Idiopathic Nephrotic Syndrome in Childhood - Regional Guideline for the Management of

Publication: 26/06/2012  --
Last review: 23/04/2018  
Next review: 23/04/2021  
Clinical Guideline
CURRENT 
ID: 62 
Approved By: Trust Clinical Guidelines Group 
Copyright© Leeds Teaching Hospitals NHS Trust 2018  

 

This Clinical Guideline is intended for use by healthcare professionals within Leeds unless otherwise stated.
For healthcare professionals in other trusts, please ensure that you consult relevant local and national guidance.

Regional Guideline for the Management of Idiopathic Nephrotic Syndrome in Childhood

Scope of Guideline:

The guideline is for use by paediatricians and paediatric nurse specialists caring for children aged 1-10 years presenting with nephrotic syndrome in Yorkshire.

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Background

Nephrotic syndrome is a triad of proteinuria, hypoalbuminaemia and oedema. Another key feature is hyperlipidaemia with raised serum cholesterol and triglycerides.

Nephrotic syndrome can be classified as congenital, idiopathic or secondary (e.g. nephrotic syndrome associated with systemic lupus erythematosus or Henoch-Schönlein purpura nephritis).

The most common cause in children is idiopathic nephrotic syndrome. The incidence of idiopathic nephrotic syndrome is 1-2/100,000 in Europe and North America.(1) The underlying pathology in idiopathic nephrotic syndrome is varied.  Minimal change disease (MCD) accounts for the majority of cases.(1) Most of the other cases can be attributed to focal segmental glomerulosclerosis (FSGS) and membranoproliferative glomerulonephritis (MPGN).(2)

This guideline outlines the clinical features, investigations and current management options for patients with idiopathic nephrotic syndrome.

At present there is a study in progress (the PREDNOS trial) looking at the use of corticosteroids in idiopathic nephrotic syndrome. Any relevant findings will be used to update this guideline accordingly.

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Definitions

Nephrotic syndrome
          Proteinuria 3+ or more on dipstick
          Plasma albumin <25g/L
          Oedema

Remission
          Trace or negative proteinuria on dipstick for 3 consecutive days

Relapse
          3+ or more proteinuria for 5 consecutive days
          OR     3+ or more proteinuria for 3 consecutive days with oedema

Frequent relapses
          2 or more relapses within 6 months after diagnosis
          OR     4 or more relapses in a 12 month period

Steroid dependent
2 consecutive relapses or 2 of 4 relapses in 6 months whilst on steroids or within 14 days of stopping steroids

Steroid resistance
Absence of remission after 28 days of continuous steroid therapy at 60mg/m2/day

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Clinical features

Children presenting to primary care with features of nephrotic syndrome require immediate referral to their local paediatric team.

Presentation is usually with oedema of varying degree. There may also be poor urine output, poor appetite, malaise, diarrhoea and abdominal pain. The first presentation can be with any one of the numerous complications of nephrotic syndrome.
Relevant aspects of the history to elicit include:

  • Age
  • Preceding history of viral illness/upper respiratory tract infection (URTI)
  • Features suggestive of an undiagnosed vasculitis (rash, family history)
  • Length of symptoms
  • Macroscopic haematuria
  • Drug history

A general systemic examination should be performed with specific attention to assessment of hydration status including blood pressure (BP) and weight. Assess the severity of oedema and examine the abdomen carefully looking for ascites and eliciting any abdominal tenderness or guarding. Also look for aphthous ulcers/rashes/joint involvement suggesting systemic diseases or vasculitides.

Clinical assessment and investigations should be used to identify patients with atypical features of nephrotic syndrome as these patients are less likely to have MCD and therefore require a different approach to management:

Atypical features of Nephrotic syndrome:

  • Age <1year or >10years
  • Macroscopic haematuria (microscopic haematuria can occur in MCD)
  • Persistent hypertension
  • Extra-renal disease (rash, arthritis, anaemia)
  • Family history of nephrotic syndrome
  • Deranged renal function
  • Abnormal complement or autoantibody profile

Patients with atypical features should be discussed/referred to a paediatric nephrologist.

