Case 3

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Case 3

• Johan Mölne, MD, PhD
• Clinical Pathology and Cytology, Sahlgrens
  University Hospital,
• Göteborg, Sweden

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• 40 year-old woman, previously healthy presented
  with acute gastroenteritis in Thailand.
• When she returned to Sweden she was hospitalised
  due to renal failure.

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Clinical work-up

• S-creatinine 200 µmol/L (2 mg /dL)
• No proteinuria, microscopic hematuria.
• Slight rise in liver enzymes and CRP.
• Viral serologies (hepatitis, CMV, EBV) and
  malaria tests were negative.
• ANA, ANCA, anti-DsDNA and ENA were all negative.
• She had a raised blood pressure and was put on
  ACE-inhibitors.

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• Kidney ultrasound showed a small left kidney (6
  cm) and a normal right kidney.
• Due to unknown kidney failure a biopsy was
  performed in February 2010.

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Biopsy findings 1

• Glomeruli - normal
• 13/64 global sclerosis
• Tubuli and interstitium
• focal scarring with atrophic tubules and chronic
  interstitial inflammation - lymphocytes and
  plasma cells, but few eosinophils, no granuloma.
• The tubular epithelial cells had giant nuclei.
  The nuclei were generally irregular with focally
  prominent nucleoli and course chromatin.
• Arteries
• Atherosclerosis - moderate

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Biopsy findings 2

• Immunohistochemistry
• Glomeruli - negative
• IgM and C5b-9 were seen in arterioles as in
  arteriolohyalinosis.
• Staining for CMV, adenovirus and polyomavirus
  (SV40) negative.
• Electron microscopy
• Enlarged nuclei with irregular contours in
  tubular cells

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Diagnosis

• Karyomegalic tubulointerstitial nephritis

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Outcome

• After the kidney biopsy she was put on steroids
• Creatinine continued to rise but no improvement,
  steroids were withdrawn
• July 2011 - creatinine remains around 250 µmol/L
  and CRP is low. She works part time and is
  checked regularly

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Discussion

• Karyomegalic changes in the tubular epithelium
• First reported in 1979 by Michael Mihatsch et al
• (observed by Burry in 1974)
• Only 20 cases reported in the literature

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Morphology

• Marked karyomegaly in the tubular epithelium
• chronic interstitial nephritis
• Nuclear changes
• marked enlargement- up to 5-6 fold (12-26 µm)
• hyper chromatic, irregular distribution (EM)
• irregular outlines
• no inclusions

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Pathogenesis

• Unknown
• Mutation or other genetic defect?
• Familiar clustering
• HLA clustering
• A9/B35
• Inhibition of mitosis
• Ki-67 increased in one study, normal in another
• marked DNA ploidy

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• Karyomegalic changes in the tubular epithelium
• Associated with
• Heavy metal toxicity (nuclear inclusions)
• Busulphan therapy ?
• Cyclophosphamide ?
• Mycotoxins - ochratoxin A (mainly in pigs)
• Lithium therapy (very few enlarged nuclei)
• Viral infections (no inflammation, neg IP)

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SV40
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Other organs with giant nuclei

• Smooth muscle cells (intestinal, arteries)
• Schwann cells
• Bile ducts
• Liver - Kuppfer cells, fibroblasts
• Pancreas - acinar cells
• Brain - astrocytes
• Mesenchymal cells - several organs including skin

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Clinical picture

• Progressive renal failure
• sCr 200µmol/L (2 mg/dl)
• proteinuria (0,5-1 g/24h)
• hematuria - variable
• Beginning in the third decade
• Previous infections
• often recurring, mainly involving the upper
  respiratory tract
• Raised liver enzymes

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References

• 1. Mihatsch MJ et al. Clin Nephrol (1979)
  1254-62 (original report)
• 2. Monga G et al. Clin Nephrol (2006) 65349-355
  (case and review)
• 3. Spoendlin M et al. Am J Kidney Dis (1995)
  25242-252 (familiar clustering)
• 4. Godin M et al. Adv Nephrol (1996) 25187-211
  (ochratoxin A, 2 cases)
• 5. Baba F et al. Pathology Res and Pract
  (2006) 202555- 559 (case)
• 6. Bhandari S et al. Nephrol Dial Transplant
  (2002) 171914- 1920 (6 cases)

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Final conclusion

• Uncommon disease that is easy to recognize if you
  know about it