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)
Light Microscopic Patterns of Lupus Nephritis
IV
III
Diffuse Proliferative
Focal Proliferative
V
II
Membranous
Mesangioproliferative
Systemic Lupus Erythematosis
Patient 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)
Diffuse Proliferative Nephritis (IV)
Diffuse GN (WHO IV)
Austin, Sem Nephrol 19:2, 1999
Racial Disparity
100
80
60
40
20
0
Black
Boumpas, Lancet 340:741, 1992; Dooley, KI, 1997
White
Rapidly progressive glomerulonephritis (GN)
Serologic analysis
Anti-neutrophil cytoplasmic
autoantibodies (ANCA)
Anti-GBM
autoantibodies
Immune complex
constituents
+
+
+
No extrarenal disease
Pulmonary
Systemic
necrotizing
necrotizing
granulomas
arteritis
“Idiopathic”
crescentic GN
Polyarteritis Wegener’s Goodpasture’s
nodosa granulomatosis syndrome
ANCA-associated GN
Lung
hemorrhage
CryoAnti-DNA
No lung
Anti-strep
globulins
autoantibodies
hemorrhage
antibodies
Anti-GBM
GN
Anti-GBM antibodymediated GN
Lupus
GN
Other
PostOther
Cryoglobstrep GN ulinemic immune
complex
GN
GN
Immune complex-mediated GN
Modified from: Jennette JC et al. Med Clin North Am 1990; 74:893.
Invitation: Nephrology Elective for
…. the rest of the story.
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
Immune
Anti-GBM Complex
PauciImmune
>80%
ANCA+
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
Organ-limited
Pauci-Immune
Vasculitis
Organ-limited
Pauci-Immune
Vasculitis
Microscopic
Polyangiitis
No
granulomatous
inflammation
or asthma
ChurgStrauss
Syndrome
Wegener’s
Granulomatosis
Granulomatous
inflammation
but no asthma
Granulomatous
inflammation,
asthma, and
eosinophilia
ANCA Small Vessel Vasculitis
vascular predilection
Aorta
Arteries
Vein
Arteriole
Capillary
Venule
Anti-Neutrophil Cytoplasmic
Autoantibodies (ANCA)
C-ANCA Cytoplasmic Pattern
Anti-Proteinase 3
PR3-ANCA
P-ANCA Perinuclear Pattern
Anti-myeloperoxidase
MPO-ANCA
% ANCA-Positive By
EIA and IFA
C-ANCA &
PR3-ANCA
MCG
FSGS
MEM
IGAN
SLEGN
MPGN
ICGN
ICCGN
AGBM
P-ANCA &
MPO-ANCA
PICGN
90
80
70
60
50
40
30
20
10
0
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.
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.
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.
Pauci-Immune (ANCA) Crescentic
Glomerulonephritis
Acute ANCA Glomerulonephritis
Segmental fibrinoid
necrosis and apoptosis
Segmental fibrinoid necrosis with
GBM lysis, apoptosis, and early
crescent formation
Acute ANCA Renal Vasculitis
Necrotizing
Glomerulonephritis
Necrotizing
Medullary Angiitis
Necrotizing Arteritis
Segmental Fibrinoid Necrosis
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
JCJ
and fibrinous
insudation
ANCA
ANCA Antigen
Cytokine
Cytokine Receptor
Fc Receptor
Adhesion Molecule
Adhesion Molecule Receptor
Jennette & Falk: Nephrol Dial Trans
1998; 13 [Suppl 1]: 16-20
JCJ
Priming
• Infection
• Environment
– Silica
– Great Earthquake, Kobe, Japan
Humans with ANCA-GN
Cutaneous Manifestations of
Vasculitis
•
•
•
•
•
•
•
•
Purpura
Petechiae
Ecchymoses
Erythematous macules
Papules
Nodules
Urticaria
Livedo raticularis
•
•
•
•
Necrosis
Ulceration
Vesicles
Bullae
– Pyoderma gangrenosumlike lesions
– Erythema nodosum-like
lesions
– Sweet’s like lesions
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
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
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
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.
Trimethoprim Sulfamethoxazole for Prevention of Relapse of Wegeners
Pediatric ANCA-GN
Source N
GDCN
Age
DX (%)
23 2-20 MPA 60
CRI (%) ESRD (%) Death (%)
10
35
13
19.5
29
3
33
14
0
WG
35
NCGN 5
Hattori
31 5-17
MPA 68
NCGN 32
Valentini 7 11-17
Ellis
3 4-14
33
0
Hall
4 7-13 WG 100
50
0
Orlowski 6 13-20 WG 100
17
50
29.7
9.5
Total
74
2-20
16.4
Pediatric ANCA
GDCN Baseline Data
Age
Female
Race
White
Black
Prodrome (w)
GFR
Mean
13.4+4.5
70%
84%
16%
11+17
52+43
Range
2-20
2-72
4-124
Pediatric ANCA
Organ Involvement
System
Kidney
Pulmonary
Sinusitis
Gastrointestinal
Musculoskeletal
Nervous
Skin
% Affected
100
70
25
45
55
15
35
Pediatric ANCA
Therapy
• Individualized
• Corticosteroids - 91%
• Cyclophosphamide - 74%
– Oral - 39%
– Intravenous - 35%
• None - 9 %
– 1 normal GFR
– Sclerotic at baseline
Pediatric ANCA
Histopathology
Feature
Survivors Nonsurvivors
p value
Crescents%
39.7+38.1 83.6+42.1
0.01
Glomerular
Necrosis
Glomerular
Sclerosis
Tubulointerstitial
Disease
Activity Score
1.5+1.1
2.1+1.5
0.3
1.2+1.3
1.4+0.7
0.5
1.2+0.9
2.3+0.7
0.01
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
Pediatric ANCA
Survival
Renal and Patient Survival
1.2
1.0
No Acute Dialysis
.8
.6
.4
*
.2
Acute Dialysis
0.0
-.2
-10
0
10
20
0
10
20
Time (months)
0
30
30
40
40
*mean survival 6.8 months
50
50
Risk Factors for Death and ESRD in
Patients with ANCA Peds v Adults
Hogan, JASN, 1996; Gibson and Gipson, JASN, 2001
Adults
RR
Risk of Death
Hemoptysis
8.6
Risk of ESRD
Baseline Cr
2.9
Children
Risk of Death and ESRD
Crescents
Acute dialysis
Injury score
P value
0.0002
0.0002
0.01
< 0.001
< 0.01
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
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
Recurrence of ANCA-SVV After
Renal Transplantation
Nachman PH et al. Kidney Int 1999; 56:1544-50
Alternative Treatment
•
•
•
•
•
•
Pulse intravenous gamma globulin
Trimethoprim sulfamethoxazole
Methotrexate
Azathioprine
Mycophenolate mofetil (Cellcept)
TNF receptor inhibitor