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Investigations

Urine tests

  • dipstick for protein and blood
  • first morning urine for protein:creatinine ratio
  • MC+S if history or dipstick suggestive of infection

Blood tests

  • Full blood count (FBC)
  • Urea and electrolytes
  • Calcium, albumin
  • Triglycerides, cholesterol
  • Varicella serology

If the history is suggestive of atypical features of nephrotic syndrome consider

  • Hepatitis B serology
  • Immunoglobulins
  • Complement levels (C3, C4)
  • Anti-streptolysin O titre (ASOT)
  • Autoimmune screen: anti-nuclear antibody (ANA), anti-neutrophil cytoplasmic antibody (ANCA), double stranded DNA
  • Anti-glomerular basement membrane antibody
  • Human immunodeficiency virus (HIV) serology

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Treatment

1. General management

At presentation and with significant relapses, patients should be admitted for monitoring of fluid balance, daily weight, regular BP (at least daily - ore frequent if clinically indicated) assessment and to aid parental education. The length of inpatient stay is variable. Once the patient is clinically well, weight and fluid balance are stable and parents/patients are comfortable with the management strategy the patient can be safely discharged with a plan for regular (initially weekly to monthly whilst on treatment) review in outpatients.

Salt/fluid restriction
During relapses and when oedematous, parents/patients should be advised to minimise salt intake by having a no added salt diet. A moderate fluid restriction may be advised by the paediatric team caring for the patient but this should be used cautiously as during a relapse patients can become intra-vascularly depleted. Fluid restrictions must also be lifted once the patient’s urine output improves and proteinuria decreases as they go into remission.

Diary
Parents/patients should be taught to test the urine for proteinuria. It is essential that they keep a diary of proteinuria, doses of prednisolone and other drugs used for treatment and the frequency of relapses.

2. Steroids

First episode: 
Corticosteroids are the mainstay of treatment in idiopathic nephrotic syndrome. Data suggest that an 8 week course of corticosteroids can be used to induce remission in 95% of patients with MCD and 20% of patients with FSGS.(3) The current treatment regimen uses a longer initial course of steroids as this has been shown to reduce the relapse rate.(3)

Doses of prednisolone are calculated using body surface area. Body surface area can be derived using the Boyd equation or using the tables in the rear glossy appendix of the British National Formulary for Children (BNFC).(4)

Patients should receive a total of 12 weeks of prednisolone irrespective of when they go into remission.
Prednisolone should be given as a single daily dose in the morning.

  • 60mg/m2/day (maximum 60mg*) as a single daily dose for 4 weeks
  • then 40mg/m2 (maximum 40mg*) on alternate days for 2 weeks
  • followed by a further gradual reduction over the subsequent 6 weeks (see p18 for a patient treatment plan)
    • 30mg/m2 on alternate days for 1 week then
    • 25mg/m2 on alternate days for 1 week then
    • 20mg/m2 on alternate days for 1 week then
    • 15mg/m2 on alternate days for 1 week then
    • 10mg/m2 on alternate days for 1 week then
    • 5mg/m2 on alternate days for 1 week then stop

*please note that steroid schedule/regimen may vary in patients involved in clinical trials

Treatment of relapse:

60% of patients with nephrotic syndrome who have achieved remission with corticosteroid therapy will have five or more relapses.(3) Often these relapses are precipitated by viral infections. Patients with steroid responsive nephrotic syndrome can be managed with shorter courses of corticosteroids: (5)

Prednisolone should be given as a single daily dose in the morning.

First relapse

  • 60mg/m2/day (maximum 60mg) once daily until in remission
  • then 40mg/m2 (maximum 40mg) on alternate days for 1 week
  • followed by a gradual reduction over the subsequent 5 weeks (see p19 for a patient treatment plan).
    • 30mg/m2 on alternate days for 1 week then
    • 25mg/m2 on alternate days for 1 week then
    • 20mg/m2 on alternate days for 1 week then
    • 15mg/m2 on alternate days for 1 week then
    • 10mg/m2 on alternate days for 1 week then stop

Frequently relapsing nephrotic syndrome
Some patients relapse more often and require a different approach to treatment. Steroid sensitive patients not showing signs of steroid toxicity can be treated with further courses of prednisolone, aiming to wean them over a longer period of time. There is little data to advise on the best method of weaning steroids in this group of patients and so regimens are variable.(5)

Nephrotic syndrome has a variable course and knowledge of how the disease affects individual patients helps devise steroid regimens that are patient specific. Aim not to over respond to the development of proteinuria alone if not oedematous. Treat with prednisolone as for the first relapse but ideally try and use the lowest possible dose of steroids that induces remission (look back at previous relapses and use diary). Once remission is induced, reduce steroids over the next 4-6 weeks to 10mg/m2 on alternate days using a similar pattern to that described previously. Maintain treatment at this level aiming to stop the steroids completely over the next 3-6 months.

Patients with no signs of steroid toxicity who continue to relapse despite prolonged weaning of steroids, can be maintained on low dose alternate day steroids to reduce relapses e.g. doses ≤10mg/m2 on alternate days.

