Idiopathic nephrotic syndrome in children, management

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Objectives

Clinical questions answered by this guideline:

  1.    What is the recommended approach to initial investigation and diagnosis?
  2.    What are the referral criteria for atypical cases?
  3.    What is an appropriate initial steroid treatment regimen?
  4.    What other management strategies are recommended at initial presentation?
  5.    What are the best-practice treatments of complications of nephrotic syndrome?
  6.    Use of albumin infusion
  7.    Management of hypertension
  8.    Management of infection, including vaccination
  9.    Venous thrombosis
  10.    What are the recommended management strategies for relapsing nephrotic syndrome?
  11.    What follow-up and monitoring do nephrotic syndrome patients require? 

Scope

Children with idiopathic nephrotic syndrome.

Audience

This document provides information on the investigation, treatment and management of nephrotic syndrome in children at initial presentation and in relapse of the condition.  The guideline applies to children throughout Scotland with typical idiopathic nephrotic syndrome. The guideline may not be relevant to the management of children with atypical presentations and does not apply to children with congenital nephrotic syndrome, steroid resistant nephrotic syndrome and nephrotic syndrome secondary to other systemic disease (e.g. SLE) or other structural glomerular disease (e.g. Alport Syndrome).  

This document is intended for use by all health professionals (for example, doctors, nurses, dieticians and pharmacists) who look after children with nephrotic syndrome within Scotland. 

Definition and initial features of Nephrotic Syndrome

This document relates only to the management of idiopathic nephrotic syndrome in childhood. The features that characterise nephrotic syndrome result from a glomerular capillary leak causing heavy loss of protein traditionally defined as >1g/m2/day, but currently quantified using urine protein (or albumin) creatinine ratio on a first early morning urine. Children who present with the typical features of nephrotic syndrome are generally responsive to steroid treatment and are likely to show minimal changes on histology, although biopsy is not usually indicated. 

Children with typical features are started on steroids without renal biopsy. Steroid responsiveness is a better indicator than histology of long term outcome for renal function.

95% of patients with Minimal Change Nephrotic Syndrome (MCNS) and 20% with Focal Segmental Glomerulosclerosis (FSGS) achieve remission after an 8week course of prednisone (60 mg/m2 daily for 4 weeks then 40 mg/m2 on alternate days for 4 weeks). For MCNS patients 75% achieve remission by 2 weeks.

Those with atypical features are more likely to be unresponsive to steroid treatment. Those with atypical features at presentation should be discussed early with a paediatric nephrologist. A renal biopsy may be indicated before receiving steroid treatment. 

Characteristic diagnostic features

  • Nephrotic range proteinuria
    • Suspect for urine ‘stix’ testing > ++.
    • Quantify as urine protein:creatinine (P:CR) >200mg/mmol. 
  • Hypoalbuminaemia
    • serum albumin <25 g/l 
  • Generalised oedema 

Initial presenting clinical features

Onset of oedema may be insidious. Features include

  • Peri-orbital swelling
  • Ankle and lower limb swelling – pitting oedema
  • Abdominal swelling and scrotal/vulval oedema
  • Less commonly
    • frank haematuria
    • frothy urine

The findings of fluid retention and heavy proteinuria in a child should lead to an urgent referral to the local general paediatric department.  

Classification 

  • Idiopathic (primary) nephrotic syndrome 
    • Minimal change (MCNS) (80-90%) 
    • Focal segmental glomerulosclerosis (FSGS) (10-20%)
      An increased incidence of FSGS is reported over the last 3 decades. 
  •   Secondary nephrotic syndrome (HSP, SLE, MPGN) 
  •   Congenital nephrotic syndrome 

For further reviews see:

  1. Eddy and Symons. Nephrotic syndrome in childhood (Seminar)Lancet, 2003
  2. Oxford Specialist Handbook: Paediatric Nephrology
  3. Hahn D, Hodson EM, Willis, Narelle S, Craig JC. Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database of Systematic Reviews, 2015.
  4. Pravitsitthikul N, Willis NS, Hodson EM, Craig JC. Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children. Cochrane Database of Systematic Reviews, 2013 
Initial Assessment and Investigation at presentation

Confirm diagnostic and presenting features (see above). 

