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

Publication: 26/06/2012  
Next review: 10/05/2025  
Clinical Guideline
CURRENT 
ID: 62 
Supported by: Paediatric Renal Governance
Approved By: Trust Clinical Guidelines Group 
Copyright© Leeds Teaching Hospitals NHS Trust 2022  

 

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

Abbreviations

AKI Acute kidney injury
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
EAR
Estimated average requirements
FBC
Full blood count
FSGS
Focal segmental glomerulosclerosis
FRSSNS
Frequently relapsing steroid-sensitive nephrotic syndrome
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
PCR
Polymerase chain reaction
RNI
Reference nutrient intake
SDNS
Steroid dependent nephrotic syndrome
SRNS
Steroid resistant nephrotic syndrome
URTI
Upper respiratory tract infection
VZIG Varicella zoster immunoglobulin

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Scope of Guideline

The guideline is for use by healthcare professionals to aid in the management of children with idiopathic nephrotic syndrome across Yorkshire and the Humber. The primary aim of the guideline is to achieve a consistent approach to the management of children with idiopathic nephrotic syndrome across the region and therefore improve the care that they receive.

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Summary of Guideline

Idiopathic nephrotic syndrome affects 2/100000 children in the UK, mainly presenting with oedema. Patients that fit the diagnostic criteria (see below) should be admitted for assessment and to initiate treatment with the aim of inducing remission. Those with atypical features should be discussed at presentation with the oncall paediatric nephrologist. Steroids are the mainstay of treatment alongside careful fluid management, dietary advice and trying to minimise complications using antibiotic prophylaxis and immunisations. Good patient/parental education is vital and patients will require regular follow up. Some patients develop more complex disease and require more extensive treatment and these patients should be under the care of paediatric nephrology.

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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.

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Diagnosis

Definitions

Nephrotic syndrome

Definition of nephrotic syndrome
  1. Proteinuria (3+ or more on urine dipstick)
  2. Hypoalbuminaemia (<25g/L)
  3. Oedema

Remission
Trace or negative proteinuria on dipstick for 3 consecutive days

Relapse
3+ or more proteinuria for 3 consecutive days
OR
3+ or more proteinuria for 2 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 with prednisolone at 60mg/m2/day followed by intravenous methyl prednisolone at 500 mg/m2 (maximum 500 mg) once daily for 3 days.

Incidence

Idiopathic nephrotic syndrome has an overall incidence of 2/100000 children in the UK, making it the commonest childhood glomerular disorder [1]. The incidence is higher in children from South Asia [2].

Pathology

The underlying pathology in idiopathic nephrotic syndrome varies. In the majority of cases (76.6%) it is minimal change disease (MCD) with the other cases mainly attributed to focal segmental glomerulosclerosis (FSGS) and membranoproliferative glomerulonephritis (MPGN) [3].

Presentation

The main presentation of nephrotic syndrome is with oedema. This can include peripheral oedema, ascites or peri-orbital oedema. Other symptoms include poor urine output, poor appetite, malaise, dizziness, diarrhoea and abdominal pain. Occasionally patients will present with one of the complications of nephrotic syndrome.

Patients with suspected nephrotic syndrome who present to primary care should be immediately referred to their local paediatric unit. All patients who present with their first episode of nephrotic syndrome or significant relapses should be admitted.

History

Key points to elicit in the history 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
  • Immunisation history
  • History of childhood infections especially chickenpox
  • Family history
Examination
  • General systemic examination
  • Blood pressure
  • Heart rate
  • Assessment of hydration status
    • Features of hypovolaemia may include:
      • tachycardia, paradoxical hypertension or hypotension (late sign), prolonged capillary refill time, cool peripheries, poor urine output
    • Features of fluid overload may include:
      • tachycardia, hypertension, low oxygen saturations or respiratory distress, raised JVP, hepatomegaly, warm peripheries
  • Weight
  • Height
  • Severity of oedema
  • Abdominal examination assessing for pain, guarding, ascites
  • Look for aphthous ulcers/rashes/joint involvement suggesting systemic diseases or vasculitides
Atypical versus typical nephrotic syndrome

It is important to establish which patients have atypical features of nephrotic syndrome as these patients are less likely to have MCD and therefore need discussing with a paediatric nephrologist early as they will require a different approach to management. For other indications for referral to a paediatric nephrologist please see page 17.