Patients who are steroid toxic on low dose steroid regimen will require treatment with second line agents.

Steroid dependent nephrotic syndrome (SDNS):
A quarter of patients with nephrotic syndrome will become steroid dependent.(5) Such patients who have no signs of steroid toxicity can be treated with prednisolone, aiming to use the lowest dose possible and tailoring treatment to individual patients. Increase the steroids to the lowest dose known to induce remission for the patient. Once remission is achieved, quickly reduce the steroids to a dose just above the dose that the patient relapsed on. Subsequently wean the steroids very gradually over the next 3-6 months.

As with frequently relapsing nephrotic syndrome low dose alternate day steroids may be used to maintain remission in some patients. Careful consideration should be given to the use of second line therapies in patients who develop side effects of steroids.

Steroid resistant nephrotic syndrome (SRNS):
Steroids do not achieve remission in a small proportion of patients. These patients need to be under the care of a paediatric nephrologist and will be considered for renal biopsy and subsequent management with immunosuppressive therapy (second line therapies and indications for renal biopsy).

3. Penicillin

Oral penicillin prophylaxis is given during proteinuric phases although the data to support this are limited. (3)

Children 1-6 years: Phenoxymethyl penicillin 125mg twice daily
Children > 6 years: Phenoxymethyl penicillin 250mg twice daily

Penicillin can be stopped once in remission but it is recommended that it is restarted with any relapse. Erythromycin is an alternative for patients who are allergic to penicillin.

4. Albumin

Albumin infusions are not normally required to treat patients with nephrotic syndrome. The prime indication for human albumin solution (HAS) is hypovolaemia (see below). It can also be considered for patients with symptomatic oedema.

4.5% HAS
For use in patients who are clinically shocked. Restoration of circulating volume can be with a bolus of 10ml/kg of 0.9% saline or 4.5% HAS.

20% HAS
Should not be used in patients who are clinically shocked.
Patients who are clinically stable but symptomatic of oedema can be treated with 5ml/kg of 20% HAS over 4 hours with an intravenous dose of 1mg/kg of furosemide midway through the infusion (seek advice from a paediatric nephrologist if unsure as to whether 20% HAS is indicated).

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Complications

Hypovolaemia

Proteinuria leads to reduction in oncotic pressure and peripheral oedema with intravascular volume depletion. In severe relapses or indeed at first presentation patients can be hypovolaemic. They may be symptomatic feeling generally unwell, complaining of abdominal pain and/or have diarrhoea. Signs include cool peripheries, prolonged capillary refill time, poor urine output, tachycardia and paradoxical hypertension. Treatment should be with intravenous fluid/albumin as described above. If patients are significantly unwell consider covering for infection with appropriate antibiotics (see below).

Infection

Children with nephrotic syndrome are at increased susceptibility to infection due to renal loss of complement proteins and immunoglobulins. They are at particular risk of infection with encapsulated organisms e.g. streptococcus pneumoniae and also gram negative organisms.(3) During relapses patients are treated with penicillin prophylaxis. Children presenting acutely unwell or with suspected infection should be treated with appropriate antibiotics as per local guidelines covering for potential pathogens.

Thrombosis

In addition to urinary loss of albumin, patients with nephrotic syndrome lose proteins which are integral to the clotting cascade. Loss of anti-thrombin IIIa predisposes to thrombotic events. 2-5% of patients will develop thromboembolisms and the risk is greatest during relapses.(5) Patients with SRNS appear to be at greater risk.(5) At present there are no data to suggest a role for anticoagulants in nephrotic syndrome but all efforts should be made to minimise other risk factors like indwelling catheters, immobilisation etc.(3) Patients with thromboembolic complications should be managed by a paediatric nephrologist with haematology input.

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Immunisations and exposure to infections

Children with nephrotic syndrome should receive all vaccinations as per the UK schedule.(6) Live vaccines should be delayed until 3 - 6 months of completion of high dose steroid treatment or immunosuppressive treatment. Live vaccines should not be given whist patients are receiving immunosuppressive treatment.

Streptococcus pneumoniae infection is a serious complication in nephrotic syndrome. All children should now receive the pneumococcal vaccine as routine but if they have not, it is strongly advised. Both prevenar 13 (current paediatric schedule) and Pneumovax II for children over the age of 2 years are recommended. For current recommendations for vaccination regimes in patients at high risk of pneumococcal infection refer to guidance from the Health Protection Agency (HPA).(6)

Varicella zoster status should be checked in all patients at presentation. Parents should be advised to seek medical advice should their child have a chicken pox contact whilst on treatment or within 3 months of completion of steroids or up to 6 months after completion of an immunosuppressive agent (e.g. ciclosporin, cyclophosphamide). In the event of contact with varicella, children who are not immune to varicella zoster should be treated with varicella zoster immunoglobulin (VZIG) following discussion with a consultant virologist. Any child who develops chicken pox should be treated with oral aciclovir. Those unwell or with severe symptoms may need admission for intravenous aciclovir and treatment of any complications. For further information refer to the HPA website.

