Management of The Complications of Nephrotic Syndrome

MANAGEMENT OF THE COMPLICATIONS OF NEPHROTIC
SYNDROME
1. 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.
2. 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
3. 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.
4. 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.
5. 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.
1 About 80% of children 1to 12 years of age with idiopathic have minimal change
nephrotic syndrome.
2 93.1 - 97% of patients MCNS respond to corticosteroid therapy 3,4.
3 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
4 Steroid resistant nephrotic syndrome defined as failure to achieve remission despite 4

weeks of adequate corticosteroid therapy.
Other indications
5 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.
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 1940s, 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 al 8 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:
6 60 mg/m2/day (maximum 80 mg/day) for 4 weeks
7 40 mg/m2/48 hours for 4 weeks only.
Long initial prednisolone regime:

Prednisolone dosage at:
8 60 mg/m2/day (maximum 80 mg/day) for 4 weeks
9 40 mg/m2/48 hours for 4 weeks.
10 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/m 2/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 .
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
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:
11 A second course of cyclophosphamide
12 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.
13 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.
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.

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MANAGEMENT OF THE COMPLICATIONS OF NEPHROTIC

3. Acute renal failure

This is a rare complication in children with steroid responsive nephrotic syndrome.

This complication if suspected should be thoroughly investigated and treated to

Treatment consists of anticoagulation with the various anticoagulants available. The

5. Acute Adrenal Crisis

A renal biopsy is also NOT required prior to cytotoxic therapy. 4,6,7

Main indication for renal biopsy

4 Steroid resistant nephrotic syndrome defined as failure to achieve remission despite 4

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

Corticosteroids was found to be effective in inducing remission of nephrotic syndrome

Long initial prednisolone regime:

3.4.3 Frequent relapses and steroid dependence

Re-induction of any relapse with corticosteroids is as described in the section 3.4.2 on

A renal biopsy is not needed prior to cyclophosphamide therapy.4,6,7.

Cyclophosphamide therapy is indicated for the treatment of steroid dependent nephrotic

3.6. RELAPSES POST CYCLOPHOSPHAMIDE

3.7 URINE ALBUMIN MONITORING

It is advocated that monitoring of urine albumin excretion be done regularly either at

*Discontinue *Steroid taper at 25% monthly

5. Relapses post cyclophosphamide

* choice depends on attending paediatrician.

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Discontinue Steroid taper at 25% monthly