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Case

Case. 17 yo AA female Fatigue x 1 mo Weight loss x 5 # Flank pain Urine is brown. Nephritis in SLE Epidemiology. Adults: 25-50% Pediatrics: 82% Silent disease 3/27 Minimal lesion 12/27 Focal lesion 12/27 Diffuse lesion (Mahajan, Medicine 56:493-510, 1977).

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Case

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  1. Case • 17 yo AA female • Fatigue x 1 mo • Weight loss x 5 # • Flank pain • Urine is brown

  2. Nephritis in SLE Epidemiology • Adults: 25-50% • Pediatrics: 82% • Silent disease 3/27 Minimal lesion 12/27 Focal lesion 12/27 Diffuse lesion (Mahajan, Medicine 56:493-510, 1977)

  3. Systemic Lupus ErythematosisPatient Survival • w/o Nephritis 95 % at 5 years • w/ Nephritis • Untreated proliferative nephritis: 50% at 14 months • Treated 92 % at 5 years • Age disparity • Racial disparity (Pollak J Lab Clin Med 57:495, 1961; Cervera, Medicine 78:167-75, 1999)

  4. Diffuse Proliferative Nephritis (IV)

  5. Diffuse GN (WHO IV) Austin, Sem Nephrol 19:2, 1999

  6. Racial Disparity Boumpas, Lancet 340:741, 1992; Dooley, KI, 1997

  7. Rapidly progressive glomerulonephritis (GN) Serologic analysis Anti-neutrophil cytoplasmic autoantibodies (ANCA) Anti-GBM autoantibodies Immune complex constituents + + + Pulmonary necrotizing granulomas No extra-renal disease Cryo- globulins Other Anti-DNA autoantibodies Lung hemorrhage Systemic necrotizing arteritis No lung hemorrhage Anti-strep antibodies Polyarteritis nodosa “Idiopathic” crescentic GN Wegener’s granulomatosis Anti-GBM GN Goodpasture’s syndrome Post-strep GN Other immune complex GN Cryoglob- ulinemic GN Lupus GN ANCA-associated GN Anti-GBM antibody- mediated GN Immune complex-mediated GN Modified from: Jennette JC et al. Med Clin North Am 1990; 74:893.

  8. Invitation: Nephrology Elective for …. the rest of the story.

  9. Immune Complex Pauci- Immune Anti-GBM >80% ANCA+ Crescentic Glomerulonephritis is Categorized as Anti-GBM Mediated, Immune Complex Mediated, or Pauci-Immune (i.e., with a paucity of staining for immunoglobulin) Crescentic Glomerulonephritis

  10. Anti-glomerular basement membrane disease • Goodpastures syndrome • Linear staining of GBM • With therapy: 70% risk of ESRD or Death • Control with Cytoxan, Steroids, and Plasmapharesis • Does not tend to be a relapsing disease

  11. Anti-Neutrophil Cytoplasmic Autoantibodies (ANCA) C-ANCA Cytoplasmic Pattern Anti-Proteinase 3 PR3-ANCA P-ANCA Perinuclear Pattern Anti-myeloperoxidase MPO-ANCA

  12. % ANCA-Positive By EIA and IFA 90 80 70 60 50 40 30 20 10 0 C-ANCA & PR3-ANCA P-ANCA & MPO-ANCA MCG ICGN FSGS IGAN MPGN MEM AGBM ICCGN PICGN SLEGN

  13. Microscopic Polyangiitis Necrotizing vasculitis with few or no immune deposits affecting small vessels, i.e. capillaries, venules and arterioles. Necrotizing arteritis involving small and medium-sized arteries may be present. Necrotizing Glomerulonephritis is very common. Pulmonary capillaritis often occurs.

  14. Wegener’s Granulomatosis Granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis affecting small to medium-sized vessels, e.g. capillaries, venules, arterioles, and arteries. Necrotizing glomerulonephritis is common.

  15. Churg-Strauss Syndrome Eosinophil-rich and granulomatous inflammation involving the respiratory tract, and necrotizing vasculitis affecting small to medium-sized vessels, associated with asthma and blood eosinophilia.

  16. Pauci-Immune (ANCA) Crescentic Glomerulonephritis

  17. Acute ANCA Glomerulonephritis Segmental fibrinoid necrosis with GBM lysis, apoptosis, and early crescent formation Segmental fibrinoid necrosis and apoptosis

  18. Acute ANCA Renal Vasculitis Necrotizing Glomerulonephritis Necrotizing Medullary Angiitis Necrotizing Arteritis Segmental Fibrinoid Necrosis

  19. Pathogenesis of ANCA Necrotizing Vasculitis 1. If ANCA cause vasculitis, they must induce the following sequence of events: 2. Leukocyte margination, adherence, and diapedesis 3. Leukocyte activation with degranulation and generation of toxic oxygen metabolites 4. Vascular necrosis with karyorrhexis and fibrinous insudation JCJ