Measles can be a life threatening infection in immunosuppressed patients and children who come into contact with measles, irrespective of immunisation status, should be closely monitored and possibly receive human normal immunoglobulin (HNIG) following discussion with a consultant virologist. For further information refer to the HPA website.

Influenza immunisation should be given annually to all children with nephrotic syndrome. 

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Second Line Treatment

These should be commenced following consultation with a paediatric nephrologist.

1. Levamisole

2.5mg/kg (max 150mg) on alternate days for 12 months
Prednisolone should be tapered slowly during levamisole treatment to a maintenance dose of 10mg/m2 on alternate days before attempting to withdraw the steroids if possible.

Levamisole is an unlicensed anthelmintic medication which has also been used as an adjuvant in malignant disease.  Levamisole is an immune-modulator which has been shown to have a steroid sparing effect in children with steroid sensitive nephrotic syndrome.(1) It is generally well tolerated. Monitor FBC (particularly neutrophils), renal and liver function tests (LFT) every 3-4 months whilst on treatment.

A patient information leaflet regarding levamisole treatment in nephrotic syndrome can be found on the medicines for children website.

http://www.medicinesforchildren.org.uk/search-for-a-leaflet/levamisole-for-nephrotic-syndrome/

2. Cyclophosphamide (oral)

2-3mg/kg once daily by mouth for 8 weeks
Remission is induced in patients with the use of steroids. Maintenance steroids (≤10mg/m2 on alternate days) are continued during the course of cyclophosphamide and subsequently weaned.

Cyclophosphamide is an alkylating agent which has been shown to reduce the incidence of relapse in patients with steroid sensitive nephrotic syndrome when compared to prednisolone alone.(1) It induces a sustained remission in 40%, and 24% of children with SDNS at 2 and 5 years respectively.(5) Cyclophosphamide has not been shown to be more effective than prednisolone alone at inducing remission in patients with SRNS.(2) Its use is limited by side effects which include marrow suppression and haemorrhagic cystitis. Other side effects include nausea, alopecia and deranged LFT. In the long term there are concerns regarding gonadal toxicity and malignancy.(7)

Monitor FBC (for neutropenia), renal function and LFT weekly for the first month then every 2 weeks during the course.

3. Ciclosporin

3 mg/kg twice daily
The dose may be increased if necessary in SRNS. Maintenance doses should be the lowest effective dose according to blood ciclosporin concentrations, proteinuria and renal function. Prednisolone should be tapered slowly during ciclosporin treatment to a maintenance dose of 10mg/m2 on alternate days before attempting to withdraw the steroids if possible.

Ciclosporin is a calcineurin inhibitor with a UK licence for the treatment of SDNS or SRNS in both adults and children. It has been shown to be beneficial as a steroid sparing agent in children with frequently relapsing steroid sensitive nephrotic syndrome (5) and in inducing remission in children with SRNS.(2) Patients should be stabilised on a particular brand of oral ciclosporin as switching between formulations may lead to clinically important alterations in blood ciclosporin levels. To avoid inadvertent switching between preparations prescribe ciclosporin by brand name.(4)

Ciclosporin levels, FBC and renal function should be checked every 1-2 months aiming for a 12 hour ciclosporin trough level of 50-100nanograms/mL.

Ciclopsporin has several side effects including immunosuppression, gum hyperplasia, hypertrichosis and nephrotoxicity.(1) Further information can be found at www.medicines.org.uk/emc (8). If ciclosporin treatment duration exceeds a year a renal biopsy should be performed to look for signs of calcineurin induced nephrotoxicity.

5. Mycophenolate mofetil

This antiproliferative agent inhibits T and B cell proliferation and may have benefit as an immune modulator in some children with steroid sensitive, frequently relapsing nephrotic syndrome. It is less nephrotoxic than the calcineurin inhibitors but more robust data on its efficacy and the reduction in relapse rates are required.(9)

Note: Mycophenolate should only be initiated by a paediatric nephrologist.

6. Rituximab

Rituximab is a monoclonal antibody against the CD20 marker on B-cells which mediate complement dependent cell lysis. It depletes peripheral B-cells and may be considered (by a paediatric nephrologist) for the treatment of children with steroid dependent, frequently relapsing nephrotic syndrome who have failed treatment with current standard therapies. Several case reports and some larger series suggest that rituximab may be a viable treatment option in patients with steroid sensitive nephrotic syndrome.(9)

Note: Rituximab should only be prescribed by a paediatric nephrologist.

