CONSENSUS STATEMENT:
MANAGEMENT OF IDIOPATHIC NEPHROTIC SYNDROME IN CHILDHOOD
Contents Page
Working group and workshop participants 1
1. Definition of nephrotic syndrome 3
2. Investigations at initial presentation 3
3. Management 4
3.1. Management of oedematous state 4
3.2. Management of complications of nephrotic syndrome 5
3.3. Indications for renal biopsy 6
3.4. Corticosteroids in nephrotic syndrome 6
3.4.1. At initial diagnosis 6
3.4.2. Relapse 7
3.4.3. Frequent relapses and steroid dependence 8
3.5. Cyclophosphamide 8
3.6. Relapses post cyclophosphamide 9
3.7. Urine albumin monitoring 9
4. Schema of treatment of idiopathic nephrotic syndrome 10
5. Definitions 11
6. References 12
1
CONSENSUS STATEMENT:
MANAGEMENT OF IDIOPATHIC NEPHROTIC SYNDROME IN CHILDHOOD
WORKING GROUP FOR INITIAL DRAFT
Adivisor : Dr. Mohd Sham Kasim
Consultant Paediatrician and Head
Department of Paediatrics
Hospital Kuala Lumpur
Chairman: Dr. Lim Yam Ngo
Consultant Paediatric Nephrologist
Department of Paediatrics
Hospital Kuala Lumpur
Dr. Indon Lajin
Consultant Paediatric Nephrologis
Subang Jaya Medical Centre
Subang Jaya
Dr. Susan Pee
Consultant Paediatric Nephrologist
Department of Paediatrics
Hospital Sultanah Aminah
Johor Baru
Dr. Amir Hamzah
Paediatric Clinical Specialist
Department of Paediatrics
Hospital Kuala Lumpur
Dr. Lynster Liaw
Trainee in Paediatric Nephrology
Department of Paediatrics
Hospital Kuala Lumpur
WORKSHOP PARTICIPANTS
Representatives from the Ministry of Health
Dr. Wong Swee Lan
Consultant Paediatrician
Hospital Seremban
Dr. Kwan Geok lan
Consultant Paediatrician
Hospital Melaka
Dr Pyar Kaur
Consultant Paediatrician
Hospital Pulau Pinang
Dr. Soo Thian Lian
Consultant Paediatrician
Hospital Queen Elizabeth
Kota Kinabalu
2
Dr. S Tharam
Consultant Paediatrician
Hospital Ipoh
Dr. Leow Poy Lee
Paediatrician
Hospital Muar
Dr. Jamaluddin Hj Mohamad
Paediatrician
Hospital Tengku ampuan Afzan
Kuantan
Dr. Margaret Kannimmel
Paediatrician
Hospital Tengku Ampuan Rahimah, Kelang
Dr. Angeline Yeoh
Paediatrician
Hospital Seberang Jaya
Dr Kamarul Azahar
Paediatrician
Hospital Seremban
Dr. Irene Cheah
Consultant Paediatrician
Hospital Kuala Lumpur
Dr. Nur Khatijah Nurani
Paediatrician
Hospital Kangar
Dr. Neoh Siew Hong
Paediatrician
Hospital Taiping
Dr. Wong See Chang
Paediatrician
Hospital Sibu
Dr Tam Pui Ying
Paediatrician
Hospital Sultanah Aminah
Johor Baru
Dr. Low Bin Hooi
Paediatrician
Tawau Hospital
Representatives from the Universities
Dr. Hans Van Rulenberghe
Paediatric Nephrologist
Hospital University Sains Malaysia
Kubang Kerian
Dr. Christopher CC Chua
Paediatrician/Lecturer
University Hospital, Kuala Lumpur
Assoc Prof Zulkifli Ismail
Department of Paediatrics
Universiti Kebangsaan Malaysia
Assoc Prof Ong Lai Choo
Department of Paediatrics
Universiti Kebangsaan Malaysia
Representatives from Private Sector
Dr Gnanambai Athi
Consultant Paediatrician
Medical Specialist Centre
Air Keroh, Melaka
Dr. David Manickam
Consultant Paediatrician
Ipoh Specialist Centre, Ipoh
Dr. Nazeli Hamzah
Paediatrician
Klinik Perdana
Kota Bharu, Kelantan
3
CONSENSUS STATEMENT:
MANAGEMENT OF IDIOPATHIC NEPHROTIC SYNDROME IN CHILDHOOD
Idiopathic nephrotic syndrome in childhood is diagnosed by the presence of significant
proteinuria, hypoalbuminaemia and oedema, the underlying cause of which is unknown.
