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Idiopathic nephrotic syndrome in children, management

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Objectives

This document provides information on the investigation, treatment and management of nephrotic syndrome in children at initial presentation (Part 1) and in relapse (Part 2) of the condition.  

Scope

The guideline applies to children throughout Scotland with typical idiopathic nephrotic syndrome (INS). 

Audience

This document is intended for use by all health professionals (doctors, nurses, dietitians and pharmacists) who look after children with typical INS within Scotland.

Definition and initial features of Nephrotic Syndrome

INS is the commonest childhood glomerular disorder.

  • Annual incidence: 2 per 100,000 children in the UK.
  • Presentation: median age of 2-3 years
  • Gender prevalence:  2x more prevalent in boys
  • Racial demographics: 4-6x more prevalent in people of South Asian origin. 

> 80-90% of children who present with INS respond to a course of high dose prednisolone with the current practice to treat empirically without a renal biopsy.  Steroid responsiveness is a better indicator than histology of long-term outcome for renal function.

Definition   

Steroid sensitive nephrotic syndrome (SSNS):

Responds to steroids within 4 weeks.

A variety of histological appearances can be seen in INS.

Histologically >90% will have Minimal change nephrotic syndrome (MCNS), the majority of the rest will have Focal segmental glomerulosclerosis (FSGS).  The small remainder will have appearances such as mesangial hypercellularity/diffuse mesangial proliferation.  

Approximately, 80-90% of children with MCNS will response to steroids.

Generally a biopsy is not required for this group.

Steroid resistant nephrotic syndrome (SRNS):

Proteinuria does not remit with 4 weeks of daily steroids.

Histologically the frequency of different appearances varies with age.  The vast majority in childhood have FSGS.  Other appearances seen are Membranoproliferative glomeluronephritis (MPGN); Membranous glomerulonephritis; C3 glomerulopathy; IgA nephropathy.  

Part 1 - first presentation

Clinical Features

Diagnostic and Clinical Features:

  1. Heavy proteinuria (3+/4+ on dipstick) or urine protein:creatinine (PCR) >200 mg/mmol.
  2. Hypoalbuminaemia: serum albumin <25 g/L
  3. Generalised oedema:
    Peri-orbital swelling, noticed particularly in the morning
    Ankle and lower limb swelling – pitting oedema  Abdominal swelling and scrotal/vulval oedema

Typical versus atypical features

Typical Features   

Age 1-10 years

Normotensive

Normal creatinine

Microscopic haematuria (≤25%)

Atypical Features   

<1yr, >10years Hypertensive

Macroscopic haematuria

+/- Family history of nephrotic syndrome

Those presenting with atypical features are more likely to be unresponsive to steroid treatment.

Initial Assessment

Initial clinical assessment to include:  

  • Height and weight
  • Calculation of body surface area - √([Ht (cm) x Wt (kg)] / 3600) Cardiovascular status and perfusion
    • Heart rate
    • Blood pressure
    • Capillary refill time
    • Jugular venous pressure (JVP) or presence of hepatomegaly – particularly in older children
  • Assessment of oedema - Lower limb
    • Spine – sacral
    • Ascites
    • Scrotal/vulval
  • Assessment of fluid status
    • Fluid overload
      (tachycardia; hypertension; warm peripheries; respiratory distress; hepatomegaly; raised JVP)
    • Euvolemia
    • Hypovolemia
      (tachycardia; hypertension; cool peripheries; delayed capillary refill time; severe abdominal pain)

Note: Hypovolemia is relatively common and can lead to serious complications. Tachycardia and hypertension can be present in both fluid overload and hypovolemia. Peripheral and central perfusion remain the most discriminatory physical findings with warm peripheries and possible respiratory distress in fluid overload, and cool peripheries with delayed capillary refill time in hypovolemia.

Initial Investigations 

Investigations to be performed in all children. 

Children with nephrotic syndrome can be difficult to bleed due to oedema, therefore only take the following bloods on initial assessment.