  20. ANCA ANCA Antigen Cytokine Cytokine Receptor Fc Receptor Adhesion Molecule Adhesion Molecule Receptor JCJ Jennette & Falk: Nephrol Dial Trans 1998; 13 [Suppl 1]: 16-20

  21. Priming • Infection • Environment • Silica • Great Earthquake, Kobe, Japan

  22. Humans with ANCA-GN

  23. Purpura Petechiae Ecchymoses Erythematous macules Papules Nodules Urticaria Livedo raticularis Necrosis Ulceration Vesicles Bullae Pyoderma gangrenosum-like lesions Erythema nodosum-like lesions Sweet’s like lesions Cutaneous Manifestations of Vasculitis

  24. Signs and Symptoms of Necrotizing Small Vessel Vasculitis • Cutaneous purpura, nodules and ulcerations • Hemoptysis and pulmonary infiltrates or nodules • Peripheral neuropathy (mononeuritis multiplex) • Abdominal pain and blood in stool • Necrotizing (hemorrhagic) sinusitis • Myalgias and arthralgias • Muscle and pancreatic enzymes in blood • Hematuria, proteinuria and renal insufficiency

  25. Treatment of ANCA-GN IV pulse methylprednisolone 7 mg/kg x 3 days Prednisone 1 mg/kg X 4 weeks then tapered with either IV cyclophosphamide 0.5 g/m2* X 6 months or Oral cyclophosphamide 2 mg/kg* X 6 to 12 months *adjusted based on leukocyte count

  26. Corticosteroids Alone Do Not Work • Remission rate • cyclophosphamide 85% • corticosteroids 56% (p = 0.003) • Risk of relapse increased 3-fold in corticosteroids alone group • (RP = 3.2, 95% CI, = 1.2, 8.3*) • *controlling for age, serum creatinine, duration of treatment, and presence of arteriosclerosis on biopsy

  27. Cyclophosphamide Versus Azathioprine During Remission Induction with Prednisone and oral Cytoxan Oral Cytoxan Azathioprine No difference in creatinine, BVAS score, or vasculitic damage index. D Jayne. J Am Soc Nephrol 1999, 105A.

  28. Trimethoprim Sulfamethoxazole for Prevention of Relapse of Wegeners

  29. Pediatric ANCA-GN Source N Age DX (%) CRI (%) ESRD (%) Death (%) GDCN 23 2-20 MPA 60 10 35 13 WG 35 NCGN 5 Hattori 31 5-17 MPA 68 19.5 29 3 NCGN 32 Valentini 7 11-17 33 14 0 Ellis 3 4-14 33 0 Hall 4 7-13 WG 100 50 0 Orlowski 6 13-20 WG 100 17 50 Total 74 2-20 16.4 29.7 9.5

  30. Pediatric ANCAGDCN Baseline Data Mean Range Age 13.4+4.5 2-20 Female 70% Race White 84% Black 16% Prodrome (w) 11+17 2-72 GFR 52+43 4-124

  31. Pediatric ANCA Organ Involvement System % Affected Kidney 100 Pulmonary 70 Sinusitis 25 Gastrointestinal 45 Musculoskeletal 55 Nervous 15 Skin 35

  32. Pediatric ANCA Therapy • Individualized • Corticosteroids - 91% • Cyclophosphamide - 74% • Oral - 39% • Intravenous - 35% • None - 9 % • 1 normal GFR • Sclerotic at baseline

  33. Pediatric ANCAHistopathology

  34. Pediatric ANCASurvival No Acute Dialysis * Acute Dialysis 0 0 10 20 30 40 50 *mean survival 6.8 months

  35. Risk Factors for Death and ESRD in Patients with ANCA Peds v Adults Hogan, JASN, 1996; Gibson and Gipson, JASN, 2001 Adults RR P value Risk of Death Hemoptysis 8.6 0.0002 Risk of ESRD Baseline Cr 2.9 0.0002 Children Risk of Death and ESRD Crescents 0.01 Acute dialysis < 0.001 Injury score < 0.01

  36. IV Versus Oral Cyclophosphamide • No difference in remission or relapse rate • Higher incidence of leukopenia with the use of oral cyclophosphamide • Clinically significant higher risk of major side effects

  37. ANCA Resistance and Relapse • Resistance 23% • Female • Race (AA>CA) • Severe kidney disease at presentation • Relapse 42% • PR3-ANCA • Lower respiratory tract disease • Upper respiratory tract disease Hogan, 2005

  38. Recurrence of ANCA-SVV After Renal Transplantation Nachman PH et al. Kidney Int 1999; 56:1544-50

  39. Alternative Treatment • Pulse intravenous gamma globulin • Trimethoprim sulfamethoxazole • Methotrexate • Azathioprine • Mycophenolate mofetil (Cellcept) • TNF receptor inhibitor

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