Aysin Bakkaloglu, M.D.

Hacettepe University Faculty of MedicinePediatric Nephrology and Rheumatology

Ankara, TURKIYE

ESPN 2008 Lyon, FRANCE

TREATING DIFFICULT PATIENTS OF RENAL VASCULITIS

TREATING DIFFICULT PATIENTS OF RENAL VASCULITIS

Plan of the talkPlan of the talk

Treatment of difficult patients of renal

vasculitis

– ANCA associated vasculitis

- Wegener granulamatosis

- Microscopic polyangiitis

– Classic polyarteritis nodosa

– Takayasu arteritis

ANCA ASSOCIATED VASCULITISANCA ASSOCIATED VASCULITIS

Wegener’s granulomatosis

Microscopic polyangiitis

Renal limited vasculitis

Churg-Strauss syndrome

Histologic similarities

Potential contribution of ANCA to theirpathogenesis

Similar responses toimmunosuppressive therapy

Nat Clin Rheumatol 2006; 2: 661-670

GOALS of TREATMENT in ANCA ASSOCIATED VASCULITIS

GOALS of TREATMENT in ANCA ASSOCIATED VASCULITIS

Patient survival

Induce remission of active state

Reduce disease relapse

Minimize therapeutic toxicity– Least toxic and most effective therapy – Prevent and monitor toxicity

CHALLENGES in TREATING ANCA ASSOCIATED VASCULITIS

CHALLENGES in TREATING ANCA ASSOCIATED VASCULITIS

Rarety of ANCA associated vasculitis in children

High morbidity and mortality

Definitions of – disease stages

– activity stages

– outcome measures

Duration of treatment

CASE 1 CASE 1

12 year old girl

Weakness, periumblical abdominal pain

Loss of appetite

Nausea, vomiting

Pallor

Decreased urine output with hematuria

Besbas N et al. Pediatr Nephrol 2003;18: 696-699

Laboratory TestsLaboratory Tests

Hb : 7.8 g/dl

WBC : 7300 /mm3

Platelet : 240 x103 /mm3

CRP : 10.2 mg/dl

ESR : 120 mm/hr

BUN : 51 mg/dl

Cre : 5.84 mg/dl

T. prot : 7.3 g/dl

Alb : 3.2 g/dl

Urinary pH : 6.5 density : 1020 protein : 4 +

7-8 RBC / hpf

Urinary protein : 87.5 mg/m2/hr

GFR : 18 ml/min/ 1.73 m2

ANA : Negative

Anti ds-DNA : Negative

ANCA:

– p-ANCA: strong positive (IFA)

– MPO-ANCA: 250 EU/ml (ELISA)

Anti-GBM: positive

Besbas N et al. Pediatr Nephrol 2003;18: 696-699

Renal BiopsyRenal Biopsy

Besbas N et al. Pediatr Nephrol 2003;18: 696-699

1 mo 2 mo 3 mo 4 mo 5 mo 6 mo 9 mo 12 mo 15 mo 18 mo 21 mo 24 mo

0.5 mg/kg/d prednisone0.5 mg/kg/d prednisone

MP

ZM

PZ

2 mg/kg/d cyclophosphamide

2 mg/kg/d azathiopurine

Plasma exchangePlasma exchange

MMFMMF

EtanerceptRituximabEtanerceptRituximab

Ser

um

cre

atin

ine

(mg

/dl)

Nine years after successful renal transplantation– Cre: 0.98 mg/dl– GFR: 112 ml/min/1.73 m2

CASE 2CASE 2

Necrotic tissue (soft palate, digits and uvula)

Arthritis

Myalgia

Limitation of motion

URTI

Hoarseness, swollen edematous tongue, speech abnormality,

wt loss

URTI

Hoarseness, swollen edematous tongue, speech abnormality,

wt loss

Fatigue, worsening of the symptoms and myalgia

Fatigue, worsening of the symptoms and myalgia

Glossitis, iv penicilinGlossitis, iv penicilin

Fever

Subcutaneous nodules (fingertips, nose)

Generalized maculopapular rash

Necrotic lesions (right foot sole)

Generalized edema

Fever

Subcutaneous nodules (fingertips, nose)

Generalized maculopapular rash

Necrotic lesions (right foot sole)