Bloods:

  • FBC
  • U&Es – including bicarbonate; chloride
  • Bone profile – calcium; phosphate; serum albumin
  • LFTs
  • Varicella IgG
  • Vitamin D

Urine:

  • Urinalysis including glucose - document proteinuria and the presence of any haematuria
  • Urinary protein:creatinine ratio (PCR)
  • Urinary sodium concentration – helpful in aiding fluid status

 

Further investigations to be performed in children with atypical features:

  • ASOT – may be elevated in Streptococcal throat infection
  • Anti-DNaseB – may be elevated in Streptococcal skin/throat infection
  • C3/C4 – low C3 levels may be seen in post-Streptococcal/infectious glomerulonephritis (PIGN), C3 glomerulopathy (previously called MPGN types I-III), systemic lupus erythematosus (SLE)
  • Hepatitis B status in children at high risk: family history of hepatitis B infection or history of travel in endemic areas.  

 

Indications for discussion with a paediatric nephrologist

If there are any of the following features, the child/young person should be discussed with a paediatric nephrologist:

  • Any atypical features
  • Before giving IV albumin (see section)
  • Any complications: the nephrotic state can be complicated by hypovolaemia; thrombosis and infection
  • If not responsive to Prednisolone after 4 weeks

Management

Fluid Restriction

Fluid restriction may also be helpful in limiting the increase in oedema. However, if a child is felt to be intravascularly deplete and peripherally shut down (cool peripheries, prolonged capillary refill time, tachycardic, and/or hypotensive) then fluid restriction may increase the risk of thrombotic episodes so the need for a fluid restriction should be evaluated carefully and reviewed daily. Discussion with nephrology is advised if in doubt.

General Recommendations for fluid restriction:

<5 years: 750 mL per day

>5 years: 1000 mL per day

These restrictions should always be lifted once the child goes into remission.  An increased urine output is often an early sign of entering remission. 

Remember hidden fluids may be present in certain foods (e.g. soups, yogurts, ice lollies, fruit). 

Dietary Advice

A low salt diet limits thirst and also prevents further fluid retention and oedema.

Dietetic advice regarding calorie control should be given whilst on steroids.  Dietetic restrictions can be lifted once in remission.  

Drug Treatment 

Drug treatment in children with INS can prove challenging. 

Pharmacy advice is helpful in many aspects of appropriate drug treatment in NS: 

  • Drug dosing and administration
  • Appropriate formulation
  • Steroid treatment and tapering regimen
  • Antibiotic prophylaxis
  • Gastro-protection
  • Vitamin D supplementation

A Renal Medication Information Booklet should be issued to all patients. 

Prednisolone

Prednisolone is the drug of choice in INS. Patients should be issued with a steroid warning card.

Dose 

Currently an 8-12-week initial course is recommended. 

Note – increased risk of adrenal suppression after 4 weeks of high dose steroids. See below for further comment.

Prednisolone dose is based on body surface area (BSA). 

(BSA = √([Ht (cm) x Wt (kg)]/3600) Mosteller method.
Height is essential to calculate BSA.

  • 60 mg/m2/day for 4 weeks (maximum 60 mg/day)
  • 40 mg/m2 on alternate days for 4 weeks (maximum 40 mg/day)

  • Then reduce dose by 5-10 mg/m2 each week for another 4 weeks, then stop.

An alternative regimen is to stop after 8 weeks total. Risk of adrenal suppression should be considered.

Dosing regimen for initial presentation for ranges of BSA, with rounding of dose can be found in Appendix 2.

Monitoring  

Monitor BP and urine PCR.

If proteinuria persists beyond the first 4 weeks of steroid treatment, then children should be referred to the paediatric nephrology team.

Adverse effects 

Steroids can be associated with stomach ache, nausea, vomiting, indigestion, increased appetite, weight gain, trouble sleeping and nightmares, low mood, emotional lability, and changes in behaviour.

Long-term use of prednisolone can result in adrenal suppression, short stature, cataracts, and hypertension.

For all first presentations, a steroid warning card should be issued, as required for steroid usage > 6 weeks and adrenal suppression guidelines should be followed. Adrenal suppression secondary to exogenous glucocorticoid - guidance for children on long term steroid therapy (scot.nhs.uk)

Availability & Prescribing

Prednisolone liquid (10 mg/mL) can be sourced through pharmacy. The use of liquid prednisolone (rather than tablets) in young children has improved compliance considerably and outweighs the cost.

Prednisolone dispersible 5 mg tablet

Prednisolone plain tablets: 1 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, 25 mg, 30 mg (these contain lactose)

Prednisolone enteric-coated (EC) tablets: 1 mg, 2.5 mg, 5 mg (these contain lactose)

Antibiotic Prophylaxis – Phenoxymethylpenicillin (Pen V)

Infection remains the main cause of death in children with nephrotic syndrome. Whilst nephrotic, children are at increased risk of infection, particularly with encapsulated organisms such as Pneumococcus. Recommendations on the use of antibiotic prophylaxis vary as there is no strong evidence of its benefit. Grossly oedematous children are at particular risk of cellulitis/peritonitis and may benefit from antibiotic prophylaxis.

