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  • Insidens TMA CNI: 4-6%. Relatert til Vasokonstriksjon, endothel toxicitet, prothrombogen og antifibrinogenisk action Treatment: PE. switch
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    1. 1. Case 2 <ul><li>Erik Heyerdahl Strøm </li></ul><ul><li>Division of Pathology </li></ul><ul><li>Willy Aasebø </li></ul><ul><li>Department of Nephrology </li></ul>Oslo University Hospital, Rikshospitalet Norway Co-author Lars Ola Thorud Innlandet Hospital, Lillehammer
    2. 2. Case history -1 <ul><li>Male, born 1955 </li></ul><ul><li>2002: Nephritis, creatinine >500, SR 120, C-ANCA: positive </li></ul><ul><li>Renal biopsy </li></ul>
    3. 3. Initial biopsy native kidney 2002 Fibrocellular crescents
    4. 4. Initial biopsy native kidney 2002 Fibrocellular crescents
    5. 5. Initial biopsy native kidney 2002 <ul><li>Immunofluorescence: Negative </li></ul>
    6. 6. Initial biopsy (EM) native kidney 2002 No electron dense immune deposits
    7. 7. Diagnosis native kidney biopsy 2002 <ul><li>Focal segmental necrotizing glomerulonephritis with fibrocellular crescents without immune deposits. </li></ul><ul><li>Consistent with ANCA-related glomerulonephritis as in Wegener’s granulomatosis </li></ul>
    8. 8. Case history -2 <ul><li>Hemodialysis from – August 2002 </li></ul><ul><li>Kidney transplantation – January 2006 </li></ul>
    9. 9. Case history -3 <ul><li>November - December 2008: gradually increased dyspnoea + oedema, anaemia, and fever. </li></ul><ul><li>S-creatinine: 120 to 180 µmol/l </li></ul><ul><li>C-reactive protein: 15 to 70 mg/l </li></ul><ul><li>Protein/creatinine (urine): 60 to 400 mg/mmol </li></ul><ul><li>Urine microscopy: Nephritic sediment. </li></ul>
    10. 10. Due to increase in s-creatinine and proteinuria A graft biopsy was obtained 6 weeks after debut of symtoms
    11. 11. What to consider in a transplant biopsy <ul><li>Acute rejection? </li></ul><ul><li>cellular rejection (T-cell mediated) </li></ul><ul><li>antibody-mediated rejection (C4d) </li></ul><ul><li>Chronic rejection? </li></ul><ul><li>Ischemia? </li></ul><ul><li>Drug toxicity? </li></ul><ul><ul><li>CNI (CyA, tacrolimus)? </li></ul></ul><ul><ul><li>Antibiotics? </li></ul></ul><ul><li>Infection? </li></ul><ul><ul><li>Virus (polyoma, CMV) </li></ul></ul><ul><ul><li>Systemic infection? </li></ul></ul><ul><li>De novo nephritis? </li></ul><ul><li>Recurrence of native disease? </li></ul><ul><li>Other? (Post transplant lymphoproliferative disease - PTLD) </li></ul>
    12. 12. Minimal tubulitis No vasculitis Biopsy of the transplant
    13. 14. Double contour capillary wall Mesangial cell interposition Transplant glomerulopathy
    14. 16. Necrosis? Thrombotic material?