Generalized edema

Ceftriaxone and clindamicin ivCeftriaxone and clindamicin iv Iloprost, Pentoxiphyllin

Amlodipine, Captopril

Piperacillin-Tazobactam, Vancomycin,

Rifampicin, Fluconazole

Iloprost, Pentoxiphyllin

Amlodipine, Captopril

Piperacillin-Tazobactam, Vancomycin,

Rifampicin, Fluconazole

daysdays0022

4466

10 year old, girl10 year old, girl

Physical ExaminationPhysical Examination

BP: 130/60 mmHg

Pulse: 92 /min

BW: 40 kg (75p)

Height: 146 cm (50-75p)

BP: 130/60 mmHg

Pulse: 92 /min

BW: 40 kg (75p)

Height: 146 cm (50-75p)

Maculopapular rash

Edema (pretibial and dorsum of hand)

Tongue atrophy and tissue loss

Necrotic lesions

Laboratory TestsLaboratory Tests

Hb : 7.4 g/dl

WBC : 20100 /mm3

Platelet: 550x103 /mm3

CRP : 14.9 mg/dl

ESR : 90 mm/hr

BUN : 8 mg/dl

T. prot : 6.17 g/dl

Alb : 2.39 g/dl

Urinary ph: 6.5 density:1020 protein: - , 1-2 RBC

IgA : 158 mg/dl (68-378)

IgM : 144 mg/dl (50-250)

IgG : 2050 mg/dl (650-1600)

ANA : Negative

Anti-DNA : Negative

c-ANCA : Mild staining at IIFNegative for MPO, PR3

Thrombotic panel including ACLs all (-)

MEFV : V726A/-

Paranasal CT

Necrotizing VasculitisNecrotizing Vasculitis

Ora

l p

red

nis

on

e (2

mg

/kg

/day

)

Ora

l cy

clo

ph

osp

ham

ide

(2 m

g/k

g/d

ay)

Ora

l p

red

nis

on

e (2

mg

/kg

/day

)

Ora

l cy

clo

ph

osp

ham

ide

(2 m

g/k

g/d

ay)

daysdays1515

Pu

lse

ster

oid

Pu

lse

ster

oid

1717

Pla

sma

exch

ang

eP

lasm

a ex

chan

ge

1919

Pla

sma

exch

ang

eP

lasm

a ex

chan

ge

2121

Pla

sma

exch

ang

eP

lasm

a ex

chan

ge

2323P

lasm

a ex

chan

ge

Pla

sma

exch

ang

e2525

Pla

sma

exch

ang

eP

lasm

a ex

chan

ge

60603232

Pla

sma

exch

ang

eP

lasm

a ex

chan

ge

Hem

atu

ria,

p

rote

inu

ria,

dys

pn

eaH

emat

uri

a,

pro

tein

uri

a, d

ysp

nea

1414

Classification of a child as WG:

3 of the following six should be present:

1. Abnormal urinalysis* 2. Granulomatous

inflammation on biopsy*3. Nasal-sinus inflammation*4. Subglottic, tracheal or

endobronchial stenosis5. Abnormal chest x-ray or CT*6. PR3 ANCA or C-ANCA

staining

Classification of a child as C-PAN:

Biopsy showing small and/or mid-size artery necrotizing vasculitis and/or angiographic abnormalities+2 out of the following 7 criteria

1. Skin involvement* 2. Myalgia or muscle tenderness*3. Systemic hypertension 4. Mononeuropathy or polyneuropathy5. Abnormal urinalysis and/or impaired

renal function*6. Testicular pain or tenderness7. Signs or symptoms suggesting

vasculitis of any other major organ system (gastrointestinal, cardiac, pulmonary, or CNS)*

EULAR/PRES Criteria. Ann Rheum Dis; 2006

Prednisolone– oral 2 mg/kg – IV 15 mg/kg/dose

CYC– Oral 2 mg/kg– 500 mg/m2

Cre (> 500 mmol/l )

Vital organ involvementplasma exchange

• AZA: 1-2 mg/kg/d• CS: 0.25 mg/kg/alternate day

Risk factors for ERSD and relapse:

• Upper or lower respiratory tract disease

• Proteinase-3 ANCA seropositivity

• Severe kidney disease

• Female sex

3-6 months

12 months or longer

Bakkaloglu A et al. Arch Dis Clin 2001; 85: 427-430.Besbas N et al. Pediatr Nephrol 2000; 14: 325-327.