Although said to be uncommon in the West at about 3 new cases per 100,000 child
population, data suggests that Asians have a higher incidence at about 16 new cases per
100,000 child population .1 Although there is no available local data, it is felt that the
incidence in Malaysia is also higher than in the West.
There are variations in the definition, investigation and management of nephrotic
syndrome in childhood. This has occasionally led to dire consequences to the physical
health of the child as well as the mental health of his/her parents. In addition, more
evidence is now available for a reasonable guideline to be formulated.
The obvious outcome of treatment of this condition is prolonged and sustained remission
of the nephrotic syndrome with minimal side effects from treatment.
1. DEFINITION OF NEPHROTIC SYNDROME:
A clinical syndrome of massive proteinuria defined by:
1. Urine protein excretion greater than 40 mg/m2/hour on a timed urine collection or an
early morning urine protein creatinine index of >200 mg/mmol;
2. Hypoalbuminaemia of <25 g/l,
3. Oedema.
4. Hypercholesterolaemia is not needed in definition.
It is important to ensure that there is no known primary renal disorder that has led to
the nephrotic syndrome, in particular that associated with post infectious
glomerulonephritis as the treatment for the nephrotic syndrome then depends on the
treatment of the primary renal disease.
2. INVESTIGATIONS AT INITIAL PRESENTATION
a) Full blood count,
b) Renal profile,
c) Serum albumin,
d) Urinalysis and quantification for urinary protein excretion.
e) Other investigations e.g. complement levels depends on the clinical features and the
physician in charge.
In general, the above list of investigations may suffice for children below 8 years of age
presenting with nephrotic syndrome without any other clinical features.
4
The International Study of Kidney Disease in Children (ISKDC) had found that at the
initial presentation of children with minimal change nephrotic syndrome -
20.7% of children had systolic blood pressure above 98th percentile for age;
22.7% had microscopic haematuria
32.5% had transiently raised plasma creatinine concentration
3. MANAGEMENT
3.1 MANAGEMENT OF THE OEDEMATOUS STATE.
A. Bed rest
This is not required and usually not practical unless the child has gross oedema.
B. Diet
A normal protein diet with adequate calories is recommended. Previous
recommendations of high protein diet had not been shown to improve serum albumin
concentration.
Salt intake should be reduced during the oedematous state.
C. Antibiotics.
Children with nephrotic syndrome are more prone to primary bacterial peritonitis.
Prophylactic oral penicillin at doses of 125 mg BD or 250 mg BD depending on the
size of the child is recommended during relapse particularly with gross oedema in
view of the lack of home albuminuria monitoring and long distance from the hospital.
Pneumococcal vaccine can be considered. However, it must be cautioned that the
vaccine does not cover all strains of pneumococci and some children with nephrotic
syndrome have been shown to be poor responders to this vaccine.
D. Hypovolaemia.
Children with nephrotic syndrome can present with hypovolemia, the manisfestations
of which include abdominal pain, cold peripheries, poor pulse volume, hypotension,
and haemoconcentration.
The treatment is to infuse salt poor albumin at 0.5 to 1.0 g/kg/dose over one to two
hours. If salt poor albumin is not available, other volume expanders like 5% albumin,
plasma protein derivatives or human plasma can be used.
E. Fluid restriction
This is not usually recommended except in chronic oedematous states.
5
F. Diuretics.
Diuretic therapy is not usually necessary in steroid responsive nephrotic syndrome
but if required should be used with caution as it can precipitate hypovolemia.
Salt poor albumin of 20 - 25% concentration can be used in symptomatic grossly
oedematous states together with intravenous frusemide at 1-2 mg/kg to produce a
diuresis. There is however, the danger of fluid overload with salt poor albumin
infusion and the child’s urine output and blood pressure should be closely monitored.
G. Hypercholesterolaemia
There is insufficient evidence for a recommendation to be made as yet.
3. 2. MANAGEMENT OF THE COMPLICATIONS OF NEPHROTIC
SYNDROME
A. Infections.
Children with nephrotic syndrome are prone to infections particularly cellulitis &
primary peritonitis.
Should a child with nephrotic syndrome develop primary peritonitis, the antibiotics
recommended is parenteral penicillin and a third generation cephalosporin as it has
been found that about half of primary peritonitis is due to Streptococcal pneumoniae
and the other half to gram negative bacilli.