    15. 17. Cellular crescent
    16. 18. Cellular crescent
    17. 20. Diagnosis based on light microscopy <ul><li>No acute rejection (C4d negative) </li></ul><ul><li>Transplant glomerulopathy </li></ul><ul><li>Focal necrotizing glomerulopathy with few cellular crescents (thrombi?) </li></ul>
    18. 21. Immunfluorescence (paraffin block) C1q C3 IgA, IgG and IgM were negative
    19. 22. Electron microscopy No glomeruli in the material submitted for EM EM therefore performed on material retrieved from the paraffin block
    20. 23. Electron microscopy (paraffin block) Transplant glomerulopathy (doubling of basement membrane)
    21. 24. Electron microscopy (paraffin block) Mesangial deposits
    22. 25. Subendothelial deposits
    23. 26. Biopsy diagnosis of transplant <ul><li>No definite acute rejection (i1 t1 v0, C4d negative) </li></ul><ul><li>Transplant glomerulopathy as in chronic rejection </li></ul><ul><li>Focal necrotizing glomerulonephritis with cellular crescents in 2 of 13 glomeruli (obs thrombi) </li></ul>
    24. 27. Biopsy diagnosis of transplant <ul><li>Consider </li></ul><ul><li>Recurrence of Wegener’s granulomatosis </li></ul><ul><li>Systemic infection </li></ul><ul><li>Thrombotic microangiopathy </li></ul>
    25. 28. Possible diagnosis -1 Thrombotic microangiopathy ? TTP/HUS?
    26. 29. Thrombotic Microangiopathy after Tx <ul><li>As a complication to CNI`s: -- 4-6 %. Usually during the first weeks after Tx. </li></ul><ul><li>Other medicines </li></ul><ul><li>Acute rejection </li></ul><ul><li>Infection (viral, bacterial) </li></ul><ul><li>Carcinoma </li></ul><ul><li>Anti-cardiolipin antibodies </li></ul><ul><li>(Associated with OKT3) </li></ul>
    27. 30. Case history -4 <ul><li>Hgb: 9,2. Thrombocytes: 220 10 9 . Lactate dehydrogenase: 356 U/l, Bilirubin: 15 µmol/l, (Haptoglobine: not analyzed) </li></ul><ul><li>No symptoms from CNS </li></ul><ul><li>Conclusion: no TTP-HUS! </li></ul><ul><li>! Few crescents are found in 5% of HUS! </li></ul>
    28. 31. Possible diagnosis -2 Recurrence of Wegener’s granulomatosis?
    29. 32. ANCA positive vasculitis after Tx <ul><li>N=35 with ANCA-associated vasculitis </li></ul><ul><ul><li>20: microscopic polyangitis </li></ul></ul><ul><ul><li>15: Wegener </li></ul></ul><ul><li>Median time from diagnosis to Tx: 25 months </li></ul><ul><li>15: ANCA positive at Tx </li></ul><ul><li>Overall graft survival 5 years: 94% </li></ul><ul><li>Death censored graft survival: 100% </li></ul><ul><li>Relapse: Microscopic polyangitis: 1/20, Wegener: 2/15 </li></ul><ul><li>All relapses: Non-renal </li></ul>Gera M. Kidney int. 2007
    30. 33. Patient and Graft survival after renal transplantation in Wegener, PKD, IgA-nephropathy and diabetes Schmitt W, Curr Opin Rheumatol, 2003
    31. 34. Case history -5 <ul><li>ANCA: negative </li></ul><ul><li>PR3 and MPO: <9 (negative) </li></ul><ul><li>ANA: negative </li></ul><ul><li>Anti GBM: neg </li></ul><ul><li>C3 : 1.44 g/l (0.80 – 2.00) (normal) </li></ul><ul><li>C4: 0.28 g/l (0.10-0.50) (normal) </li></ul>Conclusion: No recurrence of Wegener
    32. 35. Possible diagnosis -3 Systemic infection?
