Steroid-resistant nephrotic syndrome: diagnosis and therapy - GPN

Steroid-resistant nephrotic
syndrome: diagnosis and therapy
Christian Plank, Department of Pediatrics, Pediatric
Nephrology, University Hospital Erlangen

1 ½ year old boy, transfered from a nearby pediatric
hospital
Four weeks ago edema, proteinuria 90 mg/m²/d,
hypalbuminemia 16,7 mg/dl, and
hypercholesterinemia 298 mg/dl
Initial diagnosis: idiopathic nephrotic syndrome
Start with prednisone 60mg/d (according GPN)
?
Now still edema, proteinuria 60 mg/m²/d
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C. Plank, GPN 2009, Amsterdam

What do to do next
proteinuria > 40 mg/m 2 BSA/h
Hypalbuminemia < 25 mg/dl
edema
age > 1 and < 10 years ?
secondary nephrotic syndrome ?
Syndromatic nephrotic syndrome ?
Initial therapy:
prednisone p.o.
60 mg/m2 BSA in 3 doses
no
yes
Renal biopsy
remission within 4
weeks (~90%)
No remission within 4
weeks (~10%)
Further diagnostics ?
Further therapy ?
Steroid sensitive
nephrotic syndrome
Primary steroid
resistant nephrotic
syndrome
According to Dötsch et al., Monatsschrift Kinderheilkunde, 2004
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C. Plank, GPN 2009, Amsterdam

Primary nephrotic syndrome
MCNS, FSGS
Mesangial proliferative GN, IgA-GN, MPGN,
membranous GN
Genetic forms of nephrotic syndrome
Congenital nephrotic syndrome (eg. NPHS1)
Familial and sporadic steroid resistant
nephrotic syndrome (eg. NPHS2)
Nephrotic syndrome in syndromal disease (eg.
WT1, Schimke‘s disease, Alport Syndrome)
Secondary nephrotic syndrome
Paraneoplastic and toxic
Chronic infections (eg. hepatitis B, HIV)
Vasculitis and systemic disease (eg. SLE)
…
hypertension,
hematuria, C3 level,
antistreptococcal
antibodies
Infantil age
Genetic screening
(NPHS1 + 2, WT 1)
Syndromal clinical
features
History, X-ray,
ultrasound, WBC
History, serology
History, C3 level,
antinuclear
antibodies

Differences between
steroide senitive (%) steroide resistant (%)
age (years median) 2,5 6
age < 1 year 2 11
male 76 55
hematuria 21 50
non selective proteinuria 10 83
hypertension 6 11
minimal change disease 93 7
end stage renal failure (10 y) 1 40
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C. Plank, GPN 2009, Amsterdam

Renal biopsy !!!
Histology in nephrotic children
Prof. K. Amann, Nephropathology, University
Hospital Erlangen
% steroid response within
8 weeks (%)
Minimal change nephropathy 77,1 93
FSGS 7,9 30
Focal global glomerulosclerosis 1,7 75
Diffus mesangial proliferation 2,5 56
Membranoproliferative GN 6,2 7
Membranous GN 6 0
According to ISKDC, The primary nephrotic syndrom ein children. Identification of patients with minimal change nephrotic
syndrome from initial response to prednisone. J Pediatrics 1981, 98:561-564
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C. Plank, GPN 2009, Amsterdam

Therapy: Aims
Stop proteinuria!
Stop hyperhydratation and edema!
Prevent infections and thrombembolic events!
Prevent progression of renal failure!
Prevent cardiovascular comorbidity!
Prevent recurrence!
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C. Plank, GPN 2009, Amsterdam

clinical features and symptomatic therapy:
edema
infection
Hypovolemic shock and
nephrotic crisis
Hypercoagulability
hyperlipidemia
hypertension
Chronic renal failure
1. sodium intake ↓, fluid intake↓
2. Furosemid p.o. 2-6 mg/kg/d 3-4 doses per day
3. Furosemid iv, ggf. hydrochlorothiazide,
spironolacton
4. 20% albumin (1g/kg 2-4 h) + Furosemid (1-2 mg/
kg iv) in severe cases
surveillance (sepicemia/peritonitis), early antibiotic
treatment, vaccination against pneumococcal and
varicella vaccine
moderate volumen depletion, therapy controll by body
weight, fluid balance and blood pressure,
hemofiltration
mobilisation, no central venous lines, aspirin, heparin
In chronic cases statins (eg. pravastatin)
ACE-inihibitors or AT II blockers preferred
Conservative treatment, dialysis and transplantation

Therapeutic options:
prednisone
cyclosporine A
ACE-inhibitors
methylprednisolone
Cyclophosphamid
plasmapheresis
mycophenolatmofetil
tacrolimus
rituximab
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C. Plank, GPN 2009, Amsterdam

Anti-proteinuric effect of ACE-inhibition
by enalapril (0.2 vs. 0.6 mg/kg/d) in SRNS children
Bagga A et al., Enalapril dosage in steroid-resistant nephrotic
syndrome Pediatric Nephrology, 2004: 19:45-50
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C. Plank, GPN 2009, Amsterdam

Cyclophosphamide pulses:
Therapeutic option in SRNS?
Bajpai A et al., Intravenous cyclophosphamide in steroidresistant
nephrotic syndrome. Ped Nephrology 2003
18:351-356
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C. Plank, GPN 2009, Amsterdam

