAJB9 免疫染色已正式取代剛果紅，成為確診 FGN 之國際黃金標準！〔PMID 29866458〕
• +/- IgM, IgA, C1q
• EM
  • Randomly oriented(vs. immunotactoid glomerulopathy) fibrillar deposits in the mesangium and glomerular capillary walls
    • fibrils比amyloidosis粗
    • 纖維/微管直徑與病理鑑別速查表(必考病理題)

• 纖維與微管之詳細直徑、排列特徵及鑑別診斷詳見上方速查表（FGN 12-30 nm 實心無序 vs ITG 30-50 nm 中空平行）
• 臨床上常 nephrotic syndrome，電鏡下可見瀰漫性足細胞足突融合 (foot process effacement)

• Immunotactoid glomerulopathy
  • Far less common than fibrillary GN
  • 基本上只會deposit in kidney
  • 大多有monoclonal gammopathy with restricted light chains(either k or λ)
    • 所以要小心survey lymphoproliferative disorders(尤其CLL or B cell lymphoma)
    • 但似乎HCV or cryoglobulinemia or anti-GBM disease or SLE也可immunotactoid glomerulopathy
  • LM
    • Nonspecific, 可mesangial proliferation, endocapillary proliferative, crescent, membranous pattern(?)..., 可mesangial expansion with acellular amorphous material(像DM的K-W lesion or amyloidosis or MIDD, 所以需要congo red/EM來分)
      • 不過MPGN為主
  • Immunofluorescence
    • 多IgG, C3, k or λ(註:polyclonal in fibrillar, monoclonal in immunotactoid)
  • EM
    • Formation of microtubules(30-50nm), organized(tendency to align in parallel arrays)(vs. fibrillary GN)
      • 可以看到空心的橫截面
      • Microtubules大小需D/D cryoglobulin(其也是MPGN pattern), cryoglobulinemia的microtubules大多較短
• Diagnosis(both disease)
  • By EM
  • 需check HCV, AIR, IFE, malignancy surveillance
    • 小心有時候malignancy之後才會出現, 所以uptodate建議CBC/DC, IFE, SFLC至少Q1Y
• Tx(both disease)
  • Tx of underlying(the most important)
  • ACEI/ARB
  • Immunosuppressions if idiopathic(?)
    • Unknown, no RCTs
  • Renal transplantation:可recurrent glomerulopathy(higher recurrent rate in monoclonal gammopathy, 所以在monoclonal gammopathy者renal transplantation角色未知)
    • Recurrence之後, graft CKD progression速度多比之前自己的kidney慢

3.Others[Staining for Ig is (-)]#

• Fibronectin glomerulopathy
  • AD
    • in Caucasians and Asians
  • S/S
    • 約20-40 y/o開始proteinuria, microscopic hematuria and HTN, then progress to ESRD over 15-20 yrs(所以進展不快); normal complements
      • 主要還是以nephrotic syndrome表現
    • 可type IV RTA
  • Diagnosis
    • By renal biopsy
      • LM
        • 有點像MPGN but minimal cellular proliferation(=nodular pattern)

• Staining of soluble/plasma form fibronectin(小心其他glomerulopathy也可有insoluble/cellular form fibronectin depositions(like:wire loop of LN and K-W nodule of DMN) over mesangium and capillary walls(主要是subendothelial?))

• 註:Fibronectin 有soluble/plasma form (which circulates in blood) and an insoluble/cellular form (which is seen in basement membranes and extracellular matrix)
• Immunofluorescence
  • Nil
• EM
  • 大多homogenous, finely granular(occasionally fibrillar; if fibrillar則約寬12 nm, 長125nm, 多排列不規則; 那這樣和fibrillary GN怎分??(用IF(-)分)) electron dense depositions over mesangium and subendothelial area
• Tx
  • ACEI/ARB
  • Others unknown
  • Unknown risk of recurrence after renal transplantation(不過有些蠻快的(可within 1yr))
• Collagenofibrotic glomerulopathy(=collagen type III glomerulopathy)(atypical type III collagen fibrils depositions in mesangium and subendothelial area)
  • AR
    • More frequently in adult Indian populations in a sporadic, non-familial manner
  • S/S
    • TMA, proteinuria(60% nephrotic syndrome), microscopic hematuria, progressive to ESRD around 10 yrs after diagnosis
  • Diagnosis
    • LM
      • 可mesangial expansion with acellular/hypocellular amorphous material(=nodular pattern) but H-E stain pale, PAS(-), silver stain(-), masson trichrome stain(-, pale blue), Congo red(-)
      • 可類似MPGN with double contour?
    • IF
      • (-)
    • EM
      • Deposition of fibers(transverse band structure with a distinctive periodicity of approximately 60 nm, the same as that of type III collagen) in mesangium and subendothelial space

• Tx
  • Unknown