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Henoch-Schönlein Purpura:
Can we prevent nephritis and
progression ?
Dr. Ayşe Öner
Trakya University, Edirne / TURKEY
ESPN 2008, LYON
Can we prevent the progression of HSP
nephritis?

Kidney damage is the principal prognostic determinant in
Henoch-Schönlein purpura (HSP), affecting between 1590% of the patients.

Of the children with Henoch-Schönlein Nephritis (HSN),
more than 1-7% progress to end-stage renal failure

In long-term studies 19-20% develop ESRD in selected
pts
Koskimies et al. (1981)Arch Dis Child 56:482–484
Niaudet P et al (1993) Adv Nephrol 2: 121–140.
Schärer K et al (1999). Pediatr Nephrol 13: 816–823
Tzard EJ Arch Dis Child Educ Pract Ed(2008);93:1-8
Can we prevent the progression of
Henoch-Schönlein nephritis ?
1- Do we need to treat every patient with HSN ?
2-Which group of patients would be more likely to suffer from
long term morbidity ?
3- What the therapy should consist of?
4-How effective is the treatment in altering the clinical course of
HSN in short and long- term ?
Do we need to treat every patient with HSN ?

HSP children with renal involvement
Grade I
Isolated microscopic hematuria
Grade II
Hematuria and mild proteinuria
Grade III
Acute nephritic syndrome
Grade IV
Proteinuria >1 gr/ day / or nephritic syndrome
Grade V
Acute nephritic syndrome /nephrotic syndrome
Which group of patients with HSN would be
more likely to suffer from long term morbidity ?
Risk factors for developing CRF in children with HSN
A- Clinical risk factors






Age >7
Nephrotic syndrome
Persistent proteinuria
Initial renal insufficiency
Nephrotic / nephritic syndrome
High blood pressure
Goldstein A R et al (1992) . Lancet 339:280–282
Shaerer K. Pediatr Nephrol (1999). 13: 816-2
Coppo R, 2006. Am J Kidney Did;47:993–1003.
Mir S et al. Pediatr Nephrol (2007).22:1;67-70
Which group of patients would be more likely to
suffer from long term morbidity ?
B- Hystological changes


Grade IVGrade V


Crescentic GN (> 50%)
48 % patients
Tubulointerstitial changes ( chronic)
55% patients
67% patients
Counahan R et al BMJ (1977) 2: 11-14
Goldstein AR et al .Lancet.1992;339:280-2
Niaudet P et al Ann Med Int ( 1994) 145: 577-80
Foster B et al J Pediatr (2000) 136: 370-5
CRF
CRF
What the treatment of HSN should consist
of?

There is no consensus on therapy
- Steroid alone ( oral or pulse )
- Steroid in combination with
Cyclophosphamide
Azathioprine
Cyclosporine A
Mycophenolate mofetil
ACE-I
Vit E
- Plasmapheresis
- IVIG
Other: Antiplatelet agents
Dipyridamole
Factor XIII
Wyatt RJ –HoggRJ.Pediatr Nephrol(2001) 156-167
Tzard EJ Arch Dis Child Educ Pract Ed(2008);93:1-8
Different immunosuppressive and –modulative
treatments and outcome in children with severe HSN
First author
Year
No. Of
patients
Thearpy
Mean
Follow-up
In
Remission
Minory
urinary
abnormalities
Chronic
renal
disease
ESRD
Niaudet
et al.
1998
38
MP, P
8
27
3
4
4
Öner
et al.
1995
12
MP, P, CP, D
0.5
7
3
1
1
Kawasaki
et al.
2003
56
MP, U, P, D
9.7
39
10
5
1
Singh
et al.
2002
11
MP, P, Az
4.7
9
1
1
0
Tanaka
et al.
2003
9
P, CP
6.5
7
2
0
0
Iijima
et al.
1998
14
P, CP, H, D
7.5
9
4
1
0
Kawasaki
et al.
2004
6
PP, MP, U, P,
D
4.6
2
3
1
0
Öner
et al.
2008
43
MP, P, CP, D
3.5
21
17
2
3
MP: Pulse prednisolone, Az: azothioprine, CycA: Cyclosporine A; PP: Plasmapheresis, CP:
Cyclophosphamide
Different immunosuppressive and –modulative
treatments and outcome in children with severe HSN
First author
Year
No. Of
patients
Thearpy
Mean
Follow-up
In
Remission
Minory
urinary
abnormalities
Chronic
renal
disease
ESRD
Tarshish
et al.
2004
28
CP
>3.7
13
8
4
3
Tarshish
et al.
2004
28
Only
supportive
>3.7
14
6
4
4
Shin
et al.
2005
10
Az, P
>1
6
4
0
0
Shin
et al.
2005
10
P
>1
4
2
1
3
MP: Pulse prednisolone, Az: azothioprine, CycA: Cyclosporine A; PP: Plasmapheresis, CP:
Cyclophosphamide
Does the treatment effect outcome in severe HSN ?




