case
DESCRIPTION
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). - PowerPoint PPT PresentationTRANSCRIPT
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Case
• 17 yo AA female
• Fatigue x 1 mo
• Weight loss x 5 #
• Flank pain
• Urine is brown
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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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II
IV III
V
Light Microscopic Patterns of Lupus Nephritis
Diffuse Proliferative Focal Proliferative
Membranous Mesangioproliferative
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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)
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Diffuse Proliferative Nephritis (IV)
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Diffuse GN (WHO IV)
Austin, Sem Nephrol 19:2, 1999
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Racial Disparity
Boumpas, Lancet 340:741, 1992; Dooley, KI, 1997
0
20
40
60
80
100
Black White
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Rapidly progressive glomerulonephritis (GN)
Serologic analysis
Anti-neutrophil cytoplasmic autoantibodies (ANCA)
Anti-GBM autoantibodies
Immune complex constituents
No extra-renal disease
“Idiopathic” crescentic GN
Lung hemorrhage
Goodpasture’ssyndrome
Anti-DNAautoantibodies
LupusGN
+ + +No lung
hemorrhageSystemic
necrotizing arteritis
Pulmonary necrotizing granulomas
Anti-strepantibodies
OtherCryo-globulins
Polyarteritis nodosa
Wegener’s granulomatosis
Anti-GBMGN
Post-strep GN
Cryoglob-ulinemic
GN
Other immune complex
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.
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Invitation: Nephrology Elective for …. the rest of the
story.
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Crescentic Glomerulonephritis Immune
ComplexAnti-GBMPauci-
Immune
>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)
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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
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Aorta
Arteries
ArterioleCapillary
Venule
Vein
MicroscopicPolyangiitis
Wegener’sGranulomatosis
Churg-Strauss
Syndrome
Nogranulomatousinflammation
or asthma
Granulomatousinflammationbut no asthma
Granulomatousinflammation,asthma, and eosinophilia
ANCA Small Vessel Vasculitis
Organ-limitedPauci-Immune
Vasculitis
Organ-limitedPauci-Immune
Vasculitis
vascular predilection
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Anti-Neutrophil Cytoplasmic Autoantibodies (ANCA)
P-ANCA Perinuclear PatternAnti-myeloperoxidase
MPO-ANCA
C-ANCA Cytoplasmic PatternAnti-Proteinase 3
PR3-ANCA
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% ANCA-Positive By EIA and IFA
90
80
70
60
50
40
30
20
10
0
C-ANCA &
PR3-ANCA
P-ANCA &
MPO-ANCA
PIC
GN
AG
BM
ICC
GN
ICG
N
MP
GN
SL
EG
N
IGA
N
ME
M
FS
GS
MC
G
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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 verycommon. Pulmonarycapillaritis often occurs.
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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.
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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.
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Pauci-Immune (ANCA) Crescentic Glomerulonephritis
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Acute ANCA Glomerulonephritis
Segmental fibrinoid necrosis and apoptosis
Segmental fibrinoid necrosis with GBM lysis, apoptosis, and early
crescent formation
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Acute ANCA Renal Vasculitis
Necrotizing Glomerulonephritis
Necrotizing Medullary Angiitis
Necrotizing Arteritis
Segmental Fibrinoid Necrosis
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JCJ
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
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ANCAANCA AntigenCytokineCytokine ReceptorFc ReceptorAdhesion MoleculeAdhesion Molecule Receptor
JCJ
Jennette & Falk: Nephrol Dial Trans 1998; 13 [Suppl 1]: 16-20
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Priming
• Infection
• Environment– Silica– Great Earthquake, Kobe, Japan
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Humans with ANCA-GN
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Cutaneous Manifestations of Vasculitis
• 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
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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
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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
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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
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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.
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Trimethoprim Sulfamethoxazole for Prevention of Relapse of Wegeners
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Pediatric ANCA-GN
Source N Age DX (%) CRI (%) ESRD (%) Death (%)
GDCN 23 2-20 MPA 60 10 35 13WG 35NCGN 5
Hattori 31 5-17 MPA 68 19.5 29 3NCGN 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
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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
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Pediatric ANCA Organ Involvement
System % Affected
Kidney 100
Pulmonary 70
Sinusitis 25
Gastrointestinal 45
Musculoskeletal 55
Nervous 15
Skin 35
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Pediatric ANCA Therapy
• Individualized • Corticosteroids - 91%• Cyclophosphamide - 74%
– Oral - 39%– Intravenous - 35%
• None - 9 %– 1 normal GFR– Sclerotic at baseline
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Pediatric ANCAHistopathology
Feature Survivors Non-survivors
p value
Crescents% 39.7+38.1 83.6+42.1 0.01
Glomerular Necrosis
1.5+1.1 2.1+1.5 0.3
Glomerular Sclerosis
1.2+1.3 1.4+0.7 0.5
Tubulointerstitial Disease
1.2+0.9 2.3+0.7 0.01
Activity Score 5.5+3.1 9.4+3.2 0.02
Chronicity Score 3.9+3.1 6.5+2.6 0.09
Injury Score 9.4+4.0 15.3+2.8 <0.01
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Pediatric ANCASurvival
Renal and Patient Survival
Time (months)
50403020100-10
Cu
mm
ula
tive
Su
rviv
al
1.2
1.0
.8
.6
.4
.2
0.0
-.2
No Acute Dialysis
Acute Dialysis*
*mean survival 6.8 months
0 0 10 20 30 40 50
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Risk Factors for Death and ESRD in Patients with ANCA Peds v Adults
Hogan, JASN, 1996; Gibson and Gipson, JASN, 2001
Adults RR P valueRisk of Death Hemoptysis 8.6 0.0002Risk of ESRD Baseline Cr 2.9 0.0002ChildrenRisk of Death and ESRD Crescents 0.01 Acute dialysis < 0.001 Injury score < 0.01
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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
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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
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Recurrence of ANCA-SVV After Renal Transplantation
Nachman PH et al. Kidney Int 1999; 56:1544-50
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Alternative Treatment
• Pulse intravenous gamma globulin
• Trimethoprim sulfamethoxazole
• Methotrexate
• Azathioprine
• Mycophenolate mofetil (Cellcept)
• TNF receptor inhibitor