Our policy is to give Phenoxymethylpenicillin prophylaxis only in children who are severely oedematous/ascitic on first presentation.

Note Penicillin V is generally not recommended in relapses.

Age <1 year:         62.5 mg twice daily

Age 1-5 years:      125 mg twice daily

Age ≥6 years:       250 mg twice daily

If penicillin allergic, consider Erythromycin as per BNFc

Pneumococcal vaccination is recommended for children with NS not previously vaccinated. See Vaccination advice below.

Gastroprotection

Protection against steroid-induced gastric irritation should be started at the time of commencing steroids. 

Use a proton pump inhibitor (PPI) as per local policy, dosing as per BNFc.

Consider stopping the PPI once the Prednisolone dose is weaned to 10 mg on alternate days in the absence of gastric symptoms.

Diuretics

Whilst not routine, there may be a role for diuretics in persistent oedema with no hypovolemia. Discussion with nephrology is advised.

Diuretics should only be used in a child/young person who is not clinically hypovolaemic. Furosemide alone may be tried initially. However, if oedema is severe, the addition of spironolactone or amiloride may be more effective.

  • Furosemide: 0.5-1 mg/kg twice daily orally. Give second dose before 6pm to avoid the effect disturbing sleep.
  • Spironolactone: 0.5 -1 mg/kg twice daily orally; or Amiloride: 0.1-0.2mg/kg twice daily orally

Patients on diuretics need close and regular review as they are at risk of intravascular depletion if entering remission. If discharged, review within 48-72 hours is advised to assess the ongoing need for diuretics. A maximum 5 day supply is advised.  Review should include clinical assessment with weight measurement, urine PCR quantification and assessment of renal function.

If diuretics are felt to be required beyond 7 days then there is an additional need to monitor ionised calcium levels.

Vitamin D

This is measured as levels of 25-hydroxyvitamin D, see Table 1 for definition. 

Definition

Serum 25-hydroxyvitamin D

Severe deficiency

<12 nmol/L

Deficiency

12-50 nmol/L

Insufficiency

50-75 nmol/L

Sufficiency

>75 nmol/L

Table 1: Definition of serum levels of 25-hydroxyvitamin D  

Follow local policy for management of vitamin D deficiency and treatment.

Manage Complications

Hypovolaemia

Hypovolaemia in an oedematous child is common, particularly on first presentation. Hypovolaemia is associated with a risk of thrombosis.

Hypovolaemia management can be challenging. Seek nephrology input early on.

Consider fluid repletion if the initial assessment suggests hypovolemia. This can be delivered with 5% Albumin (5-10 mL/kg). The rate will vary depending on clinical severity and this is generally given over 1- 4 hours.

Severe Oedema

Albumin infusion

Albumin infusions are associated with a significant risk of fluid overload and pulmonary oedema. 20% albumin should not be given out with daytime hours and only with medical supervision readily available.

  • Ideally this should be done with adequate nursing supervision, in a high dependency unit, if possible and only following consultation with the on-call paediatric nephrologist.
  • Estimate dry weight to establish dose of albumin. It is safer to round down and give less.
  • Administer 1 g/kg (5 mL/kg) 20% albumin over 4-6 hours. In severe oedema, or if a child has previously been treated for hypovolaemia, give over 6 hours.
  • Administer 1 mg/kg IV furosemide mid-way through infusion and a further 1 mg/kg IV furosemide at end of infusion. Prior to end dose, carry out a clinically assessment of the child to assess if it is clinically safe for a second dose of furosemide. If the child remains peripherally cool to touch with reduced perfusion then it may be reasonable to omit the second dose of furosemide provided their lung fields are clear with no tachypnoea, and no tachycardia or hypertension.

    See Nursing Albumin Standard Operating Procedure(SOP)

Hypertension

Most children presenting with nephrotic syndrome are normotensive when their BP is checked in the setting of them being relaxed and using an appropriate sized cuff on an upper limb. If the BP is truly elevated, it is often associated with oedema and should resolve when oedema subsides. Adhering to the set fluid restriction and a low salt diet is helpful. Fluid removal using diuretics will help reduce BP. If it persists, antihypertensives may be required in the short term. However, this should be discussed with a paediatric nephrologist. 