Similar efficacy of cyclophosphamide po and iv in
combination with steroids after 6 months
CPH iv (6 x)
+ prednisone po (4 months)
+ enalapril po
Dexamethason iv (16 x)
+ CPH po (3. -14. weeks)
+ prednisone po (4 months)
+ enalapril po
Mantan M et al., Efficacy of intravenous pulse cyclophosphamide tretament versus combination of
intravenous dexamethasone and oral cyclophosphamide tretament in steroid-resistant nephrotic
syndrome. Ped Nephrology 2008 23: 1495-1502
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C. Plank, GPN 2009, Amsterdam

Positive effect of cyclosporin A po in metaanalysis
Hodson et al, Cochrane Database Syst Rev. 2006
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C. Plank, GPN 2009, Amsterdam

Comparison of ciclosporin A + prednisone po
versus cyclophosphamide iv + prednisone po
Prednisone
500 mg/m² iv
Plank C, Kalb V, Hinkes B, Hildebrandt F, Gefeller O, Rascher W for Arbeitsgemeinschaft
für Pädiatrische Nephrologie. Ciclosporin A is superior to cyclophosphamide in children
with steroid resistant nephrotic syndrome – a randomized controlled multicentre trial by
the APN. Ped Nephrol 2008; 23:1483-1493
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C. Plank, GPN 2009, Amsterdam

Plank C, Kalb V, Hinkes B, Hildebrandt F, Gefeller O, Rascher W for
Arbeitsgemeinschaft für Pädiatrische Nephrologie. Ciclosporin A is superior to
cyclophosphamide in children with steroid resistant nephrotic syndrome – a
randomized controlled multicentre trial by the APN. Ped Nephrol 2008;
23:1483-1493

in total 11 % endstage renal
failure
56 % remission/partial remission
on CSA in follow up
Plank C, Kalb V, Hinkes B, Hildebrandt F, Gefeller O, Rascher W for Arbeitsgemeinschaft für
Pädiatrische Nephrologie. Ciclosporin A is superior to cyclophosphamide in children with
steroid resistant nephrotic syndrome – a randomized controlled multicentre trial by the APN.
Ped Nephrol 2008; 23:1483-1493
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C. Plank, GPN 2009, Amsterdam

Toxicity ?
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C. Plank, GPN 2009, Amsterdam

Treatment protocol for patients with idiopathic steroid-resistant nephrotic syndrome and FSGS
(Group 1)
Ehrich, J. H. H. et al. Nephrol. Dial. Transplant. 2007 22:2183-2193; doi:10.1093/ndt/
gfm092
Copyright restrictions may apply.

Remission rate after initiation of two different immunosuppressive therapies in children with
idiopathic steroid-resistant nephrotic syndrome and focal and segmental glomerulosclerosis
(FSGS) (group 1A = 25 patients, group 1B = 27 patients) CSA, ciclosporin A; PRED, prednisolone
Copyright restrictions may apply.
Ehrich, J. H. H. et al. Nephrol. Dial. Transplant. 2007 22:2183-2193; doi:10.1093/ndt/
gfm092

Alternative therapy scheme with mycophenolat mofetil
and ACE-inhibitor: proteinuria reduced by 72% over 6
months
3 6
Montane B, Abitbol C et al., Novel therapy of focal glomerulosclerosis with
mycophenolate and angiotensin blockaed, Pediatri Nephrolo 2003, 18:772

the positive end ….
Complete remission by CSA and alternate prednison
po after 3 months
hypertension treated by enalapril and atenolol
Early end of CSA and prednison therapy after 12
months
Follow up over 8 years without relapse and stable
renal function
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C. Plank, GPN 2009, Amsterdam

CSA+Pred po
PD HD TX
Enalapril
Risk of
recurrence ?
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C. Plank, GPN 2009, Amsterdam

~ 30% recurring FSGS after renal transplantation:
option of therapeutic plasmapheresis
Bosch T, Wendler T. Extracorporeal Plasma Treatment in Primary and
Recurrent Focal Segmental Glomerular Sclerosis: A Review, Therapeutic
Apheresis, 2001 5(3):155–160
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C. Plank, GPN 2009, Amsterdam

Example for a therapeutic algorithm on SRNS
Steroid-resistant
nephrotic syndrome
Genetic testing for NPHS1,
NPHS2 and WT1
positive
supportive therapy
Renal biopsy
Minimal change or FSGS
Other GN‘s
or secondary nephrotic
syndromes
specific therapy
D.: Primary idiopathic steroid-resistant nephrotic syndrome
Combination of
-Optional Induction: methylprednisolone pulses i.v. (eg. 6 x
300mg/m² in 3 weeks)
- Ciclosporin A p.o. (150mg/m²/day → C 0 120-140 ng/ml)
- Prednisone/prednisolone p.o. (tapering doses starting
with 40mg/m2/48h at least over 6 months)
- ACE-Inhibitor (eg. Enalapril 0,3-0,6 mg/kg/d)
No Remission after 6 months:
„Rescue“ with eg.
ciclosporine A + mycophenolate
mofetil
tacrolimus
plasmapheresis
Relapse:
Ciclosporine A (C 0 120-140 ng/
ml)
start with prednison (60mg/m²/
d) with or without
methylprednisolon pulses
Remission after 6 months:
Ciclosporine A (C 0 80-120ng/
ml) for 2- 3 years
C. Plank, GPN 2009, Amsterdam