The parents and children should be advised and cautioned about contact with
chickenpox and measles, and if exposed should be treated like any
immunocompromised child. If varicella-zoster immunoglobulin (VZIG) is available,
it should be given within 72 hours after exposure to chickenpox. If VZIG is not
available, some units recommend giving a single dose of intravenous
immunoglobulin.
B. Immunisation.
While the child is on corticosteroid treatment and within 6 weeks after its cessation,
only killed vaccines may be safely be administered to the child. Live vaccines can be
administered 6 weeks after cessation of corticosteroid therapy
6
C. Acute renal failure
This is a rare complication in children with steroid responsive nephrotic syndrome.
The actual cause is not known although hypovolemia has been implicated. Intrarenal
factors have also been postulated to play a role.
D. Thrombosis
This complication if suspected should be thoroughly investigated and treated to
prevent fatal complications.
Treatment consists of anticoagulation with the various anticoagulants available. The
duration of anticoagulation required is still controversial.
E. Acute Adrenal Crisis
This may be seen in children who have been on long term corticosteroid therapy
(equivalent to 18 mg/m2 of cortisone daily) when they undergo situations of stress.
Adequate cover with corticosteroids during these periods of stress is recommended to
be given in 3 divided doses.
3.3. INDICATIONS FOR RENAL BIOPSY
A renal biopsy is not required for children presenting with idiopathic nephrotic syndrome
for the following reasons.
About 80% of children 1to 12 years of age with idiopathic have minimal change
nephrotic syndrome.
93.1 - 97% of patients MCNS respond to corticosteroid therapy 3,4
.
91.8% of steroid responders have minimal change disease1.
A renal biopsy is also NOT required prior to cytotoxic therapy. 4,6,7
Main indication for renal biopsy
Steroid resistant nephrotic syndrome defined as failure to achieve remission despite 4
weeks of adequate corticosteroid therapy.
Other indications
This would depend on the associated features of the nephrotic syndrome and shall be
left to the discretion of the attending paediatrician in consultation with the paediatric
nephrologist.
7
3.4. CORTICOSTEROIDS IN NEPHROTIC SYNDROME
3.4.1 At Initial diagnosis
A paediatrician should be consulted before initiation of therapy in a child with newly
diagnosed nephrotic syndrome
Corticosteroids was found to be effective in inducing remission of nephrotic syndrome
from the 1940’s, and has since then been used as first line therapy in the treatment of
idiopathic nephrotic syndrome although no controlled trial was ever conducted about its
efficacy
Controversy lies in the dosage and duration of corticosteroids used at initial diagnosis of
the nephrotic syndrome. Various regimes of corticosteroids have been used. The two
regimes discussed were the modified ISKDC regime; and the so called longer initial
steroid induction regime proposed and studied by Ueda et al8 and Ksiazek and
Wysznska9, who showed a 2 year relapse free rate of 50% for the long initial
prednisolone dose versus 27.3% for the modified ISKDC regime.
Modified ISKDC regime
Prednisolone dosage at:
60 mg/m2/day (maximum 80 mg/day) for 4 weeks
40 mg/m2/48 hours for 4 weeks only.
Long initial prednisolone regime:
Prednisolone dosage at:
60 mg/m2/day (maximum 80 mg/day) for 4 weeks
40 mg/m2/48 hours for 4 weeks.
Reduced by 25% monthly over the next 4 months
The choice of using either regime was left to the individual attending paediatrician.
A child with nephrotic syndrome who fails to respond to an initial four week treatment
with corticosteroids should be referred to a paediatric nephrologist for a renal biopsy.
3.4.2 Relapse
The majority of children with idiopathic nephrotic syndrome will relapse 11,12
. A relapse
is defined by urine albumin excretion of > 40 mg/m2/hour or urine dipstix of 2+ or more
for 3 consecutive days.
Treatment of relapse
Prednisolone at 60 mg/m2/day (maximum 80 mg) is to be given until remission defined as
urine dipstix is trace or nil for 3 consecutive days after which the prednisolone dose is
reduced to 40 mg/m2/48 hours for 4 weeks .
8
It has not been shown that giving more corticosteroids for treatment of relapses results in
longer period of remission.
Breakthrough proteinuria may occur with intercurrent infection and usually does not
require corticosteroid therapy if the child has no oedema and remains well.