Feature

Typical nephrotic syndrome

Atypical nephrotic syndrome

Age

1-12 years

<1 year or >12 years

Haematuria

Can have microscopic

Macroscopic

Blood pressure

Usually normal

Persistent hypertension

Extra-renal disease

Unlikely

Rash, arthritis, anaemia

Family history

Unlikely

Present

Renal function

Normal

Deranged

Complement or autoantibody profile

Normal

Abnormal

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Investigations

Urine tests
  • Dipstick for protein and blood
  • Early morning urine for protein:creatinine ratio
  • MC+S if history or dipstick suggestive of infection
Blood tests
  • Full blood count
  • Urea and electrolytes
  • Calcium, albumin
  • Triglycerides, cholesterol
  • Varicella serology
  • Measles serology
Specialist tests

If the history is suggestive of atypical features of nephrotic syndrome the following investigations may be considered after discussion with a paediatric nephrologist.

  • 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/Management

Overview

The aim of treatment is to induce remission using steroids. The following flowchart gives an overview of the initial management of patients with idiopathic nephrotic syndrome. Each section of the management will be covered in more detail subsequently.

General management

All first presentations and those with significant relapses of nephrotic syndrome should be admitted. This will aid patient management and help with 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 ward or outpatient review initially 1-2 times per week and gradually less often depending on clinical need.

Fluid management

Patients can become very fluid overloaded and whilst the steroids are expected to induce remission, until they do this it is important to manage the patient’s fluid status.

Although patients may appear oedematous they may have simultaneous intra-vascular volume depletion and hypovolaemia with severe relapses or at first presentation. These patients can be extremely unwell and develop significant acute kidney injury and must be discussed with the oncall paediatric nephrologist early.

In hypovolaemic patients who are clinically shocked, restoration of circulating volume should be with an intravenous bolus of 10ml/kg of 0.9% sodium chloride or 4.5% Human Albumin Solution (HAS) (never 20% HAS in this situation). These patients may also have associated septicaemia and consideration should be given for treatment with appropriate intravenous antibiotics.

In oedematous patients where there are no concerns about intra-vascular volume depletion or acute kidney injury, oedema can be managed conservatively by introducing a moderate fluid restriction:

<750ml/day for under 5 years of age
<1L/day for over 5 years of age

Fluid restrictions must be lifted once the patient’s urine output improves and proteinuria decreases as the patient goes into remission.

During the admission monitor fluid balance, observations including blood pressure, assess hydration status and monitor the weight daily. Sometimes assessment of weight and hydration status are necessary more than once a day. If there is uncertainty, please discuss with the oncall paediatric nephrologist.

Some patients develop worsening oedema despite good dietary management (see below) and a fluid restriction. These patients may benefit from low dose oral diuretics or treatment with 20% HAS with intravenous diuretics. These strategies are rarely required and should only be used in clinically stable patients with oedema refractory to conservative management or those with severe symptomatic oedema. These patients may need transfer to Leeds Children’s Hospital. Patients should undergo a careful clinical assessment with subsequent discussion with the paediatric nephrologist oncall to advise on what further treatment is required and where that treatment should be delivered.

Assessment of hydration status and fluid management can be challenging especially if the patient has developed acute kidney injury or is oligo-anuric. In such situations, please discuss with the paediatric nephrologist on-call for advice.

Dietary advice

Salt contributes to increased thirst and weight gain through fluid retention. During relapses and when oedematous, parents/patients should be advised to minimise salt intake by having a no added salt diet and by avoiding salty food items like bacon, sausages, smoked meat and fish, soy sauce, stock cubes as well as avoiding processed foods like cereals, crisps, pizza and ready meals [4, 5].

Aim to reduce salt intake below maximum recommendations as outlined below:

Age

Salt g/day (sodium g/day)

<1year

<1g salt (0.4g sodium)

1-3 years

< 2g salt (0.8g sodium)

4-6 years

< 3g salt (1.2g sodium)

7-10 years

< 5g salt (2g sodium)

11 year+

< 6g salt (2.4g sodium)

Patients may be on high dose steroids for prolonged periods so should also receive dietary advice on calorie control.