Initial clinical assessment to include: 

  • Height, weight, surface area
  • Volume status
    • Perfusion
    • Capillary refill
    • CP∆T
    • Heart rate and BP
    • JVP or hepatomegaly
  • Urinary sodium

 

Hypovolaemia

  • Clinical signs
    • cool peripheries (capillary refill time > 2 secs)
    • core-peripheral temperature gap (CP∆T) of > 2 C
    • tachycardia
    • initial paradoxical hypertension before hypotension may be present.
    • hypotension is a late sign of hypovolaemia.
  • Assess intravascular volume. Oedematous patients may also be intravascularly depleted.
  • Other symptoms: abdominal pain, dizziness, poor urine output
  • A urinary sodium of < 10 mmol/l useful to confirm hypovolaemia, provided diuretics have not been administered. 
  • Clinical shock: 
    • Emergency intravenous volume resuscitation with 4.5% albumin.
      Diuretics should NOT be given at this stage. 
    • Give 10ml/kg 4.5% albumin IVI over 30-60 minutes.
    • Monitor closely using nursing care plan and initial management flowchart. 
  • Hypovolaemia without shock or symptomatic oedema: 
    • For less severe hypovolaemia
    • or symptomatic oedema refractory to diuretics and fluids restriction
      • where there is skin compromise
      • scrotal or vulval oedema
      • cellulitis.
    • Give 1g/kg 20% albumin (5ml/kg) over 4 - 6 hours. 
    • Give 1mg/kg IV furosemide mid-infusion
    • Repeat 1mg/kg IV furosemide at the end of albumin infusion.
    • Strict monitoring of vital signs to detect intravascular volume overload using linked 20% albumin infusion care plan
    • Administer infusion during routine hours where possible.
    • 20% albumin is not indicated to correct hypoalbuminaemia alone. Injudicious use can lead to either volume overload or intravascular depletion. 

 

Hypertension

  • Transient hypertension may be present at initial presentation in a minority of patients. However, if persistent it may be a feature of an atypical presentation. Clinical features of volume overload should be sought. 
  • Hypertension with clinical features of intravascular volume overload should be treated with a diuretic. IV furosemide (1mg/kg) for emergency management and oral furosemide 0.5-1mg/kg/dose once or twice daily.
  • Severe or ‘urgent’ hypertension (systolic BP >99th centile + 5mmHg) can be treated with the use of hypotensive agents such as short acting nifedipine.
  • Persistent hypertension (systolic BP >95th centile) can be treated with longer acting agents such as amlodipine with incremental dose increases 
  • Ca+ channel blocker
  • Short acting Nifedipine – 0.25 – 0.5 mg/kg per dose (‘bite and swallow’). Can be repeated 
  • Long acting Amlodipine – 0.1mg/kg per day increasing in 0.1mg/kg increments every 48 hours to 0.4mg/kg/day.
  • Paradoxical hypertension can be present due to intravascular volume depletion and other features of hypovolaemia should be sought (see above). If present give intravenous volume resuscitation using 4.5% albumin. Diuretics should NOT be given at this stage. 

 

Infection

  • Loss of complement components and immunoglobulins may result in an increased risk of infection. Prophylactic Phenoxymethylpenicillin (Pen. V) should be given whilst patients have significant proteinuria.
    • Phenoxymethylpenicillin by mouth
      • Child under 1 year 62.5 mg twice daily
      • Child 1–5 years 125 mg twice daily
      • Child 5–18 years 250 mg twice daily 

 

Renal vein thrombosis

  • Loss of proteins such as anti-thrombin III contributes to a pro-coagulant state. This can be exacerbated by hypovolaemia. 
  • Clinical features raising suspicion:
    • Macroscopic haematuria
    • Fall in Hb and platelets
    • Palpable kidney
    • Reduction in renal function
    •  Hypertension
  • Renal Doppler USS and specialist referral if suspicion. 

 

Initial Investigations

Investigations to be performed in all children 

  •   Blood: FBC, U+E’s; Creatinine; LFT’s; Varicella titres 
  •   Urine: Urine culture and Urinary protein:creatinine ratio (PCR)
  •   Urinalysis including glucose 
  •   Urinary sodium concentration in those at risk of hypovolaemia

 

Investigations to be performed in selected children

  •   ASOT – strep throat infection; anti-DNaseB – strep skin infection
  •   C3/C4 – post-strep GN; MPGN; SLE
  •   Hepatitis B status in children at high risk: FH of HBV; history of travel in endemic areas.

 

Initial assessment for atypical features 

Nephrotic syndrome

Typical Features     

Age 1-10 years                                         

Normotensive                                            

Normal Renal Function                                  

Microscopic haematuria (in up to 25%) 

Atypical Features

<1yr, >10years 

Hypertensive

Elevated Creatinine

Macroscopic Haematuria

Systemic, extra-renal disease symptoms 

Positive family history of nephrotic syndrome  

 

Patients with atypical features are more likely to be unresponsive to steroid treatment. Those with atypical features at presentation should be discussed early with a paediatric nephrologist. A renal biopsy may be indicated before receiving steroid treatment. 

Initial Management of First Presentation of Typical Idiopathic Nephrotic Syndrome

Drug Treatment 

Drug treatment in children with nephrotic syndrome 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
  • Renal Medication Information Booklet should be issued to all patients. 

Prednisolone

On clinical diagnosis of nephrotic syndrome in children with typical features start prednisolone. In children with atypical features discuss with a paediatric nephrologist. A renal biopsy may be considered first. 

