Guideline for the Management of Nephrotic

Syndrome

Renal Unit
Royal Hospital for Sick Children
Yorkhill Division

Please note: the following guideline has not been assessed according to
the AGREE (Appraisal of Guidelines for Research and Evaluation) criteria.
This will take place at the next guideline review.

Nephrotic Syndrome Version: 1.1 Page 1 of 8

Author: Renal Clinicians Group Authorised by: Dr J Beattie Issue Date: November 2005
Date of Review: October 2007 Q Pulse Ref: YOR-REN-019
 Contents Page(s)
1. Introduction 2
2. Definition of Nephrotic Syndrome 2-3
3. Initial Investigation 3
4. Referral to Paediatric Nephrology 3
5. Complications 4
5.1 Hypovolaemia 4
5.2 Infection 4
5.3 Thrombosis 4
6. Treatment of Initial Presentation of Nephrotic 4
Syndrome
6.1 Prednisolone 4-5
6.2 Albumin 5
6.3 Penicillin Prophylaxis 5
6.4 Salt/Fluid Restriction 5
6.5 Vaccination 5
7. Relapse of Nephrotic Syndrome 6
8. Treatment of Relapse of Nephrotic Syndrome 6
8.1 Prednisolone 6
8.2 Albumin 6
8.3 Salt Restriction 6
8.4 Penicillin 6
8.5 Vaccination 6
9. Treatment of Frequent Relapses 6-7
9.1 Low Dose Alternate Day Prednisolone 7
9.2 Levamisole 7
9.3 Cyclophosphamide 7
9.4 Cyclosporin 7
9.5 Mycophenylate Mofitil (MMF) 7
10. Follow Up 8
11. Future Guideline Review 8

1. Introduction
This guideline represents our current practice within the Renal Unit and are intended
for use by clinicians. These guidelines are based on previous recommendations
reviewed in the light of recent literature and will be update regularly. They cover
many aspects of the management of “typical” nephrotic syndrome, but they are
not exhaustive, and many not be relevant for children with “atypical” nephrotic
syndrome. There is always a paediatric nephrology consultant on call for the unit
who will be happy to discuss difficult or unusual cases.

2. Definition of Nephrotic Syndrome

• Nephrotic range proteinuria (> 1g/m2/day)
• Hypoalbuminaemia (<25 g/l)
• Oedema

Nephrotic Syndrome Version: 1.1 Page 2 of 8

Author: Renal Clinicians Group Authorised by: Dr J Beattie Issue Date: November 2005
Date of Review: October 2007 Q Pulse Ref: YOR-REN-019
Classification
• Idiopathic (primary) nephrotic syndrome
o Minimal change (80-90%)
o Focal segmental glomerulosclerosis (FSGS) (10-20%)
• Secondary nephrotic syndrome (HSP, SLE, MPGN)
• Congenital nephrotic syndrome

This document relates only to the management of idiopathic nephrotic

syndrome. Children who present with the typical features of nephrotic syndrome
(see below) are generally responsive to steroid treatment and a renal biopsy,
were it performed, would be likely to show minimal change nephrotic syndrome.
Those with atypical features are more likely to be unresponsive to steroid
treatment, and a biopsy more likely to show FSGS or one of the other forms of
nephrotic syndrome.

Therefore children with typical features are started on steroids without recourse
to renal biopsy. Those with atypical features should therefore undergo renal
biopsy before receiving steroid treatment.

Nephrotic Syndrome
Typical Features Atypical Features
Age 1-10 years <1yr, >10years
Normotensive Hypertensive
Normal Adrenal Function Elevated Creatinine
+/- microscopic haematuria Macroscopic Haematuria

3. Initial Investigation
The following investigations should be performed in all children:
• Blood: FBC, U+E’s; Creatinine; LFT’s; ASOT; C3/C4; Varicella titres
• Urine: Urine culture andUrinary protein/creatinine ratio
• BP
• Urinalysis including glucose
• A urinary sodium concentration can be helpful in those at risk of
hypovolaemia.
• Varicella status should be known in all children commencing steroids.
• Hepatitis B status may be appropriate in children at high risk.

4. Referral to Paediatric Nephrology

• Age < 1 yr
• Age > 10-12 yrs
• Persistent hypertension
• Macroscopic haematuria
• Low C3/C4
• Failure to respond to steroids within 4 weeks

Nephrotic Syndrome Version: 1.1 Page 3 of 8

Author: Renal Clinicians Group Authorised by: Dr J Beattie Issue Date: November 2005
Date of Review: October 2007 Q Pulse Ref: YOR-REN-019
5. Complications
The main complications of nephrotic syndrome are hypovolaemia, infection and
thrombosis.