Early studies using per oral steroids for the treatment of HSN showed no
benefit
No differences in outcomes between patients receiving corticosteroids,
immunosuppressives or both and patients with no treatment
In a recent prospective study patients provided with only supportive
treatment had a similar outcome to those treated with
cyclophosphamide
Early treatment may also prevent the histological progression of the
disease.
Counahan R et al BMJ (1977) 2: 11-14
Tarshihs P et al Pediatr Nephrol (2004) 19:51-56
Tanaka H, (2003) Pediatr Nephrol 18: 347–350.
Does the treatment effect outcome in
severe HSN ?

In the past HS nephritis → 15% of children with ESRD

More recent HSN →1.8–3% of children with ESRD

More aggressive treatment may have had a beneficial
impact on the outcome.
Narchi H.. Arch Dis Child2005;90:916–20.
Meadow SR.Clinical Nephrology 1978;9:87–90.
Niaudet P et al .Pediatr Nephrol 1998;12:238–43.
Triple Therapy Protocol
1-MPZ (iv.pulse) (30mg/kg/day, 3 days), followed by oral
prednisolone 45 mg/m2/day with tapering doses( over 3
months)
2. Oral cyclophosphamide, 2mg/kg/day, (2-3 months)
3. Dipyridamole 5 mg/kg/day ( 6 months)
The effect of Triple Therapy Protocol on
rapidly progressive type of HSN in short-term
follow-up period

Follow-up Period:9-39 months
7 pts complete remission
4 pts partial remission
1 patient CRF
Conclusion:
Triple therapy prevent the Progresion of Rapidly
Progresive type of Henoch Schönlein Nephritis in the
early course of the disease
The effect of Triple Therapy Protocol on
Rapidly Progressive Type of HSN in
Long-Term Follow-up Period
Case 1; İT


Age: 12 years
Sex: male

Renal involvement at the first admission:
Acute nephritic and nephrotic syndrome (Grade 5)
–
–
–
–

Edema-oliguria
hypertension
decreased GFR (14 ml/min per 1.73 m2)
proteinuria (4.8 g/m2 per day).
He fulfilled the clinical criteria of RPGN.
Case 1;İT

Renal biopsy was not available.
Initation of treatment: > 2 months( after onset)

Treatment protocol: Triple therapy

He discharged with partial remission with a serum
creatinine level of 2 mg/dl.

Case 1; İT

He was lost to follow-up for 30 months.

He readmitted with acute nephritic and nephrotic syndrome,

Renal biopsy
60-75% fibroepithelial and fibrous crescents
extensive fibrotic changes in tubulointerstitial tissue.

Duration of follow-up: 14 years
Outcome: End stage renal failure(4 years after first admission
CAPD-Renal transplantation- Graft rejection- HemodialysisEXITUS
Case 2, KA

Age: 11 years Male

Renal involvement at the first admission:
Acute nephritic and nephrotic syndrome (Grade 5)
–
–
–
–
hypertension
proteinuria (9.6 g/m2 per day)
decreased GFR (25 ml/min per 1.73 m2)
oliguria/acute periton dialysis
Case 2, KA



Renal biopsy
80% fibroepithelial and fibrous crescents,
mild tubulo-interstitial fibrosis
Initation of treatment: > 6 weeks
Treatment: Triple therapy
acute periton dialysis
Follow-up: 16 years
Outcome:
Partial remission with persistent proteinuria
(< 1 g/day)
Case 3, Ş.Ç.

Age: 14 years

Sex: female
Acute nephritic and nephrotic syndrome (Grade 5)
– edema
– Hypertension
– decreased GFR (36 ml/min /1.73 m2)
– proteinuria (8.5 g/m2 /day).
Case 3, Ş.Ç.

Renal biopsy
Endo and extracapillary proliferative glomerulonephritis
(60% epithelial and fibroepithelial crescents)

Initation of treatment: 5 weeks

Treatment: Triple therapy
Outcome Complete remission

Duration of follow-up: 16 years
2 pregnancies with transient hypertension and proteinuria
having 2 healthy babies

Clinical status at the latest visit:
Complete remission
Case 4; G.Ö.



Age: 8 years
Sex: female
Renal involvement at the first admission:
Acute nephritic and nephrotic syndrome (Grade 5)
– gross hematuria
– decreased GFR (34 ml/min per 1.73 m2)
– proteinuria (4.2g/m2 per day)

Initation of treatment: 5 weeks
Case 4; G.Ö.

Treatment protocol: Triple therapy

Renal biopsy: 60 % epithelial crescent formation
Clinical status (after 3 years of onset )


Complete remission
Case 4; G.Ö.

2006 ( After 8 years of remission)

She had complaint of macroscopic hematuria with concurrent
pharyngitis

She developed nephritic/nephrotic syndrome
No extrarenal symptoms

Serum Ig A level was high
DİAGNOSIS:
IgA nephropathy
Case 4; G.Ö.
•
Treatment:
MP pulse therapy (6 months)
Cyclosporine A (3 mg/kg/day 18 months)
ACE inh.
(1 mg/kg/day)
Dypiridamole (5 mg/kg/day )
Prophylaxy
( benzathine penicilline)
•
She responded well to the therapy,went into
remission ( after six months)

Duration of follow-up:15 years
REMISSION
What we learned from the long term follow up
of these four patients?