The Cochrane Review in 2015 updates studies on initial courses of Prednisolone and duration of treatment. It suggests there is no benefit of increasing the duration of prednisone beyond two or three months in the initial episode of SSNS [5].Further guideline advice awaits the report of the UK Prednos Study due to report in spring 2017. 

Currently a 12-week initial course is recommended.

  •   60 mg/m2 /day for 4 weeks (maximum 80 mg) 
  •   40 mg/m2 /on alternate days for 4 weeks (maximum 60mg) 
  •   Reduce dose by 5-10mg/m2 each week for another 4 weeks then stop

Prednisolone dose is based on body surface area.

(BSA = √(Ht x Wt/3600). For BSA using weight only tables in the BNF for children can be used. 

Dosing regimen for initial presentation for ranges of BSA, with rounding of dose can be found in Appendix 4

Prednisolone can be given as a single dose in the morning with food, or as divided doses during the day, particularly if the dose is large. 

Patients should be issued with a steroid warning card.

Side effects and risks of steroid treatment should be discussed. 

Antibiotic Prophylaxis – Penicillin V 

Whilst nephrotic, children are at increased risk of infection, particularly with encapsulated organisms such as pneumococcus. Infection remains the main cause of death in children with nephrotic syndrome. Recommendations on the use of antibiotic prophylaxis vary as there is no strong evidence of its benefit. Our policy is to give Penicillin V prophylaxis while there is proteinuria and discontinued when the child goes into remission. Grossly oedematous children are at particular risk of cellulitis and may benefit from antibiotic prophylaxis.  

Pneumococcal vaccination is recommended for children with NS not previously vaccinated. Consider giving this at the time of diagnosis. 

Gastroprotection 

Protection against steroid induced gastric irritation should be considered for the duration of steroid treatment.

  • Ranitidine
    • 2 – 4 mg (max. 150 mg) twice daily
  • Omeprazole
    • For weight 10 – 20 kg 10mg once daily
    • For weight over 20 kg 20mg once daily 

Albumin Infusion 

Clinical indications for albumin include 

  • Clinical hypovolaemia (see earlier)
  • Symptomatic oedema 
  • skin compromise
    • cellulitis
    • scrotal or vulval oedema
  • Primary peritonitis
  • Respiratory compromise – pleural effusions

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

If clinically shocked give 10ml/kg 4.5% albumin without diuretic.

If there is evidence of hypovolaemia without shock or symptomatic oedema, give 1 g/kg as 20% albumin (5ml/kg) over 4 - 6 hours. Give 1mg/kg of IV furosemide mid-infusion and repeat at end unless good diuretic response in progress.

Children should be closely monitored following the linked 20% albumin infusion care plan and where possible it should be administered during working hours.  

Dietary and Fluid Management 

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

Dietetic advice regarding calorie control (Appendix 5) should be given while on steroids. 

Complications 

The main complications of nephrotic syndrome are hypovolaemia, infection and thrombosis.  

Hypovolaemia without shock 

The on-going assessment of children with nephrotic syndrome includes assessment of intravascular volume status. Children may be very oedematous, but may also have intravascular volume depletion. 

Clinical features are detailed above - Initial assessment and Investigation at presentation.

Hypotension is a late sign of hypovolaemia, but paradoxical hypertension may be present with hypovolaemia. A urinary sodium of < 10 mmol/l is a useful investigation to confirm hypovolaemia.

If there is evidence of hypovolaemia without shock or symptomatic oedema, give 1 g/kg as 20% albumin (5ml/kg) over 4 - 6 hours. Give 1mg/kg of IV furosemide mid-infusion and repeat at end unless good diuretic response in progress.

Children should be closely monitored following the linked 20% albumin infusion care plan and where possible it should be administered during working hours.  

Hypertension 

  • Paradoxical: volume resuscitation
  • Volume overload: diuretic
  • Steroid induced
  • Ca+ channel blocker
    • Short acting Nifedipine – 0.25 – 0.5 mg/kg per dose (‘bite and swallow’). Can be repeated 
    • Long acting Amlodipine – 0.1mg/kg per day increasing in 0.1mg/kg increments every 48 hours to 0.4mg/kg/day. 

Hypertension is unusual in the acute setting and if persistent should lead to reconsideration of other possible underlying glomerulonephritis. 

Infection 

Loss of complement components and immunoglobulins results in an increased risk of infection, particularly pneumococcal infection. Prophylactic Penicillin V (Phenoxymethylpenicillin) should be given whilst patients have significant proteinuria. 

Cellulitis risk is increased and should be treated promptly. 20% IV albumin infusion with furosemide cover should be given to reduce oedema in the presence of cellulitis.

Varicella zoster (VZ) status should be documented clearly in the case notes and on any electronic patient record.

