1. Case 3 Johan Mölne, MD, PhD Clinical Pathology and Cytology, Sahlgrens University Hospital, Göteborg, Sweden

2. 40 year-old woman, previously healthy presented with acute gastroenteritis in Thailand. When she returned to Sweden she was hospitalised due to renal failure.

3. 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.

4. 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.

13. 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

14. 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

15. Diagnosis Karyomegalic tubulointerstitial nephritis

16. Outcome After the kidney biopsy she was put on steroids Creatinine continued to rise but no improvement, steroids were withdrawn July 2011 - creatinine remains around 250 µmol/L and CRP is low.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

17. 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

18. 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

19. 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

20. 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)

21. SV40

22. 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

23. 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

24. References 1. Mihatsch MJ et al. Clin Nephrol (1979) 12:54-62 (original report) 2. Monga G et al. Clin Nephrol (2006) 65:349-355 (case and review) 3. Spoendlin M et al. Am J Kidney Dis (1995) 25:242-252 (familiar clustering) 4. Godin M et al. Adv Nephrol (1996) 25:187-211 (ochratoxin A, 2 cases) 5. Baba F et al. Pathology – Res and Pract (2006) 202:555- 559 (case) 6. Bhandari S et al. Nephrol Dial Transplant (2002) 17:1914- 1920 (6 cases)

25. Final conclusion Uncommon disease that is easy to recognize if you know about it