    33. 36. Case history -7 <ul><li>Bacterial growth in blood cultures: </li></ul><ul><li>- Streptococcus sanguis </li></ul>
    34. 37. Dr. S. Urheim, Dept. of Cardiology, Rikshospitalet Ultrasound of the heart
    35. 38. Ultrasound of the heart Dr. S. Urheim, Dept. of Cardiology, Rikshospitalet
    36. 39. Case history -8 <ul><li>Ecco-cardiography: aortic valve with vegetations on all three cusps. </li></ul><ul><li>Endocarditis!!! </li></ul>
    37. 40. Possible diagnosis -3b Renal affection related to endocarditis
    38. 41. Renal disease in infective endocarditis <ul><li>Embolic disease --Microbiological emboli Drug-induced disease --Acute interstitial nephritis - antibiotics --Acute tubular necrosis - Aminoglycosides </li></ul><ul><li>Postinfectious immune complex-mediated glomerulonephritis </li></ul>
    39. 42. Renal pathological findings in infective endocarditis <ul><li>354 Patients with endocarditis </li></ul><ul><li>62: Renal tissue for examination (20+42) </li></ul>Majumdar A, NDT 2000 3 3 0 Normal Kidney 5+1 1+1 4 Pre-existing glom disorder or Hydronephrosis 6 1 5 Acute Interstitial nephritis 6 6 0 Cortical necrosis 12 8 4 Acute tubular damage 16 7 9 Acute glomerulonephritis 19 19 0 Localized infarction Total (n=62) Autopsi (n=42) Renal biopsy (n=20) Findings in the Kidney
    40. 43. Postinfectious glomerulonephritis in general <ul><li>Previously associated with streptococcus. </li></ul><ul><li>Now: associated with several infectious syndromes and a wide variety of bacteria, fungi, viruses and parasites. </li></ul>
    41. 44. Postinfectious glomerulonephritis clinical manifestations <ul><li>Acute Nephritic Syndrome. </li></ul><ul><li>--Hematuria, proteinuria, edema, often hypertension, and a mild degree of kidney injury </li></ul><ul><li>Rapidly progressive nephritic syndrome </li></ul><ul><li>--Rare (4,6% of biopsies). Rapidly increase in s-creatinine. Crescent formation (often limited) </li></ul><ul><li>Subclinical or asymptomatic glomerulonephritis </li></ul><ul><li>--Low grade proteinuria, microscopic hematuria. 4-19 times as common as “classic acute nephritic syndrome” </li></ul>
    42. 45. Postinfectious glomerulonephritis histological findings <ul><li>In light microscopy : </li></ul><ul><li>- diffuse exudative proliferation without crescents </li></ul><ul><li>- diffuse endocapillary proliferation with crescents </li></ul><ul><li>-mild segmental, mesangial proliferation </li></ul><ul><li>-membranoproliferative glomerulonephritis </li></ul><ul><li>Immunofluorescence: </li></ul><ul><li>-most commonly: deposition of C3 often IgG, </li></ul><ul><li>-occasionally: IgM, rarely: IgA (except in patients with diabetes-particularly Staphylococcal infections) </li></ul><ul><li>- “Full house”: IgG. IgA, IgM, C3, C4 and C1q is frequently reported </li></ul><ul><li>Electron microscopy: </li></ul><ul><li>-mesangial, subendothelial and ”humps” </li></ul>Kanjanabuch T, Nature Reviews Nephrology, 2009
    43. 46. Final diagnosis : <ul><li>Postinfectious glomerulonephritis related to acute endocarditis </li></ul><ul><li>Transplant glomerulopathy </li></ul>
    44. 47. Case history -9 <ul><li>Treatment: Penicillin + Gentamycin for 6 weeks </li></ul><ul><li>13.1-2009: removal of the affected aortic valve: Implant: biological aortic valve </li></ul><ul><li>8 months after surgery: S-creatinine: 128 µmol/l Urea: 11.5 mmol/l </li></ul>
    45. 48. Take home message <ul><li>1: Focal glomerulonephritis with crescents </li></ul><ul><li>-----Don’t forget infection ! </li></ul><ul><li>2: ANCA-associated vasculitis vs. postinfectious glomerulonephritis: </li></ul><ul><li>-----Correct diagnosis is pertinent; treatment and outcome different </li></ul><ul><li>3: Histological findings must always be considered in concert with clinical findings </li></ul>
    46. 49. Thank you for your attention

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