INDUCTION THERAPYINDUCTION THERAPY

Prednisone ( 1-2 mg/kg/day) ± MP ( 3 pulses)Cyclophosphamide ( 2 mg/kg/day) or iv pulses

3 - 6 mo.

NORAM: MTX vs CYCMEPEX: PE vs MPCYCLOPS: CYC iv vs oralWEGET: Etanercept vs placeboSOLUTION: ATG

Maintenance therapyNORAM: MTX vs CYCCYCAZAREM: AZA vs CYCIMPROVE: AZA vs MMFREMAIN: AZA, 24 mo vs 48 mo

Rituximab (RITUXVAS): – Several, uncontrolled studies (refractory)

Many reports observed disease remissions in relapsing and refractory patients with ANCA associated or other vasculitides

LeflunomideDeoxypergualinAnti CD52: – Predominantly leads to T-lymphocyte depletion– Its use has been complicated by a high frequency of

infection

Anti-thymocyte globulin (ATG):– Should be reserved for severe refractory WG

Recent Alternative Therapies

CASE 3CASE 3

3 year old girl

Poor appetite, fatigue, weight loss for one month

Over the past five days– Severe and frequent vomiting– Subsequently developed drowsiness and unconsciousness

– High blood pressure– Subarachnoid hemorrhage

Topaloglu R et al. Pediatr Nephrol 2005 Jul; 20 (7): 1011-5.

Physical examinationPhysical examination

Body temperature: 36.6 CPulse rate: 104 /min

Respiratory rate: 20 /min

Blood pressure: – 180/110 mm Hg (left arm)– 175/105 mm Hg (right arm)

She was unconscious

Mydriasis

Diminished light reaction in the right eye

Right third nerve and left six nerve palsies

Left hemiparesis

Deep tendon reflexes were all diminished

Topaloglu R et al. Pediatr Nephrol 2005 Jul; 20 (7): 1011-5.

Laboratory TestsLaboratory Tests

Hb : 9.9 g/dl

WBC : 22100 /mm3

Platelet: 675x103 /mm3

CRP : 10.2 mg/dl

ESR : 60 mm/hr

BUN : 8 mg/dl

Cre : 0.5 mg/dl

Urinary pH: 6.5 density: 1011 protein: protein- , 1-2 WBC /hpf

IgA : 168 mg/dl (68-378)

IgM : 1220 mg/dl (50-250)

IgG : 1450 mg/dl (650-1600)

ANA : Negative

Anti-DNA : Negative

ANCA : Negative

HBsAg : Negative

Anti-HCV: Negative

CT/MRI CT/MRI

Topaloglu R et al. Pediatr Nephrol 2005; 20: 1011-1015.

Angiography Angiography

Topaloglu R et al. Pediatr Nephrol 2005; 20: 1011-1015.

CLASSIC POLYARTERITIS NODOSACLASSIC POLYARTERITIS NODOSA

Hypertensive emergency

Subarachnoidal hemorrhage

Angiography: Diffuse aneurysmal changes

Steroid intravenous, followed by p.o. route

Cyclophosphamide 2 mg/kg, p.o., 6 mo.

Azathiopurine (12 mo.)

MMF (12 mo.)

Low dose steroid (alternate day continuing)

CASE 4CASE 4

12 year old girl

Abdominal pain, myalgia

Nausea

Fever

Rash on extremities

Recurrent abdominal pain and fever- FMF?

Blood pressure: 150/90 mmHg

Laboratory TestsLaboratory Tests

Hb : 11.7 g/dl

WBC : 12400 /mm3

Platelet: 558 x103 /mm3

CRP : 18 mg/dl

ESR : 55 mm/hr

BUN : 12 mg/dl

Cre : 0.6 mg/dl

Urinary pH: 6.5 density: 1018 protein: +++

10-15 RBC/hpf

IgA : 184 mg/dl (68-378)

IgM : 770 mg/dl (50-250)

IgG : 1850 mg/dl (650-1600)

ANA : Negative

Anti-DNA : Negative

ANCA :

– c-ANCA: positive (IFA)PR-3 ANCA : positive (ELISA)