5.1 Hypovolaemia
The initial examination of children with nephrotic syndrome needs to include
an assessment of their intravascular volume. Whilst these children may be
very oedematous, they may also be intravascularly depleted. Signs of
intravascular depletion are cool peripheries (capillary refill time > 2 secs), a
core-peripheral temperature gap of > 2oC, and tachycardia. Hypotension is a
late sign of hypovolaemia, but paradoxical hypertension may be present. A
urinary sodium of < 10 mmol/l is a useful investigation to confirm
hypovolaemia.

5.2 Infection
Loss of complement components and possibly immunoglobulins results in an
increased risk of infection. Consider antibiotic prophylaxis whilst patients have
significant proteinuria.

5.3 Thrombosis
Loss of proteins such as anti-thrombin III contributes to a pro-coagulant
state. This might be exacerbaterd by hypovolaemia.

6. Treatment of Initial Presentation of Nephrotic Syndrome

6.1 Prednisolone
When the diagnosis of nephrotic syndrome has been made, prednisolone
treatment can be started in children with typical features. Children with atypical
features should be referred to paediatric nephrology for consideration of renal
biopsy.

There is increasing evidence that longer initial courses of prednisolone are

associated with a lower incidence of relapse, and therefore a 12-week initial
course is recommended. The dose of prednisolone is based on surface area.
• 60 mg/m2/day for 4 weeks (maximim 80 mg)
• 40 mg/m2/on alternate days for 4 weeks (maximum 60mg)
• Reduce dose by 5-10mg/m2 each week for another 4 weeks then stop

Prednisolone can be given as a single dose in the morning with food, or as

divided doses during the day. Patients should be issued with a steroid warning
card, and they should be aware of the side effects and risks of steroid treatment.
Varicella status should be documented clearly in the casenotes and on HISS. If
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Author: Renal Clinicians Group Authorised by: Dr J Beattie Issue Date: November 2005
Date of Review: October 2007 Q Pulse Ref: YOR-REN-019
prednisolone causes gastric irritation, start ranitidine 2mg/kg bid for the duration
of steroid treatment.

6.2 Albumin
As discussed above the clinical indications for albumin are
• Clinical hypovolaemia
• Symptomatic oedema

A low serum albumin alone is not an indication for intravenous albumin.

If there is evidence of hypovolaemia, give 1 g/kg 20% albumin (5ml/kg) over 4 -

6 hours. Give 2mg/kg of iv frusemide mid-infusion. If clinically shocked give
10ml/kg 4.5% albumin. Children should be closely monitored during albumin
infusions, and where possible they should be administered during working hours.

6.3 Penicillin Prophylaxis

Whilst nephrotic, children are at increased risk of infection, particularly with
encapsulated organisms such as pneumococcus. There is no evidence that
antibiotic prophylaxis is of benefit, and some centres do not use prophylaxis.
Penicillin V can be given while there is proteinuria and discontinued when the
child goes into remission. Grossly oedematous children are at risk of cellulitis and
may benefit from antibiotic prophylaxis.

Dose: Under 5 yrs 125 mg bid

5yrs or above 250 mg bid

6.4 Salt/Fluid Restriction

A low salt diet is used to try to prevent further fluid retention and oedema. Fluid
restriction may also be helpful. These restrictions are lifted once the child goes
into remission.

6.5 Vaccination
Pneumococcal vaccination is recommended for children with NS. Consider giving
at the time of diagnosis. Varicella vaccination is only available on a named
patient basis.

Response To Treatment
Most children with nephrotic syndrome will respond to steroid treatment
within 2-4 weeks. A remission is defined as 3 or more days of trace or
negative on dipstick testing. Treatment is continued for a total of 12
weeks as outlined above. If proteinuria persists beyond the first 4 weeks
of steroid treatment, then children should be referred for renal biopsy.

Nephrotic Syndrome Version: 1.1 Page 5 of 8

Author: Renal Clinicians Group Authorised by: Dr J Beattie Issue Date: November 2005
Date of Review: October 2007 Q Pulse Ref: YOR-REN-019
7. Relapsing Nephrotic Syndrome
Up to 60 - 70 % of children with nephrotic syndrome may have one or more
relapse. These are diagnosed if there is +++ or ++++ proteinuria for 3 or more
days. Urine should be checked initially twice weekly, then weekly after the first
episode, and the families instructed to get in contact should a relapse of
proteinuria occur, or if there is ++ for more than 1 week.

