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)

II

IV III

V

Light Microscopic Patterns of Lupus Nephritis

Diffuse Proliferative Focal Proliferative

Membranous Mesangioproliferative

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)

Diffuse Proliferative Nephritis (IV)

Diffuse GN (WHO IV)

Austin, Sem Nephrol 19:2, 1999

Racial Disparity

Boumpas, Lancet 340:741, 1992; Dooley, KI, 1997

0

20

40

60

80

100

Black White

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.

Invitation: Nephrology Elective for …. the rest of the

story.

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)

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

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

Anti-Neutrophil Cytoplasmic Autoantibodies (ANCA)

P-ANCA Perinuclear PatternAnti-myeloperoxidase

MPO-ANCA

C-ANCA Cytoplasmic PatternAnti-Proteinase 3

PR3-ANCA

% 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

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.

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

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

ANCAANCA AntigenCytokineCytokine ReceptorFc ReceptorAdhesion MoleculeAdhesion Molecule Receptor

JCJ

Jennette & Falk: Nephrol Dial Trans 1998; 13 [Suppl 1]: 16-20

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 gangrenosum-

like 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 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

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

Pediatric ANCA Organ Involvement

System % Affected

Kidney 100

Pulmonary 70

Sinusitis 25

Gastrointestinal 45

Musculoskeletal 55

Nervous 15

Skin 35

Pediatric ANCA Therapy

• Individualized • Corticosteroids - 91%• Cyclophosphamide - 74%

– Oral - 39%– Intravenous - 35%

• None - 9 %– 1 normal GFR– Sclerotic at baseline

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

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

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

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