Persistent hypertension (systolic BP >95th centile) can be treated with longer acting agents such as Amlodipine. This is particularly useful in young children as it is a once daily dose and comes in a liquid formulation. Dose: start at 0.1mg/kg; can be increased incrementally (ideally weekly) to 0.4mg/kg per day (max 10 mg daily).

Children who have been discharged on antihypertensives should be reviewed in clinic within a week from discharge as their BP may return to normal as the oedema subsides.

Thrombosis

Patients with nephrotic syndrome are predisposed to a pro-coagulant state due to loss of anti-thrombin III in the urine and intravascular depletion. Thrombosis is a rare (occurring in approximately 3% of patients), majority within the venous circulation, but significant complication of nephrotic syndrome, contributing to significant morbidity and mortality.

Thromboses may develop in the locations including the extremities (i.e. deep venous thrombosis), renal vasculature (i.e. renal vein thrombosis), pulmonary vessels (i.e. pulmonary embolism), cerebral venous sinuses (i.e. cerebral venous sinus thrombosis) – headache being the first symptom. Any clinical features which point towards a thrombosis warrants an urgent clinical review and should be followed up by prompt imaging studies. In the event of a suspected thrombus, refer urgently to paediatric nephrology. 

Vaccination

Live vaccines should not be given to children who are on, or have recently been taking immunosuppressive medication, as defined by our immunisation guideline: Immunisation guideline for children with chronic kidney disease

Please note, particular consideration needs to be given to the following vaccines:

Pneumococcal Polysaccharide Vaccine (PPV) 23 Valent 

  • Recommended for all children with NS over 2 years.
  • Confirm prior vaccination with the pneumococcal conjugate vaccine (PCV) 13 valent.
  • Request GP to administer 23 valent if the child has previously had the 13 valent as part of routine childhood immunisations. Include this in the child’s discharge letter.
  • If the child has not had the 13 valent vaccine, refer to the vaccination schedule as per immunisation of unknown/incomplete immunisation.
  • Repeat PPV 23 vaccination every 5 years.

Varicella Zoster Vaccine

Chicken pox in children who are, or have been on immunosuppressive medication, can be a very serious illness. Establish varicella status with parents on admission and document this in the patient’s case notes.

Varicella zoster IgG should be taken with bloods on initial presentation. If negative with a positive history of having had chicken pox, this will need to be repeated as it may be a false negative. 

 Varicella status confirmed non-immune (VZIgG negative) 

  • For all children confirmed VZIgG negative, consider active immunisation with Varicella-zoster vaccine when off all immunosuppressive therapy.  

Chicken pox contact

For children who are not immune to chicken pox (VZIgG negative) and who are immunosuppressed (classified as being on ≥2 mg/kg/day of prednisolone for >1 week or 1 mg/kg/day for >1 month or on second line immunosuppression), it is important that they contact their healthcare provider if they have had a close contact exposure (deemed to be a household contact or within the same class at nursery or school). They will need to attend the hospital.

The guidance for VZ prophylaxis has changed recently due to the shortage of Varicella Zoster Immunoglobulin (VZIG) within the UK. 

Options: 

  • Oral Aciclovir or Valaciclovir treatment for 7 days. This should be started on days 7-14 post Evidence suggests that giving aciclovir immediately following exposure is actually associated with an increased incidence and severity of varicella infection, hence the recommendation for a delay. Dosing of Aciclovir and Valaciclovir is as per BNFc. This is the current option of choice.
  • Varicella-zoster immunoglobulin (VZIG) can be given if readily available. Dosing as per BNFc. VZIG would be preferential in those with significant renal impairment (whereby aciclovir may be contraindicated due to risk of nephrotoxicity) or intestinal malabsorption disorders (e.g. inflammatory bowel disease).

Chicken pox infection

All children who report a rash thought to be chickenpox should be reviewed in hospital. If chickenpox is confirmed then the child should be admitted and treated appropriately. If they remain clinically well then they may be able to be treated with a course of treatment-dose oral aciclovir. Unwell children should be given treatment-dose IV aciclovir. 

Seasonal Influenza

Annual seasonal flu vaccination is required but children/young people with NS should be given a non-live injection and NOT the live nasal vaccination. Please include this in the discharge letter.