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Indications for referral to paediatric nephrology  

  • Atypical features
  • SRNS
    • Failure to go into remission within 28 days of prednisolone at 60mg/m2/day
    • Development of steroid resistance having initially been steroid sensitive
  • Patients with signs of steroid toxicity on an appropriate dose of steroids
  • Problematic relapses

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Indications for consideration for renal biopsy 

  • SRNS
  • Deranged renal function
  • Hypertension
  • Low C3
  • Clinical features suggestive of systemic disease (rash, arthritis, anaemia)
  • Monitoring for signs of calcineurin nephrotoxicity in patients on long term cyclosporin (>1 year in duration)
  • Age <1year or >10years
  • Macroscopic haematuria (microscopic haematuria can occur in MCD)
  • Family history of nephrotic syndrome
  • Nephrotic syndrome associated with chronic infections e.g. Hepatitis B, HIV

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Provenance

Record: 62
Objective:

The aim of the guideline is to achieve a consistent approach to the management of children with idiopathic nephrotic syndrome across the Region and in doing so improve the care that they receive.

The guideline provides evidence based recommendations for the diagnosis, investigation and management of idiopathic nephrotic syndrome.

Clinical condition:

Idiopathic Nephrotic Syndrome in Childhood

Target patient group: Children aged 1 - 10 years with nephrotic syndrome
Target professional group(s): Secondary Care Doctors
Adapted from:

Evidence base

  1. Hodson E, Willis N, Craig J. Non-corticosteroid treatment for nephrotic syndrome in children. Cochrane Database of Syst Rev. 2010;(4):1–56.
  2. Hodson E, Willis N, Craig J. Interventions for idiopathic steroid-resistant nephrotic syndrome in children (Review). Cochrane Database of Syst Rev. 2010;(11):1–66.
  3. Eddy A, Symons J. Nephrotic syndrome in childhood. Lancet. 2003;362:629–39.
  4. British National Formulary for Children. British Medical Association, Royal      Pharmaceutical Society of Great Britain, Royal College of Paediatrics and Child Health, and Neonatal and Paediatric Pharmacists Group.  2011-12 online edition.  Available online at www.bnfc.org
  5. Gipson D, Massengill S, Yao L, Nagaraj S, Smoyer W, Mahan J, et al. Management of Childhood Onset Nephrotic Syndrome. Pediatrics. 2009;124(2):747–57.
  6. Green Book. Health Protection Agency. 2006;Section 25:300–5.
  7. Latta K, von Schnakenburg C, Ehrich J. A meta-analysis of cytotoxic treatment for frequently relapsing nephrotic syndrome in children. Pediatr Nephrol. 2001;16:271–82.
  8. Summary of Product Characteristics, Electronic Medicines Compendium.  Datapharm Communications Ltd.  Available from: http://www.medicines.org.uk/emc
  9. van Husen M, Kemper M. New therapies in steroid-sensitive and steroid-resistant idiopathic nephrotic syndrome. Pediatr Nephrol. 2011;26:881–92.

Approved By

Trust Clinical Guidelines Group

Document history

LHP version 1.0

Related information

Nephrotic syndrome treatment plan – first episode

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Nephrotic syndrome treatment plan - relapse

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Nephrotic syndrome diary

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List of abbreviations

ANA  Anti-nuclear antibody
ANCA Anti-neutrophil cytoplasmic antibody
ASOT Anti-streptolysin O titre
BNFC British national formulary for children
BP Blood pressure
DNA Deoxyribonucleic acid
FBC Full blood count
FSGS Focal segmental glomerulosclerosis
HAS Human albumin solution
HIV Human immunodeficiency virus
HNIG Human normal immunoglobulin
HPA Health protection agency
LFT  Liver function tests
MCD Minimal change disease
MC&S Microscopy, culture & sensitivity
MPGN Membranoproliferative glomerulonephritis
SDNS Steroid dependent nephrotic syndrome
SRNS Steroid resistant nephrotic syndrome
URTI Upper respiratory tract infection
VZIG Varicella zoster immunoglobulin

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Contact Details

Dr Kay Tyerman
Consultant Paediatric Nephrologist
Department of Paediatric Nephrology
E Floor Martin Wing
Leeds Children's Hospital
Leeds General Infirmary
Gt George St
Leeds, LS1 3EX
Tel: (0113) 392 5583
Fax: (0113) 392 5129

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