Energy

  • Aim for estimated average requirements (EAR) for chronological age and gender [6]
  • Consider calorie reduction if excessive weight gain due to frequent use of steroids
  • Discuss healthy eating principles and exercise

Protein

  • Aim for reference nutrient intake (RNI) for chronological age and gender [7]
  • No evidence to support protein adaptions in children with SSNS
  • In children with SRNS, urinary albumin losses and reduced appetite may lead to malnutrition. Ensure adequate protein from oral diet +/- oral or enteral nutrition support

Fats

  • Children with persistent heavy proteinuria are at increased risk of developing dyslipidaemia (monitor triglycerides and cholesterol)
  • Discuss healthy eating principles including use of mono- and polyunsaturated fats (olive oil, avocado, salmon, some nuts) rather than saturated fats

Micronutrients

  • Encourage RNI calcium + regular consumption of calcium dietary sources for those on long term steroids
Steroids

Corticosteroids are the mainstay of treatment in idiopathic nephrotic syndrome with data suggesting over 90% of patients will respond to a course of high dose steroids [1].

Before starting steroid treatment, side effects and risks need to be discussed with the patient and their parents. Patients will need to be issued with a steroid warning card before discharge.

Doses of prednisolone are calculated using body surface area. Body surface area can be derived using the tables in the rear glossy appendix of the British National Formulary for Children (BNFc) [8].

Longer courses of corticosteroids have been used as initial therapy when patients first present with idiopathic nephrotic syndrome but recent evidence shows no additional benefit from prolonged courses [1]. We therefore recommend an 8-week course of prednisolone at presentation as below. Patients should receive a total of 8 weeks of prednisolone irrespective of when they go into remission.
Steroid doses for first episode:

  • 60mg/m2/day (maximum 60mg*) as a single daily dose for 4 weeks
  • then 40mg/m2/day (maximum 40mg*) on alternate days for 4 weeks then stop

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

Around 80% of patients who responded well to treatment will relapse [1]. Often relapses are triggered by a viral infection. 43-50% of patients will develop frequently relapsing nephrotic syndrome or steroid dependent nephrotic syndrome [1, 9].

Relapse in patients who respond well to steroids can be managed with further corticosteroids. A proposed regime for the first relapse is outlined below with lower doses of steroids used for subsequent relapses (see frequently relapsing steroid sensitive nephrotic syndrome and steroid dependant nephrotic syndrome below) to try to minimise the side effects of steroid treatment.

Steroid doses for 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.
    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 steroid sensitive nephrotic syndrome (FRSSNS):

Subsequent relapses in patients not showing signs of steroid toxicity can be treated with further courses of prednisolone. Nephrotic syndrome has a variable course in individual patients and knowledge of how the disease affects individual patients helps devise bespoke steroid regimes for relapses. Treat with prednisolone but ideally try and use the lowest possible dose 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. In some cases, it can be helpful to wean the steroids over a prolonged period of 8-12 weeks.

Maintain treatment at ≤10mg/m2 aiming to stop the steroids completely over the next 3-6 months. Patients with no signs of steroid toxicity who continue to relapse can be maintained on low dose alternate day steroids to reduce relapses e.g. doses ≤10mg/m2 on alternate days beyond 6 months.

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

Steroid dependent nephrotic syndrome (SDNS):

Some patients with nephrotic syndrome will become steroid dependent. Those who have no signs of steroid toxicity can be treated with prednisolone as described for FRSSNS above.

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 (see page 13).

Gastric protection

Gastric protection should be considered while patients are on high dose steroids and reviewed when the dose is tapering. We recommend for those children under 30kg using 0.5-1mg/kg lansoprazole once daily, rounded to the nearest quarter, half or full tablet (maximum 15mg) and for those children over 30kg to use 15-30mg of lansoprazole once daily.

Penicillin

Children with nephrotic syndrome are at increased susceptibility to infection due to renal loss of complement proteins and immunoglobulins as well as due to the immunosuppressive agents they may be on [10]. They are at particular risk of infection with encapsulated organisms such as streptococcus pneumoniae [10]. Children with nephrotic syndrome are at risk of peritonitis, with streptococcus pneumoniae being the most likely organism [11]. The annual incidence of invasive bacterial infection is 1-2% and this is the leading cause of mortality in these patients [12].

Oral penicillin prophylaxis is recommended during proteinuric phases although the data to support this are limited [12]. The recommended doses are:

Children 1-5 years: Phenoxymethylpenicillin 125mg twice daily
Children ≥ 6 years: Phenoxymethylpenicillin 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.

Children presenting acutely unwell or with suspected infection or peritonitis should be discussed with the on call paediatric nephrologist and treated with appropriate antibiotics as per local guidelines covering for the potential pathogens.