Ongoing care

Admission and inpatient management is advisable with the first presentation. Regular review thereafter to monitor for complications and assessment of oedema is recommended. The frequency of follow-up will be guided by the patient’s clinical status.

Parental teaching and education 

INS is defined by relapses and remissions. Families need education on how to manage the condition on discharge, and how to recognise and manage relapses. Education should commence as soon as possible following admission.

Parents should be taught to test urine daily on discharge with Albustix® using a first morning urine sample. 

Areas of education:

  • Urine testing and recording.
  • Medication administration – ensure the child is taking the medication from their parents prior to discharge. Ensure parents are aware of the correct dosing and timing of medication.
  • Fluid restriction – ensure parents are aware of daily fluid allowance and to get in touch with the unit when their child starts to pass more urine, and urinary protein starts to reduce on home testing. As children respond to steroids and go into remission, they can often pass large volumes and are at risk of becoming dehydrated if still on a fluid restriction. This risk is greater if they are also on diuretics.
  • Outpatient review - children should be seen in clinic within one week of discharge or earlier if discharged home on diuretics.

Web links for patient information on Nephrotic Syndrome (NS)  

InfoKid provides information for parents and carers regarding various kidney conditions in infants, children and young people http://www.infokid.org.uk   

There are links to the Medicines for Children website regarding medications used in Nephrotic Syndrome: Leaflets – Medicines For Children

https://www.kidneykids.org.uk/ Kidney Kids Scotland have set up a Facebook page which aims to connect families if patients with nephrotic syndrome.

Nephrotic Syndrome Trust- NeST NeST | Nephrotic Syndrome Trust (nstrust.co.uk)

Discharge planning

Discharge planning and parent education should begin soon after admission and diagnosis. A checklist can be used and a printed copy can be provided to the patient and family at discharge (Appendix 1).

Nursing

See Nursing Albumin SOP

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 dipstick testing either showing trace or negative for protein. Up to 80% of patients enter remission within 14 days on steroids.

Part 2 - diagnosis and management of relapsing nephrotic syndrome

Relapses in the first year are very common (occurring in up to 80-90% of patients) and these can still occur years after the initial presentation. There may sometimes be an obvious and identifiable trigger, such as upper respiratory tract respiratory infections, allergies, or vaccinations.

Relapses

A first morning urine sample should be monitored twice weekly with Albustix® during periods of remission. Testing should be increased to daily if proteinuria is present.

Relapses are defined as proteinuria of 3+ on dipstick testing for three consecutive days.

  • Up to 90% of steroid-responsive nephrotic children will relapse.

Low grade proteinuria (<2+) may occur transiently and is often associated with an intercurrent illness. 

Urine PCR is helpful to quantify proteinuria, and this can be arranged through the patient’s GP. The child should be seen in hospital if they develop nephrotic-range proteinuria (uPCR >200 mg/mmol) or if there are parental concerns.

If the uPCR is <200mg/mmol with no oedema, a short course of low dose prednisolone could be considered. Continue daily urine testing and repeat urine PCR in 4-7 days. Occasionally, low level proteinuria may settle on its own without any treatment.

In the absence of proteinuria, as per PREDNOS 2, there is no benefit in giving steroids at the time of an intercurrent infection to prophylactically prevent a relapse.

Patients often can be managed as an outpatient with regular contact.

Frequent relapses

Frequent relapses are defined as:  

  • 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 relapses occur whilst the patient is still on steroids, or within 2 weeks of ceasing steroids.

If children have frequent relapses, strategies should be adopted to reduce the amount of steroid required. This should be discussed and agreed with a paediatric nephrologist. 

Unfortunately, around 60% of steroid-responsive patients who relapse experience five or more relapses. Some can be successfully managed with low dose alternate day steroids. This should be discussed with the paediatric nephrology team.

Drug treatment 

Prednisolone

Prednisolone treatment should be restarted once a relapse has been diagnosed. Urine should be tested daily until negative/trace for 3 days in a row. Thereafter, urine should be tested twice weekly.

  • 60 mg/m2/day (maximum 60 mg) until in remission (negative or trace only for protein in first morning urine for 3 consecutive days)
  • 40 mg/m2 (maximum 40 mg) on alternate days for 1 week.
  • 30 mg/m2on alternate days for 1 week
  • 20 mg/m2on alternate days for 1 week
  • 10 mg/m2 on alternate days for 1 week

The above is a standard weaning regimen (Appendix 3). The weaning rate may be altered dependent on individual response.