8. Treatment of Relapse Nephrotic Syndrome

8.1 Prednisolone
Prednisolone treatment should be restarted once a relapse has been diagnosed.
• 2mg/kg daily (maximum 80 mg) until the urine is negative or trace for 3 days
• 40 mg/m2 (maximum 60 mg) on alternate days for 4 weeks then stop or taper
the dose over 4-8 weeks

8.2 Albumin
The indications for albumin infusion are as for the initial presentation. It is less
likely to be needed during a relapse.

8.3 Salt Restriction

Whilst there is proteinuria (>++) a no added salt diet is advised.

8.4 Penicillin
Whilst there is proteinuria (>++) penicillin can be given.

8.5 Vaccination
Consider giving varicella vaccine between relapses in children who are varicella
seronegative.

Referral to/Discussion with Paediatric Nephrology

• Frequent relapsers
• Steroid dependency
• Steroid toxicity

9. Diagnosis and Treatment of Frequent Relapses

Frequent relapsers are diagnosed if there is:
• 2 or more relapses within the first 6 months of presentation
• 4 or more relapses within any 12 month period
This becomes steroid dependency if the relapses are occurring during steroid
tapering.

Varicella status should be repeated 6 monthly in those who are non-

immune.
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Author: Renal Clinicians Group Authorised by: Dr J Beattie Issue Date: November 2005
Date of Review: October 2007 Q Pulse Ref: YOR-REN-019
If children have frequent relapses, strategies should be adopted to try to reduce the amount
of steroid required.

9.1 Low Dose Alternate Day Prednisolone

Low dose alternate day steroid treatment (< 10-15 mg/alt days) may prevent relapses, and
result in less steroid being given overall.

9.2 Levamisole
Levamisole may be beneficial for children who have occasional relapses. It is less useful for
children who are steroid dependent. The dose is 2.5 mg/kg/ on alt days for 6 months to a
year in the first instance. Reversible neutropenia is a rare but recognised side-effect. A FBC
should be checked monthly for the first 3 months. This drug is not licensed in the UK, and
has to be imported.

9.3 Cyclophosphamide
For children with frequent relapses or those who are steroid dependent consider a course of
Cyclophosphamide 3 mg/kg/day for 8 weeks or equivalent. It is best to avoid cutting the
tablets. FBC should be monitored for the first few weeks of treatment.

9.4 Cyclosporin
Cyclosporin at a dose of 2.5 mg/kg bid usually for 1 year may be useful as a steroid sparing
agent. Levels should be checked after 1-2 weeks; aim for a 12 hour trough of 70 – 120
nmol/l (85-145 ug/l). For children under 5 yrs of age, tid dosing may be necessary.
Monitor BP and renal function.

9.5 Mycophenylate Mofitil (MMF)

There is some experience of using MMF in children with difficult to treat NS. It
may be useful for those children showing signs of cyclosporin toxicity. Doses of
600mg /m2/bid have been used. FBC should be monitored for leucopenia. The
use of MMF is associated with gastro-intestinal intolerance, mainly diarrhoea. This
is an unlicensed indication for MMF.

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Author: Renal Clinicians Group Authorised by: Dr J Beattie Issue Date: November 2005
Date of Review: October 2007 Q Pulse Ref: YOR-REN-019
10. Follow Up

GENERAL CONSIDERATIONS DURING FOLLOW UP

For children on long-term steroids:-
1) Monitor BP
2) Monitor growth (including bone age and pubertal stage where
appropriate)
3) Monitor weight – dietetic review where appropriate
4) Glycosuria / HbA1c
5) Bone mineral density / calcium supplements
6) Ophthmology review
7) VACCINATION
Pneumococcal: recommended for all children with NS.
Varicella: consider in varicella negative children with frequent relapses.
Aim to administer vaccine when prednisolone dose is low.

11. Future Guideline Development

• Should any aspect of this guideline change before the planned review (i.e.
new technology or procedural change) then this guideline should be
updated accordingly.
• Future review of this guideline should make use of the AGREE document to
ensure that up-to-date evidence and best clinical practice has been used to
inform this guideline. For further information regarding guideline
development, please contact the Chairperson of the Multi-Professional
Clinical Practice Committee.

Nephrotic Syndrome Version: 1.1 Page 8 of 8

Author: Renal Clinicians Group Authorised by: Dr J Beattie Issue Date: November 2005
Date of Review: October 2007 Q Pulse Ref: YOR-REN-019