Immunisations

Children with nephrotic syndrome should receive all vaccinations as per the UK schedule unless there are other contraindications. It may not be appropriate for patients to have some vaccinations, especially live vaccinations, if they have had recent steroids or immunosuppressive therapy. Please seek advice if uncertain. For further information refer to the Green Book chapters 6 and 7 [13]. If children do not have a documented or reliable verbal history of immunisation, they should be assumed to be unimmunised and advice sought regarding which immunisations are required.

Streptococcus pneumoniae

All children should now receive the pneumococcal vaccine as part of the routine schedule. Prevenar 13 (PCV13) is given at 12 weeks old with a further dose at 1 year of age. However, children with nephrotic syndrome are at significant risk of serious complications from infections with Streptococcus pneumoniae [10] and should receive vaccination regimes as per advice from the Health Security Agency for high-risk patients [13].

Children with nephrotic syndrome should receive the 23-valent pneumococcal polysaccharide (PPV23) at or after 2 years of age. A suggested regime based on age at presentation is below:

  • Presenting at 0-1 year
    PCV13 at 12 weeks and one year (minimum interval of 4 weeks)
    PPV23 at 2 years of age (at least 8 weeks after last PCV13 dose)
  • Presenting at 1-2 years
    PCV13 on or soon after 1st birthday
    PPV23 at 2 years of age (at least 8 weeks after last PCV13 dose)
  • Presenting at 2-10 years
    PCV13 - one dose if unimmunised or partially immunised otherwise not required
    PPV23 at 2 years of age (at least 8 weeks after last PCV13 dose)
  • Presenting at >10 years
    No further PCV13 irrespective of previous immunisation history
    PPV23 1 dose at presentation

Influenza

Influenza immunisation should be given annually to all children with nephrotic syndrome. Patients should receive the intramuscular injection rather than the intranasal spray as the injection is inactivated.

Patient and parental education

Parents/patients should be taught to test the urine for protein and will need to go home with testing strips. It is essential that parents keep a diary of proteinuria, any relapses and doses of prednisolone and other drugs used for treatment. Parents should be educated as to the importance of sticking to fluid and salt restrictions during a relapse.

Patients and/or parents should be advised to seek medical attention if patients develop a temperature due to the increased risk of invasive bacterial infection [12].

Parents should be advised to monitor for chickenpox and measles contact and seek medical attention urgently if these occur.

Varicella zoster

Varicella zoster status should be checked in all patients at presentation. Parents should be advised to seek medical advice should their child have a chickenpox contact whilst on treatment or within 3 months of completion of steroids or within 6 months of treatment with other or combination immunosuppressive medication (e.g., cyclophosphamide, tacrolimus) or within 12 months of Rituximab. Relevant contacts are those within the household, in the same classroom, or face to face contact for 15 minutes or more. For chickenpox this refers to contact 48 hours before the rash develops until all lesions crust over and for shingles this is from the day of onset of the rash until crusting. The risk is remote if the exposure is from an immunocompetent individual with shingles in a non-exposed area. Please see the Green Book for further details [13].

In the event of contact with varicella an urgent VZV IgG should be sent. If positive then no further treatment is needed unless the child or young person develops chicken pox (see below). Children who are:

  • within 3 months of completion of high dose steroids, or within 6 months of treatment with other or combination immunosuppressive medication (e.g., cyclophosphamide, tacrolimus) or within 12 months of Rituximab
  • AND varicella IgG negative
  • AND had significant exposure (see Green Book for further details [13])

Should be treated with oral aciclovir as post exposure prophylaxis [14]:

Children under 2 years of age
Aciclovir 10mg/kg four times daily, days 7-14 after exposure*

Children 2-17 years of age
Aciclovir 10mg/kg (max 800 mg) four times daily, days 7-14 after exposure*

*if patients present between day 7 and 14 after exposure, they can be risk assessed and treated with 7 days of aciclovir as above.

Any child or young person who develops chickenpox on immunosuppressive treatment or within 3 months of high dose steroids, 6 months of treatment with other or combination immunosuppressive medication or within 12 months of Rituximab should receive treatment with intravenous aciclovir (see below). For further information refer to the most up to date guidelines on the HPA website [14]. Azathioprine or mycophenolate mofetil should be discontinued until the child has fully recovered. Other immunosuppression can be continued.

By intravenous infusion*

  • For child 3 months-11 years
    • 500mg/m2 every 8 hours usually for 5 days
  • For child 12-17 years
    • 10mg/kg every 8 hours usually for 5 days

*Please check eGFR before prescribing as a dose or frequency reduction may be required. Please ensure adequate hydration whilst on treatment.