Treatment plans should be clearly documented in case records and the patient Renal Medication Book.

If the patient has been on steroids for > 6 weeks, a steroid warning card should be issued and adrenal suppression guidelines should be followed. Home - Adrenal suppression secondary to exogenous glucocorticoid - guidance for children on long term steroid therapy (scot.nhs.uk)

Other Medication

Gastroprotection should be given as in the initial presentation.

Penicillin V is not recommended in our centre for relapses.

Diuretics may be indicated based on the same clinical findings as in the initial presentation.

Second Line Therapy

Levamisole

Levamisole may be beneficial for children with frequent relapses. It is less useful in those who are steroid dependent. 

Dose 2.5 mg/kg/ on alternate days or 3 times a week rounded to 25 mg doses to max. 150mg .

After treatment has been established for 4 weeks, steroids can be tapered. 

Monitoring  

FBC check monthly for first 3 months, then at 6 months and 4-6 monthly thereafter.

Duration of Treatment

If successful, treatment can continue for up to 3 years.

Adverse Effects 

These are rare and limited.

  • ‘Idiosyncratic’ neutropenia - reversible on discontinuing the drug.
  • Rash - ‘erythema multiforme’-like.
  • GI intolerance.
  • Vasculitis (ANCA positive).

Availability & Prescribing

Levamisole tablets 50 mg (these can be crushed and mixed in water) 

Levamisole tablets are not licensed in the UK and are imported. GPs may not prescribe however Community pharmacists can access the drug by special order. Families are advised to give adequate notice for repeat prescriptions.

This medicine is NOT an immunosuppressant and is considered to be an immunomodulatory drug instead. Therefore, live vaccines can be given e.g. nasal influenza.

Cyclophosphamide

Cyclophosphamide can induce longer lasting remissions in children with frequently relapsing steroid sensitive NS.

Dose 

3 mg/kg/day for 8 weeks. Maximum cumulative dose 168 mg/kg. 

(Dose as per ideal body weight for obese children and reduce the dose in renal impairment).

Monitoring  

FBC check weekly throughout treatment. 

  • Consider dose reduction to 50-75% if neutrophils 1.0 – 1.5 x 109/L.
  • Stop if neutrophils <1.0 x 109/L and restart at 50-75% dose on neutrophil recovery >1.5 x 109/L.

Duration of Treatment 8 weeks.

Adverse effects 

  • Neutropenia and infection - FBC monitoring and dose reduction if this occurs.
  • Hair thinning - uncommon.
  • Haemorrhagic cystitis - rare; encourage fluids for 6 hours post dose.
  • Gonadal toxicity - associated with cumulative dose >200-300 mg/kg.
  • Malignancy - rare and felt that there is not a clinically significant increased risk compared with the general paediatric population.

Availability & Prescribing

Cyclophosphamide tablets 50 mg (do NOT split or crush)

Cyclophosphamide suspension 50 mg/5 mL (special manufacturer)

Discuss with pharmacist regarding handling and disposal as this is a cytotoxic. 

Ciclosporin

Ciclosporin (Neoral®) is a steroid sparing agent and has been shown to be effective in NS. It is a calcineurin inhibitor.

Dose 

2.5 mg/kg 12 hourly adjusted to achieve target trough level.

Monitoring 

Therapeutic range ciclosporin for NS : 12 hour trough of 50 – 100 nmol/L.

Check 12 hour trough level at least 1 week after treatment introduction and 1-2 weeks after any dose changes. When stable on treatment, frequency of review can reduce to 2-3 monthly (withhold morning dose until after trough level check).

Consider higher ciclosporin trough levels up to a maximum of 150 nmol/L in patients relapsing at lower trough levels where renal function and blood pressure remain normal. 

Monitor BP, uPCR and renal biochemical function.

Duration of Treatment

If successful, treatment can be continued for at least 1 year initially and can be continued for up to 2 years before a trial off therapy if relapse-free.

Adverse Effects

  • Nephrotoxicity
  • Hypertension
  • Hypertrichiosis
  • Gum hyperplasia

Availability & Prescribing

Ciclosporin prescribing should be brand name only.

Ciclosporin (Neoral®) Liquid 100 mg/mL

Ciclosporin (Neoral®) Capsules 10 mg, 25 mg, 50 mg & 100 mg 

Tacrolimus

Tacrolimus is a steroid sparing agent and has been shown to be effective in NS, it is a calcineurin inhibitor and may be preferred to Ciclosporin due to the lack of cosmetic adverse effects. Cautionary use is advised if there is a family history of diabetes.