Initial symptoms,hystological finding and timing of treatment are
very important in HSN

Early agressive treatment is necessary for severe HSN
(grade V-IV)

Pregnancy is a very important risk factor and can be
complicated by proteinuria and/or hypertension.

HSP and Ig A nephropathy can be encountered consecutively in
the same patient.
Patients


398 patients with HSP
156 patients (39.2%) with renal involvement were evaluated
retrospectively.




86 males / 70 females
mean age: 9.6 years
age range: 4-16 years
43 patients underwent renal biopsy.
156 Patients were graded according to the degree
of renal involvement.
Grade
Clinical and Laboratory
Findings
n
1
Isolated microscopic hematuria
31
2
Hematuria and mild proteinuria
60
3
Acute nephritic syndrome
4
4
Nephrotic syndrome
± hematuria
18
5
Acute nephritic and nephrotic
syndrome
43
Histopathology of ISKDC classification in
HSN
Grade I: Minimal alterations
Grade II: Mesangial proliferation
Grade III a: Focal
b: Diffuse
proliferation
<50 % crescent
Grade IV a: Focal
b: Diffuse
proliferation
50-75 % crescent
Grade V a: Focal
b: Diffuse
proliferation
>75 % crescent
Grade VI: MPGN like GN
Renal biopsy results in 43 patients
Histopathological grades
n
Class I: minimal glomerular lesions
1
Class II: mesangial proliferation, no crescents
13
Class III: crescents < 50%
9
Class IV: crescents 50-75%
Class V: crescents > 75%
12
8
Treatment modalities of 43 patients with renal
biopsy
20 patients
(Class IV and V)
Triple therapy
1. iv.pulse MPZ
30mg/kg/day, 3 days
followed by oral prednisolone in
tapering doses
2. oral cyclophosphamide
2mg/kg/day, 2-3months
3. Dipyridamole
23 patients
(Class I-III)
1. iv.pulse MPZ
30mg/kg/day, 3 days
before the result of renal biopsy
followed by oral prednisolone in
tapering doses
2. dipyridamole
Evaluation of outcome after treatment
State A: No sign of renal involvement (healthy)
State B: Minor urinary abnormalities
microscopic hematuria, proteinuria
State C: Active renal disease
Proteinuria of 40 mg/m2/h
HT,
State D: Renal insufficiency
Dialysis
Transplantation
Death
Outcomes A+B were judged to represent a good
outcome and C+D a poor outcome
Follow-up of the patients

Follow-up period:
– Mean: 303.5 months
– Range: 1-16 years.
Prognosis of the patients
Initial
presentation
Clinical
status at
the latest
observation
Complete remission
Minor urinary
abnormalities
Active renal
disease
Renal failure
GRADE A
GRADE B
GRADE C
GRADE D
Grade 1
(n: 31)
23
8
-
-
Grade 2
(n: 60)
38
22
-
-
Grade 3
(n: 4)
2
2
-
-
Grade 4
(n: 18)
8
10
-
-
Grade 5
(n: 43)
21
17
Total
(n:156)
92 (59%)
2
3
extensive fibrotic changes in crescents and
tubulointerstitial tissue
59 (38%)
2 (1%)
3 (2%)
Prognosis of the patients
2%
160
1%
38%
140
100
Renal failure
Active renal disease
80
59%
number of patients
120
60
40
Minor urinary abnormalities
Complete remission
20
0
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
degree of renal involvement
Total
Summary of the results

The prognosis of the patients with mild renal involvement
(Grade 1-3) was better.

The patients having severe forms of nephritis (Grade 4-5)
showed good prognosis with appropriate treatment.

The development of chronic renal failure is associted with
clinical nephritic and nephrotic syndrome, and
histopathological extensive crescent formation and especially
fibrotic changes in crescents and tubulointerstitial tissue.
Conclusion:

Initial presentation of renal involvement determines the prognosis
in HSN

Triple therapy appears to be effective in preventing of
progression of severe HSN especially if started before the
development
of
fibrotic
changes
in
crescents
and
tubulointerstitial tissue.

In view of the small number of patients with severe renal disease
multicentre/international studies are required to establish the role
of immunosuppressive therapy.
TREATMENT
RECOMMENDATİONS

Severe HSN Grade IV-V(Nephritic-Nephrotic Syndrome)
Induction Therapy(Triple therapy)
1. I.V.pulse MPZ (30mg/kg/day, 3 days), followed by
oral prednisolone in tapering doses
2. Oral cyclophosphamide, 2mg/kg/day, 2-3 months
3. Dipyridamole 5 mg/kg/day
Maintenance therapy ( 6 months)
Oral prednisolone
Dipyridamole 5 mg/kg/day
ACEI
Profilactive therapy (penicilline)
 Mild grades HSN Grade I-II-III
No spesific treatment supportive only.
Hypertension
ACEI
Thank you

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