3.4.3 Frequent relapses and steroid dependence
An initial responder who has 2 or more relapses within 6 months of initial response or 4
or more relapses in any 12 month period is said to have frequent relapses.
Re-induction of any relapse with corticosteroids is as described in the section 3.4.2 on
relapse i.e. Prednisolone at 60 mg/m2/day (maximum 80 mg) until urine dipstix is
nil/trace for 3 consecutive days, after which the prednisolone dose is reduced to 40
mg/m2/48 hours for 4 weeks .The prednisolone is now tapered instead of discontinued at
the end of the re-induction regime. The rate of tapering depends on the patient and the
paediatrician in charge. The prednisolone is then kept on as low an alternate day dose as
possible for 6 months. This low dose alternate day prednisolone should preferabley not
exceed 0.5 mg/kg/dose.
Should a child relapse while on low dose alternate day prednisolone, the child should be
re-induced as for a relapse; the prednisolone is again tapered to low dose alternate day
prednisolone. Cyclophosphamide should be considered if the nephrotic syndrome is
steroid dependent and the child shows signs of steroid toxicity
3.5. CYCLOPHOSPHAMIDE
A renal biopsy is not needed prior to cyclophosphamide therapy.4,6,7
.
Cyclophosphamide therapy is indicated for the treatment of steroid dependent nephrotic
syndrome with signs of steroid toxicity like stunting of growth, cataracts, striae, severe
cushingoid features and osteoporosis and should be started when the child is in remission
following induction with corticosteroids.
Various trials have shown the superiority of cyclophosphamide with prednisolone versus
prednisolone alone in maintaining prolonged remission.12,13
Various dose and duration of
oral cyclophosphamide have been used. The report by APN14
demonstrated a 2 year
remission rate of 67% for cyclophosphamide at 2 mg/kg/day for 12 weeks against 22%
for 8 weeks given for children with steroid dependent nephrotic syndrome. Ueda et al 15
in a later paper comparing the 8 week versus 12 week duration of cyclophosphamide
however, showed no difference. Concern was expressed about the side effects of
cyclophosphamide particularly on the gonads.
A total cumulative dose of cyclophosphamide of 168 mg/kg was adopted for the
treatment of steroid dependent nephrotic syndrome i.e. 2 mg/kg/day for 12 weeks or 3
9
mg/kg/day for 8 weeks. While the child is on cyclophosphamide, prednisolone therapy
which can be further reduced and discontinued once the child completes the
cyclophosphamide therapy and remains in remission. Regular fortnightly review with full
blood counts and urinalysis should be carried out while the child is on oral
cyclophosphamide.
3.6. RELAPSES POST CYCLOPHOSPHAMIDE
Relapses after a course of cyclophosphamide is treated as for relapses after the initial
diagnosis of nephrotic syndrome if the child does not exhibit any further signs of steroid
toxicity.
Should the relapse occur soon after a course of cyclophosphamide when the child is still
steroid toxic, or the child again becomes steroid toxic after multiple relapses, then a
paediatric nephrology opinion should be sought.
Options available here are not many but fortunately this group of patients make up only
about 10 – 20% of children with nephrotic syndrome. The available options available
include:
A second course of cyclophosphamide
Cyclosporine can also be used on a very selective basis by paediatric nephrologists
and has been shown to maintain remission in 80% of these patients.
Levamisole which is not available in this country
3.7 URINE ALBUMIN MONITORING
It is advocated that monitoring of urine albumin excretion be done regularly either at
home with urinary dipstix or at the nearest health centre.
10
4. SCHEMA OF TREATMENT OF IDIOPATHIC NEPHROTIC SYNDROME
1. Nephrotic Syndrome
Initial Diagnosis
Prednisolone 60 mg/m2/day (max 80/day) for 4 weeks
Response No Response
Prednisolone 40 mg/m2/48 hours for 4 weeks
Renal Biopsy
*Discontinue *Steroid taper at 25% monthly
over 4 months
2. Relapse
Prednisolone 60 mg/m2/day (max 80 mg/day) till remission,
then 40 mg/m2/48 hours for 4 weeks and discontinue.
3. Frequent Relapses
Reinduce as for (2) above, then taper and keep low dose alternate day
prednisolone at 0.1 - 0.5 mg/kg/dose for 6 months.
4. Relapse on prednisolone
As for (3) if not steroid toxic,
consider cyclophosphamide (cumulative dose 168 mg/kg) if steroid toxic.