Dose 

0.1 mg/kg 12 hourly (max 5 mg 12 hourly) adjusted to achieve target trough level.

Monitoring 

Therapeutic range Tacrolimus for NS: 12 hour trough of 4-6 ng/mL.

Check 12 hour trough level at least 1 week after treatment introduction and 1-2 weeks after any dose changes. When stable on treatment, frequency of review can reduce to 2-3 monthly (withhold morning dose until after trough level check).

Monitor BP, urine PCR, urine glucose and renal biochemical function, including bicarbonate levels and magnesium levels.

Duration of Treatment

If successful, treatment can be continued for at least 2 years initially and can be continued for up to 3 years before a trial off therapy if relapse-free.

Adverse Effects

  • Headache
  • Tremor
  • Abdominal pain
  • Visual disturbances
  • Nephrotoxicity
  • Diabetes
  • Hypomagnesaemia

Availability & Prescribing

Tacrolimus prescribing should be brand name only.

Tacrolimus (Modigraf®) sachets 0.2 mg, 1 mg (these have to be made in a certain way as the granules adhere to PVC - see SPC)

Tacrolimus (Prograf®) Capsules 0.5 mg, 1 mg, 5 mg  

Mycophenolate Mofetil (MMF)

Mycophenolate mofetil has been used successfully as a second-line steroid sparing agent in frequently relapsing and steroid dependent NS. 

Dose 

Stating dose 200 mg/m2/dose twice daily, increase weekly to:

  1. 600mg/m2/dose twice daily taken as a single agent or in combination with Ciclosporin, or
  2. 300mg/m2/dose twice daily taken in combination with Tacrolimus

The GI intolerance may be reduced by a gradual introduction of Mycophenolate mofetil with stepwise dose increases over 4 – 8 weeks. 

Monitoring  

FBC monitoring every week for the first 4 weeks then every 2 weeks for 2 months then monthly for the first year. 

Duration of Treatment

If successful, Mycophenolate mofetil treatment can be continued, with careful monitoring for 2 years, or more if clinically indicated.  

Adverse Effects

  • GI upset - mainly diarrhoea; splitting the dose to 3 or 4 times daily may help.
  • Leucopenia
  • Bone marrow suppression - children and their carers should be warned to report immediately any signs or symptoms of bone marrow suppression e.g. infection or inexplicable bruising or bleeding.
  • Caution in male or females of child bearing age as may result in congenital malformations.

Availability & Prescribing

Mycophenolate mofetil can be prescribed as a generic drug (it is not brand specific).

Mycophenolate mofetil (Cellcept®) 200 mg/mL

Mycophenolate mofetil 250 mg capsule and 500 mg tablet

Rituximab

Rituximab is a chimeric monoclonal antibody directly linked to the depletion of CD20 B cells. It has been used successfully to resolve cases of difficult nephrotic syndrome when other treatment modalities have failed.

Patients with difficult to control NS despite use of recognised second-line therapies may be considered for this treatment. 

Patients must be referred and reviewed by a paediatric nephrologist before treatment is initiated. 

See Rituximab SOP for further information.

Appendix 1: discharge planning checklist
Appendix 2: Prednisolone dosing for First Presentation of Nephrotic Syndrome
Appendix 3: Prednisolone dosing for relapse of Nephrotic Syndrome - with 4 week taper
References
  1. van Husen M and Kemper M.J. New therapies in steroid-sensitive and steroid –resistant idiopathic nephrotic syndrome. Paediatric nephrology. (2011) 26:881-892
  2. McCaffrey et al. The non-immunosuppresive management of childhood nephrotic syndrome. Paediatric nephrology. (2016) 31:1383-1402
  3. Christian and Maxted. Optimising the corticosteroid dose in steroid-sensitive nephrotic syndrome. Paediatric nephrology. 20 Feurary 2021
  4. Webb et al. Long term tapering verses standard prednisolone treatment for first episode childhood nephritic syndrome: Phase III randomised controlled trial and economic evaluation. BMJ 2019; 365
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Editorial Information

Last reviewed: 19 September 2022

Next review: 15 August 2025

Author(s): Deepa Athavale

Version: 4

Approved By: Women & Children’s Drug and Therapeutic Committee

Document Id: 201