Measles

Measles IgG status should be tested at diagnosis. Measles can be a life-threatening infection in immunosuppressed patients. Any level of contact with a measles case warrants an assessment in an immunosuppressed individual. Measles is considered infectious from 4 days prior to 4 days after the onset of the rash. Significant risk is close contracts including household contact, face to face contact of any length of time or those with more than 15 minutes in a small confined area for example room in a house, classroom or 4 bed hospital bays. Patients who come into contact with measles should be closely monitored and should be considered for treatment with human normal immunoglobulin (HNIG) following exposure. You may wish to discuss the case with a virologist if unsure. For further information refer to the HPA website [15].

Patients who are IgG positive you can assume are immune and do not need HNIG. If they do not have a positive IgG test since diagnosis then assess their vaccination history. If unvaccinated give HNIG. If they have had at least one measles vaccine do a rapid IgG test and if negative or equivocal give HNIG. If it is not possible to test within 6 days of exposure and if the patient has had 2 vaccines, assume the patient is immune and do not give HNIG. If it is not possible to test within 6 days of exposure and the patient has only had one vaccine then give HNIG.

Patients on biologic therapy such as rituximab may lose or not maintain adequate antibody level from past exposure or vaccination. If these patients have a positive IgG since diagnosis or treatment end then assume they are immune and they do not need HNIG. If there is no documentation or negative IgG since diagnosis then do a rapid IgG test and give HNIG if negative or equivocal. If not possible to test within 3 days of exposure give HNIG.

Thrombosis

In addition to urinary loss of albumin, patients with nephrotic syndrome lose proteins such as anti-thrombin III which are integral to the inhibition of haemostasis. These, together with the increased synthesis of prothrombotic factors predispose these patients to thrombotic events [16]. 2-5% of patients will develop thromboembolisms and the risk is greatest during relapses [17]. 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 and immobilisation [18]. Clinicians should consider using low molecular weight heparin prophylaxis and TED stockings in those patients with increased risk factors for thrombosis such as those that are immobile or significantly obese. Clinicians should have a high index of suspicion of thromboembolic disease if patients have signs such as swollen or painful extremities or respiratory compromise. These patients should be investigated with appropriate imaging studies to confirm the diagnosis [18]. Patients with thromboembolic complications should be managed by a paediatric nephrologist with haematology input.

Second line treatment

These should only be commenced following consultation with a paediatric nephrologist.

Non-steroid immunosuppressive agents can be beneficial both for those with steroid-resistant and steroid-sensitive nephrotic syndrome by inducing remission and reducing relapses as well as trying to minimise the side effects of prolonged courses of steroids [19].

Levamisole

Dose: 2.5mg/kg (rounded to nearest 25mg, max. dose 150mg) orally on alternate days for 12 months

Should be started once the patient is in remission. 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 [19]. It is generally well tolerated. Side-effects are rare but include neutropenia, rash, GI intolerance, seizure and ANCA positive vasculitis. Monitor FBC (particularly neutrophils), renal and liver function tests (LFT) every 3-4 months whilst on treatment.

Note this drug is not licensed in the UK and has to be imported. Community pharmacists can access the drug by special order.

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/

Cyclophosphamide (oral)

Dose: 2-3mg/kg once daily orally for 8 weeks

Patients should be in remission before commencing treatment with Cyclophosphamide. At minimum patients should be on a maintenance dose of steroids (≤10mg/m2 on alternate days) during the course of cyclophosphamide.

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 [19]. Cyclophosphamide has not been shown to be more effective than prednisolone alone at inducing remission in patients with SRNS [20]. Its use is limited by side effects which include marrow suppression and haemorrhagic cystitis. Other side effects include nausea, alopecia and deranged LFTs. In the long term there are concerns regarding gonadal toxicity and malignancy [21].

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

Available as 50mg Tablets (avoid cutting these) or an unlicensed liquid preparation via special order.

A patient information leaflet regarding cyclophosphamide treatment in nephrotic syndrome can be found on the medicines for children website. https://www.medicinesforchildren.org.uk/medicines/cyclophosphamide-for-nephrotic-syndrome/

Mycophenolate mofetil

Dose: 600 mg/m2 orally twice daily

This antiproliferative agent inhibits T and B cell proliferation and its immune modulatory effects have been shown to be beneficial as a steroid sparing agent in children with SDNS and FRSSNS [22, 23].

