nephrotic_syndrome.pdf

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



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



Dr. Indon Lajin

Consultant Paediatric Nephrologis

Subang Jaya Medical Centre

Subang Jaya

Dr. Susan Pee

Consultant Paediatric Nephrologist


Hospital Sultanah Aminah

Johor Baru

Dr. Amir Hamzah

Paediatric Clinical Specialist



Dr. Lynster Liaw

Trainee in Paediatric Nephrology



WORKSHOP PARTICIPANTS

Representatives from the Ministry of Health

Dr. Wong Swee Lan

Consultant Paediatrician

Hospital Seremban

Dr. Kwan Geok lan


Hospital Melaka

Dr Pyar Kaur


Hospital Pulau Pinang

Dr. Soo Thian Lian


Hospital Queen Elizabeth

Kota Kinabalu

2

Dr. S Tharam


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



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


Universiti Kebangsaan Malaysia

Assoc Prof Ong Lai Choo


Universiti Kebangsaan Malaysia

Representatives from Private Sector

Dr Gnanambai Athi


Medical Specialist Centre

Air Keroh, Melaka

Dr. David Manickam


Ipoh Specialist Centre, Ipoh

Dr. Nazeli Hamzah

Paediatrician

Klinik Perdana

Kota Bharu, Kelantan

3



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

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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

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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

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