HBsAg : Positive

HBV DNA: 330 pg/ml (0-5)

MEFV: M694 V/-

Renal AngiographyRenal Angiography

Liver biopsy-Chronic hepatit B infection grade 1

– Lamuvidine therapy (1 year)

Polyarteritis nodosa

– 1 mg/kg/day oral prednisone

– 4 months later steroids tapered and stopped

FMF

– More inflammation, more vasculitis among FMF patients

– Increased MEFV mutations among vasculitis patients

– 0.03 mg/kg colchicum dispert

8 years follow up, BP (normal), renal function test (normal)

Medicine (Baltimore). 2005; 84: 1-11.

CASE 5CASE 5

9 month old girlFever and irritabilityMother-carrier for HBs AgBlood pressure: 180/100 mmHgESH: 70 mm/hrUrinalysis: protein +++Angiogram: Renal and mesenteric microaneurysmsHBs Ag (+)HBe Ag (+) HBV DNA > 2000 pg/ml

Duzova A et al. Eur J Pediatr 2001; 160: 519-520

+ + + + + + + + + + + + + + + + + + + + + + + +

+ + + + + + + + + + + + + + + + + + + + + + + + HBV DNA pg/ml

HBs AgHBe Ag

Antihypertensive drugs

Prednisolone (2 mg/kg)

Cyclophosphamide (2 mg/kg)

Interferon

>2000 >2000 >2000 >2000 714

Months

302220181686420

Blo

od

pre

ssu

re (

mm

Hg)

200

180

160

140

120

100

80

60

40

Diastolic BP

Systolic BP

*

Figure 1: Time course of blood pressure, treatment and virological parameters

5x106 U/m2 10x106 U/m2

Duzova A et al. Eur J Pediatr 2001; 160: 519-520

*: anaemia and leukocytopenia

CASE 6 & 7CASE 6 & 7

Patient 6Patient 6

Age at diagnosis: 12 y

Headache

BP: 150/100 mm Hg

ESR: 44 mm/hr

ppd: positive

Urinalysis: Proteinuria

Angiography

RRA: Normal

LRA: Stenosis

Entire thoracic and abdominal artery involvement, presence of aneurysms

Medical treatment

– Prednisolone (bolus, po)

– CYC (po)

– MTX (po/sc)

– Anti-hypertensive

• CCB

• Alpha-blocker

• Beta-blocker

Anti-tbc treatment

Surgical treatment

– Left nephrectomy

Duration of follow up: 10 years

Low dose steroid

TREATMENTTREATMENT

Patient 7Patient 7

Age at diagnosis: 16 y

Arthralgia

MEFV : E148Q/-

FMF? 4 years

Headache

BP: 180/100 mm Hg

ESR: 16 mm/hr

Angiography

RRA: stenosis at the origin

LRA: stenosis at the origin

Involvement of SMA and suprarenal abdominal aorta

TREATMENTTREATMENT

Medical treatment– Prednisone (po)– MTX (po)– Anti-hypertensive

• CCB• Beta blocker

Surgical treatment• Thoraco-abdominal by pass, left aorta renal

by pass• Right aorta renal by pass

Duration of follow up: 1 yearLow dose steroid and MTX

Takayasu ArteritisTakayasu Arteritis

Mainstay of the treatment is to attenuate inflammatory process and control HTN

Corticosteroids: Therapy is continued until patients achieve remission

Cyclophosphamide (1-2 mg/kg/d)

Azathioprine (1-2 mg/kg)

Methotrexate (0.3 mg/kg/wk)

Anti-TNF

Ozen S et al. J Pediatr 2007; 150: 72-76Hoffman et al. Arthritis Rheum 2004; 50: 2296-2304

SummarySummary

Vasculitis should be excluded in any patient with renal or extrarenal symptoms and: – Elevated acute phase reactants– Constitutional symptoms– Organ involvement

Diagnosis is typically delayed 3 mo.; and the absence of extra-renal disease is associated with a longer delay.Longterm outcomes are closely related to the severity of organ dysfunction at diagnosisANCA testing enables earlier identification.In last 3 decades: MP+CYC therapy enables 75-90% remission at 6 mo. A variety of treatment options now available for AAV.Balance should be made between disease suppression and treatment toxicity.