Mycophenolate mofetil is available as 250 mg capsules and 500 mg tablets. There is also a liquid preparation, Cellcept 1g/5ml. Mycophenolate mofetil can cause gastrointestinal disturbance and should be started at a low dose (e.g., 300mg/m2 twice daily) with the dose gradually increased to 600 mg/m2 twice daily. If used in combination with other immunosuppressants lower doses may be more appropriate. Side effects can include hair loss, myelosuppression and gastrointestinal disturbance. It is less nephrotoxic than calcineurin inhibitors like tacrolimus. Mycophenolate mofetil should only be started following appropriate counselling.

FBC should be monitored every week for the first 4 weeks and then twice a month for 2 months. Subsequently the FBC should be monitored monthly for the first year.

A patient information leaflet can be found on the medicines for children website: https://www.medicinesforchildren.org.uk/mycophenolate-mofetil-nephrotic-syndrome

Tacrolimus

Weight <40kg: 150 micrograms/kg (max 5mg) orally twice daily

Weight > 40kg: 100 micrograms/kg (max 5mg) orally twice daily

The dose of tacrolimus will be altered based on whole blood tacrolimus levels aiming for a 12-hour trough level of 4-6 ug/l. Tacrolimus is a calcineurin inhibitor and works by inhibiting T-lymphocyte signalling. It is used in preference to older calcineurin inhibitors like ciclosporin because of a more favourable side effect profile such as significantly less gingival hypertrophy and hypertrichosis [21]. The data supporting the use of tacrolimus in SDNS and FRSSNS are limited however it is used based on evidence for ciclosporin use in SDNS and SRNS [19, 20].

The bioavailability of tacrolimus varies by brand so the medications should be prescribed by brand (e.g., Adoport) to avoid clinically significant alterations in blood tacrolimus levels. The medication should be taken twice daily on an empty stomach one hour before or one hour after food. Detailed counselling is required prior to starting tacrolimus because of the side effects and potential interactions with other medication. Patients on tacrolimus will require regular blood tests to monitor 12-hour trough levels of whole blood tacrolimus, FBC, renal function, electrolytes, LFT and blood glucose levels. If tacrolimus therapy exceeds 2 years patients should undergo a renal biopsy looking for evidence of calcineurin-induced nephrotoxicity.

Rituximab

Dose: 375mg/m2 (maximum 1 gram) as an infusion with a second dose two weeks later

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 for the treatment of children with FRSSNS and SDNS [19, 21]. It can be used alongside other maintenance immunosuppressive medications, under the guidance of the paediatric nephrologist.

Side effects include acute infusion reactions such as fever, headache, flushing, diarrhoea and vomiting, rash and bronchospasm. Patients should be monitored carefully during treatment. Serious side effects include pulmonary fibrosis, malignancy and pneumocystis jiroveci pneumonia [21].

For this indication Rituximab should be prescribed and administered in Leeds Children’s Hospital under the care of the paediatric nephrology team.

Prior to treatment with Rituximab the below investigations are required and it is helpful if these are organised prior to any planned infusion so that Rituximab can be prescribed and ordered in advance.

Within 14 days of a course of Rituximab:

  • Full blood count
  • Urea and electrolytes
  • Chloride and bicarbonate
  • Calcium, albumin, phosphate, magnesium
  • LFTs including gamma GT
  • CD19 count (lymphocyte subset)
  • Hepatitis B and C serology
  • CMV, EBV and adenovirus PCR

Within 6 weeks of a course of Rituximab:

  • Varicella, parvovirus, measles, CMV and EBV serology *
  • Immunoglobulins - IgA, IgG, IgM

Also consider

  • CXR and Quantiferon gold - in patients considered to be high risk
  • HIV screen - in patients considered to be at risk
  • Urinary pregnancy test - in females of child bearing age

*if patients have previously tested IgG positive it is not necessary to repeat viral serology again with subsequent infusions of Rituximab (see below)

On admission patients should have a full medical assessment paying particular attention to the below:

  • Has the patient had a previous course of Rituximab?
  • If patients have reacted previously how was this managed?
  • Does the previous reaction necessitate a change in the infusion regime? (e.g. slower rate or a different pre-medication regime)
  • Verbal consent should be taken and documented in the patient record
  • Specific points in the history include establishing any history of recent illnesses or contraindications to proceeding with Rituximab (e.g. fever or current relapse from nephrotic syndrome)
  • A full medication history and allergy status should be taken and documented
  • Document the patient’s current weight and a recent height
  • Patients should undergo a full systemic examination including assessment of observations (heart rate, respiratory rate, blood pressure, temperature, oxygen saturations)