5. Relapses post cyclophosphamide
As for (2) and (3) if not steroid toxic.
If steroid toxic, refer paediatric nephrologist to consider
a). second course cyclophosphamide or
b). cyclosporine therapy.
* choice depends on attending paediatrician.
11
5. DEFINITIONS14
1. NEPHROTIC SYNDROME:
Oedema, serum albumin < 25 g/l, proteinuria > 40 mg/m2 /hour or urine protein
creatinine ratio > 200 mg/mmol.
2. REMISSION:
Urinary protein excretion < 4 mg/m2/hour or urine dipstix nil/trace for 3 consecutive
days.
3. RELAPSE:
Urinary protein excretion > 40 mg/m2/hour or urine dipstix ++ or more for 3 consecutive
days.
4. FREQUENT RELAPSES:
Two or more relapses within 6 months of initial response or four or more relapses within
any 12 month period.
5. STEROID DEPENDENCE:
Two consecutive relapses occurring during the period of steroid taper or within 14 days
of its cessation.
6. STEROID RESISTANCE:
Failure to achieve remission in spite of 4 weeks of standard prednisolone therapy.
12
6. References
1. Sharples PM, Poulton J, White RHR. Steroid responsive nephrotic syndrome is more
common in Asians. Arch Dis Child 1985; 60:1014-1017
2. A report of the ISKDC. Nephrotic syndrome in children. Prediction of histopathology
from clinical and laboratory characteristics at time of diagnosis. Kidney Int. 1978;
13:159-165
3. A Report of the ISKDC. The primary nephrotic syndrome in children. Identification of
patients with minimal change nephrotic syndrome from initial response to prednisone. J.
Pediatr 1981; 98:561-564
4. White RHR, Glasgow EF, Mills RJ. Clinicopathological study of nephrotic syndrome
in childhood. Lancet 1970 I:1353-1359
5. Moxey-Mims MM, Bruder-Stapleton F, Feld LG. Applying decision analysis to the
management of adolescent idiopathic nephrotic syndrome. Pediatr Nephrol 1994; 8:660-
664
6. Schulman SL, Kaiser BA, Polinsky MS, Srinivasan R, Baluarte HJ. Predicting the
response to cytotoxic therapy for childhood nephrotic syndrome: Superiority of response
to corticosteroid therapy over histopathologic patterns. J Pediatr 1988; 113:996-1001
7. Matoo T. Kidney biopsy prior to cyclophosphamide therapy in primary nephrotic
syndrome. Pediatr Nephrol 1991; 5:617-619
8.Ueda N, Chihara M, Kawaguchi S et al. Intermittent versus long-term tapering
prednisolone for intial therapy in children with idiopathic nephrotic syndrome. J Pediatr
1988; 112:122-6
9. Ksiazek J, Wyszynska T. Short versus long initial prednisone treatment in steroid
sensitive nephrotic syndrome in children. Acta Paediatr 1995; 84:889-93
10. Koskimies O, Vilska J, Rapola J, Hallamn N. Long term outcome of primary
nephrotic syndrome. Arch Dis Child 1982; 57:544-48
11. Lewis MA, Baidom EM, Davis N, Houston IB, Postlethwaite RJ. Nephrotic
syndrome: From toddlers to twenties. lancet 1989 I: 255-259
12. Chiu J, McLain PN, Drummond KN. a controlled prospective study of
cyclophosphamide in relapsing corticosteroid responsive, minimal lesion nephrotic
syndrome in childhood. J Pediatr 1973; 82:607-613
13. A Report of the ISKDC. Prospective controlled trial of cyclophosphamide therapy in
children with the nephrotic syndrome. lancet 1974 I; 423-427
13
14. Report of APN. Cyclophosphamide treatment of steroid dependent nephrotic
syndrome: comparison of l8 weeks with twelve weeks. Arch Dis Child 1987; 62:1102-06
15. Ueda N, Kuno K, Ito S. Eight and 12 week courses of cyclophosphamide in nephrotic
syndrome. Arch Dis Child. 1990; 65:1147-50
16. Niaudet P, Broyer M, Habib R. Treatment of idiopathic nephrotic syndrome with
cyclosporin A in children. Clin Nephrol 1991; 35 Suppl 1:S31-36
17. British Association for Paediatric Nephrology. Levamisole for corticosteroid
dependent nephrotic syndrome in childhood. Lancet 1991; I:555