Presentation is loading. Please wait.

Presentation is loading. Please wait.

TREATING DIFFICULT PATIENTS OF RENAL VASCULITIS

Similar presentations


Presentation on theme: "TREATING DIFFICULT PATIENTS OF RENAL VASCULITIS"— Presentation transcript:

1 TREATING DIFFICULT PATIENTS OF RENAL VASCULITIS
Aysin Bakkaloglu, M.D. Hacettepe University Faculty of Medicine Pediatric Nephrology and Rheumatology Ankara, TURKIYE TREATING DIFFICULT PATIENTS OF RENAL VASCULITIS ESPN 2008 Lyon, FRANCE

2 Plan of the talk Treatment of difficult patients of renal vasculitis
ANCA associated vasculitis - Wegener granulamatosis - Microscopic polyangiitis Classic polyarteritis nodosa Takayasu arteritis

3 ANCA ASSOCIATED VASCULITIS
Wegener’s granulomatosis Microscopic polyangiitis Renal limited vasculitis Churg-Strauss syndrome Histologic similarities Potential contribution of ANCA to their pathogenesis Similar responses to immunosuppressive therapy Nat Clin Rheumatol 2006; 2:

4 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

5 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

6 CASE 1

7 Weakness, periumblical abdominal pain Loss of appetite
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:

8 Laboratory 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 : density : 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:

9 Renal Biopsy Besbas N et al. Pediatr Nephrol 2003;18:

10 2 mg/kg/d cyclophosphamide
Serum creatinine (mg/dl) Plasma exchange MPZ 0.5 mg/kg/d prednisone 1 mo 2 mo 3 mo 4 mo 5 mo 6 mo 9 mo 12 mo 15 mo 18 mo 21 mo 24 mo 2 mg/kg/d cyclophosphamide 2 mg/kg/d azathiopurine Etanercept Rituximab MMF

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

12 CASE 2

13 Fatigue, worsening of the symptoms and myalgia
10 year old, girl Fever Subcutaneous nodules (fingertips, nose) Generalized maculopapular rash Necrotic lesions (right foot sole) Generalized edema URTI Hoarseness, swollen edematous tongue, speech abnormality, wt loss Glossitis, iv penicilin days 4 2 6 Fatigue, worsening of the symptoms and myalgia Necrotic tissue (soft palate, digits and uvula) Arthritis Myalgia Limitation of motion Ceftriaxone and clindamicin iv Iloprost, Pentoxiphyllin Amlodipine, Captopril Piperacillin-Tazobactam, Vancomycin, Rifampicin, Fluconazole

14 Physical Examination Maculopapular rash
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

15 Laboratory 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: density: protein: - , 1-2 RBC IgA : 158 mg/dl (68-378) IgM : 144 mg/dl (50-250) IgG : 2050 mg/dl ( ) ANA : Negative Anti-DNA : Negative c-ANCA : Mild staining at IIF Negative for MPO, PR3 Thrombotic panel including ACLs all (-) MEFV : V726A/-

16 Paranasal CT

17 Necrotizing Vasculitis

18 14 15 17 19 21 23 25 32 60 days Oral cyclophosphamide (2 mg/kg/day)
Oral prednisone (2 mg/kg/day) Hematuria, proteinuria, dyspnea Plasma exchange Plasma exchange Plasma exchange Plasma exchange Plasma exchange Plasma exchange Pulse steroid 14 15 17 19 21 23 25 32 60 days

19 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 stenosis 5. 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 polyneuropathy 5. Abnormal urinalysis and/or impaired renal function* 6. Testicular pain or tenderness 7. Signs or symptoms suggesting vasculitis of any other major organ system (gastrointestinal, cardiac, pulmonary, or CNS)* EULAR/PRES Criteria. Ann Rheum Dis; 2006

20 plasma exchange Prednisolone oral 2 mg/kg Cre ­ (> 500 mmol/l )
IV 15 mg/kg/dose CYC Oral 2 mg/kg 500 mg/m2 Cre ­ (> 500 mmol/l ) plasma exchange Vital organ involvement 3-6 months 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 12 months or longer Bakkaloglu A et al. Arch Dis Clin 2001; 85: Besbas N et al. Pediatr Nephrol 2000; 14:

21 INDUCTION THERAPY Prednisone ( 1-2 mg/kg/day) ± MP ( 3 pulses)
NORAM: MTX vs CYC MEPEX: PE vs MP CYCLOPS: CYC iv vs oral WEGET: Etanercept vs placebo SOLUTION: ATG Prednisone ( 1-2 mg/kg/day) ± MP ( 3 pulses) Cyclophosphamide ( 2 mg/kg/day) or iv pulses 3 - 6 mo. NORAM: MTX vs CYC CYCAZAREM: AZA vs CYC IMPROVE: AZA vs MMF REMAIN: AZA, 24 mo vs 48 mo Maintenance therapy

22 Recent Alternative Therapies
Rituximab (RITUXVAS): Several, uncontrolled studies (refractory) Many reports observed disease remissions in relapsing and refractory patients with ANCA associated or other vasculitides Leflunomide Deoxypergualin Anti 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

23 CASE 3

24 Poor appetite, fatigue, weight loss for one month
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):

25 Physical examination Body temperature: 36.6 C Pulse 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):

26 Laboratory Tests IgA : 168 mg/dl (68-378) IgM : 1220 mg/dl (50-250)
Hb : 9.9 g/dl WBC : /mm3 Platelet: 675x103 /mm3 CRP : 10.2 mg/dl ESR : 60 mm/hr BUN : 8 mg/dl Cre : 0.5 mg/dl Urinary pH: density: protein: protein- , 1-2 WBC /hpf IgA : 168 mg/dl (68-378) IgM : 1220 mg/dl (50-250) IgG : 1450 mg/dl ( ) ANA : Negative Anti-DNA : Negative ANCA : Negative HBsAg : Negative Anti-HCV: Negative

27 CT/MRI Topaloglu R et al. Pediatr Nephrol 2005; 20:

28 Angiography Topaloglu R et al. Pediatr Nephrol 2005; 20:

29 CLASSIC 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)

30 CASE 4

31 12 year old girl Abdominal pain, myalgia Nausea Fever Rash on extremities Recurrent abdominal pain and fever- FMF? Blood pressure: 150/90 mmHg

32 Laboratory Tests Hb : 11.7 g/dl IgA : 184 mg/dl (68-378)
WBC : /mm3 Platelet: 558 x103 /mm3 CRP : 18 mg/dl ESR : 55 mm/hr BUN : 12 mg/dl Cre : 0.6 mg/dl Urinary pH: density: protein: +++ 10-15 RBC/hpf IgA : 184 mg/dl (68-378) IgM : 770 mg/dl (50-250) IgG : 1850 mg/dl ( ) 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/-

33

34 Renal Angiography

35 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.

36 CASE 5

37 Fever and irritability Mother-carrier for HBs Ag
9 month old girl Fever and irritability Mother-carrier for HBs Ag Blood pressure: 180/100 mmHg ESH: 70 mm/hr Urinalysis: protein +++ Angiogram: Renal and mesenteric microaneurysms HBs Ag (+) HBe Ag (+) HBV DNA > 2000 pg/ml Duzova A et al. Eur J Pediatr 2001; 160:

38 *: anaemia and leukocytopenia
> > > > HBV DNA pg/ml HBs Ag HBe Ag Antihypertensive drugs Prednisolone (2 mg/kg) Cyclophosphamide Interferon *: anaemia and leukocytopenia * 5x106 U/m2 10x106 U/m2 200 180 160 140 Blood pressure (mmHg) 120 100 80 60 Diastolic BP 40 Systolic BP 2 4 6 8 16 18 20 22 30 Figure 1: Time course of blood pressure, treatment and virological parameters Months Duzova A et al. Eur J Pediatr 2001; 160:

39 CASE 6 & 7

40 Patient 6 Angiography RRA: Normal 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

41

42 TREATMENT 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

43 Patient 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

44

45 TREATMENT 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 year Low dose steroid and MTX

46

47 Takayasu 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: 72-76 Hoffman et al. Arthritis Rheum 2004; 50:

48 Summary 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 diagnosis ANCA 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.


Download ppt "TREATING DIFFICULT PATIENTS OF RENAL VASCULITIS"

Similar presentations


Ads by Google