If the patient is felt to be suitable to proceed with the Rituximab infusion then gain intravenous access. If any repeat blood tests are required ensure these are sent at the same time. Once intravenous access is established administer pre-medications at least 1 hour before the Rituximab infusion:

Paracetamol orally: 15mg/kg (maximum 1 gram)

Chlorphenamine orally: 1 month - 5 years: 1mg, 6-11 years: 2mg, 12-17 years: 4mg

During the infusion most reactions are noted during the first few minutes, so the patient should be observed carefully during this time and following increases in the infusion rates. The patient should have close monitoring with observations at least every 15 minutes for the first hour and every 30 minutes thereafter.

Signs of an acute infusion reaction:

  • Low grade fever
  • Headache
  • Flushing
  • Nausea
  • Rash
  • URTI symptoms
  • Transient hypotension and bronchospasm - usually related to the infusion rate

If the above symptoms or signs are present, half the infusion rate and request medical review. Following medical assessment it may be appropriate to treat the patient’s symptoms with medication and continue the Rituximab infusion providing the patient’s symptoms have resolved. The patient’s clinical state and the medical assessment will guide whether the rate of infusion can be gradually increased again.

Signs of moderate-severe infusion reaction:

  • High grade fever
  • Chills
  • Rigors
  • Mucosal swelling
  • Shortness of breath
  • Hypotension by >30mmHg from baseline

If the above symptoms or signs are present, stop the infusion and request urgent medical review. The patient may be developing a severe allergic reaction and should be assessed and considered for emergency treatment for anaphylaxis. Further management will be dictated by the medical assessment at the time and on a patient by patient basis.

On completion of the infusion ensure the patient is booked in for the second infusion. If any investigations are required prior to the second infusion ensure these are organised. Patients and parents should be offered safety net advice as below:

  • Seek medical advice if there are any signs of infection including fever, sore throat, stomach pain, loose stools or dysuria.
  • Rarely, some children may develop a skin reaction some months after the infusion. If a rash is noticed patients and parents should be asked to seek medical attention as soon as possible.

Following Rituximab therapy patients should not receive any live vaccinations for at least 12 months. Inactivated vaccinations can be given 6-12 months after a course of Rituximab but there may be a reduced response to the vaccine. If possible it may be preferable to defer any vaccinations for 12 months after the Rituximab infusion. Patients and parents should be advised to seek medical advice before any vaccinations are given.

Patients will usually have follow up already organised with one of the paediatric renal consultants who will organise a CD19 lymphocyte count check after the 2 doses of Rituximab to ensure appropriate depletion.

If patients develop relapses after treatment Rituximab recheck the CD19 count and if elevated patients can be considered for a further course of Rituximab.

When to refer to a paediatric nephrologist

Reasons to refer patients to a paediatric nephrologist

  • Atypical features
  • Steroid resistant nephrotic syndrome
  • Complications such as AKI, thromboembolism or peritonitis
  • Unsure if patient needs 20% HAS
  • Signs of steroid toxicity
  • Frequently-relapsing nephrotic syndrome
  • Steroid-dependent nephrotic syndrome
  • Problematic relapses

Indications for considering renal biopsy

  • SRNS
  • Deranged renal function
  • Hypertension
  • Low C3
  • Clinical features suggestive of systemic disease (rash, arthritis, anaemia)
  • Age <1year or >12years
  • Macroscopic haematuria
  • Family history of nephrotic syndrome
  • Nephrotic syndrome associated with chronic infections e.g., Hepatitis B, HIV

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
Target patient group: Children with Idiopathic Nephrotic Syndrome in Yorkshire and the Humber
Target professional group(s): Secondary Care Doctors
Adapted from:

Evidence base

  1. Webb, N., Woolley, R., Lambe, T., Frew, E., Brettell, E., Barsoum, E., . . . Ives, N. (2019). Long term tapering versus standard prednisolone treatment for first episode of childhood nephrotic syndrome: phase III randomised controlled trial and economic evaluation. British Medical Journal, 365.
  2. Banh, T., Hussain-Shamsy, N., V Patel, J. V.-R., Borges, K., Sibbald, C., Lipszyc, D., . . . Parekh, R. (2016). Ethnic Differences in Incidence and Outcomes of Childhood Nephrotic Syndrome. Clinical Journal of the American Society of Nephrology, 1760-1768.
  3. Nephrotic syndrome in children: Prediction of histopathology from clinical and laboratory characteristics at time of diagnosis. A Report of the Internal Study of Kidney Disease in Children. (1978). Kidney International, 13(2), 159-165.
  4. NHS. (2020, October 7). Salt: the facts. Retrieved from www.nhs.uk: https://www.nhs.uk/live-well/eat-well/salt-nutrition/
  5. Shaw, V. (2014). Clinical Paediatric Dietetics (4th Edition ed.).
  6. SACN. (2011, November 1). Scientific Advisory Committee on Nutrition: Dietary Reference Values for Energy. Retrieved October 2020, from www.gov.uk: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/339317/SACN_Dietary_Reference_Values_for_Energy.pdf
  7. FAO/WHO/UNU. (1985). Energy and Protein Requirements. Geneva.
  8. BNFc. (2020). Body Surface Area in Children. Retrieved 06 30, 2020, from https://bnfc.nice.org.uk/guidance/body-surface-area-in-children-image.html
  9. Dakshayani, B., Lakshmanna, M., & Premalatha, R. (2018). Predictors of frequent relapsing and steroid-dependent nephrotic syndrome in children. Turk Pediatri Arsivi, 53(1), 24-30.
  10. Kumar, M., Ghunawat, J., Saikia, D., & Manchanda, V. (2019). Incidence and risk factors for major infections in hospitalized children with nephrotic syndrome. Brazilian Journal of Nephrology, 41(4).
  11. Gorensek, M., Lebel, M., & Nelson, J. (1988). Peritonitis in Children With Nephrotic Syndrome. Paediatrics, 849-856.
  12. McCaffrey, J., Lennon, R., & Webb, N. (2016). The non-immunosuppressive management of childhood nephrotic syndrome. Pediatric Nephrology, 31, 1383-1402.
  13. Ramsay, M. (2020). Immunisation against infectious disease (The Green Book). Retrieved 02 01, 2022, from UK Health Security Agency: https://www.gov.uk/government/collections/immunisation-against-infectious-disease-the-green-book
  14. Amirthalingam, G., Brown, K., & Ramsay, M. (2019). Updated guidelines on post exposure prophylaxis (PEP) for varicella/shingles. Retrieved from Public Health England: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/812526/PHE_PEP_VZIG_guidance_for_health_professionals.pdf
  15. PHE. (2019). Guidelines on Post-Exposure Prophylaxis for measles. Retrieved from https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/814203/Guidance_for_measles_post-exposure_prophylaxsis.pdf
  16. Sharp, W., & Olivero, J. (2018). Venous Thrombosis in Nephrotic Syndrome. Methodist Debakey Cardiovascular Journal, 14(3), 237-238.
  17. Torres, R., Torres, B., Rocha de Castilho, A., & Honorato, R. (2014). Venous sinus thrombosis in a child with nephrotic syndrome: a case report and literature review. Revista Brasileira De Terapia Intensiva, 26(4), 430-434.
  18. Kerlin, B., Haworth, K., & Smoyer, W. (2014). Venous thromboemobilism in pediatric nephrotic syndrome. Pediatric Nephrology, 29(6), 989-997.
  19. Larkins, N., Liu, I., Willis, N., Craig, J., & Hodson, E. (2020). Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children. Cochrane Database of Systematic Reviews.
  20. Hodson, E., Wong, S., Willis, N., & Craig, J. (2016). Interventions for idiopathic steroid-resistant nephrotic syndrome in children. Cochrane Database of Systematic Reviews.
  21. Rheault, M. (2016). Nephrotic Syndrome: Updates and Approaches to Treatment. Current Treatment Options in Pediatrics, 94-103.
  22. Bagga, A., Hari, P., Moudgil, A., & Jordan, S. (2003). Mycophenolate mofetil and prednisolone therapy in children with steroid-dependent nephrotic syndrome. American Journal of Kidney Diseases, 1114-20.
  23. Hogg, R., Fitzgibbons, L., Bruick, J., Bunke, M., Ault, B., Baqi, N., . . . Swinford, R. (2006). Mycophenolate mofetil in children with frequently relapsing nephrotic syndrome: a report from the Southwest Pediatric Nephrology Study Group. Clinical Journal of the American Society of Nephrology, 1173-8.

Approved By

Trust Clinical Guidelines Group

Document history

LHP version 2.0

Related information

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