Children with no previous exposure to VZV should receive VZIg if history of recent VZ exposure.

Primary VZ infection should be treated aggressively with IV Aciclovir then p.o. Valaciclovir when no new crops of vesicles are appearing. 

Herpes Zoster infection (Shingles) also requires initial IV Aciclovir for immunosuppressed patients.

Active immunisation with VZ vaccine should be considered when off all immunosuppressive therapy.

Annual flu vaccination should be administered.

See Immunisation Guideline for Children with Chronic Kidney Disease for further guidance.

Thrombosis

Loss of proteins such as anti-thrombin III contributes to a pro-coagulant state. This might be exacerbated by hypovolaemia. Clinical features raising suspicion include: macrohaematuria; fall in Hb and platelets; palpable kidney; reduction in renal function; hypertension.

Renal Doppler USS and specialist referral if venous thrombosis confirmed.

Monitoring and Observations 

Admission and in-patient management is often necessary with the first presentation. Regular review to monitor for complications and to assess the onset of remission is needed. Parental teaching and education (see below) can take place at the same time. 

Nursing

Paediatric Nursing Care Plan

  • The Nursing Care-plan Nephrotic Syndrome (Appendix 1) can guide paediatric nursing care of nephrotic in-patients, at presentation or in relapse
  • During in patient admission
    • Monitoring progress
    • Daily weight
    • Fluid balance
    • Daily EMU ‘stix’/PC:R
    • BP

Discharge planning (see Parent & family preparation & Pre-discharge checklist below)

    • Parent teaching
    • disease information
    • urine testing and recording
    • Albustix for monitoring

Laboratory monitoring 

Daily urine P:CR

Renal biochemistry in patients requiring IV albumin and diuretics.

Renal biochemistry if evidence of impaired glomerular function. Drug level monitoring if aminoglycoside/vancomycin therapy.  

Response to treatment 

Diuresis and weight reduction

Reduction in Albustix positive level

Reduction in daily urine P:CR

Most children with nephrotic syndrome will respond to steroid treatment within 2-4 weeks. A remission is defined as 3 or more days of trace or negative on dipstick testing. 80% of patients enter remission within 14 days on the dosing regimen (Appendix 4 below) used here. Treatment is continued for a total of 12 weeks.

If proteinuria persists beyond the first 4 weeks of steroid treatment, then children should be referred for renal biopsy.  

Indications for Referral to Paediatric Nephrology Service

Atypical Features 

  • Age < 1 yr 
  • Age > 10-12 yrs 
  • Persistent hypertension
  • Elevated creatinine not associated with ‘pre-renal’ uraemia
  • Macroscopic haematuria 
  • Low C3/C4
  • Systemic disease symptoms and signs
  • Failure to respond to steroids within 4 weeks  

 

Complications

  • Severe ‘pre-renal’ renal failure
  • Renal vein thrombosis 

 

Renal Biopsy 

Renal biopsy is considered mandatory in children unresponsive to steroids following at least 28 days treatment with Prednisolone at a dose of 60mg/m2/day. Histology appearances suggesting other underlying conditions may alter treatment options.

Those children with atypical features are more likely to be unresponsive to steroid treatment and a biopsy more likely to show FSGS or other forms of nephrotic syndrome. Those with atypical features should be discussed with a paediatric nephrologist as they may merit renal biopsy before receiving steroid treatment. 

Management of Relapsing Nephrotic Syndrome
  • Most important prognostic indicator - steroid responsiveness. 
    • 60–80% of steroid-responsive nephrotic children will relapse.
    • 60% of these > five relapses.
  • Predictors of fewer relapses
    • Age older than 4 years at presentation
    • Remission within 7–9 days of the start of steroid treatment in the absence of microhaematuria. 
  • Monitor urine regularly with Albustix® using a first morning urine sample.
  • Relapses identified early by the appearance and persistence of proteinuria > 2+ protein. 

Typically relapses are triggered by intercurrent illnesses, particularly viral upper respiratory infections. Families should be be more vigilant then. Low grade proteinuria (< 2+) may occur transiently and subside without steroid as the intercurrent illness settles. Studies suggesting low dose steroid ‘cover’ may reduce risk of full relapse await further research. 

Diagnosis of Relapse Nephrotic Syndrome 

Relapse diagnosed if > 2+ proteinuria on Albustix for 3 or more days.

Urine should be checked initially 2 – 3 times weekly, then weekly after the first episode. Increase monitoring to daily with intercurrent infections.

Instruct families to make contact using a designated contact number if 

  • relapse of proteinuria occurs
  • 2+ proteinuria is persistent for more than 1 week. 

If uncertain whether there is a ‘full’ relapse 

  • clinical assessment (weight, BP) for fluid retention, 
  • quantitative uP:CR 
  • measurement of serum albumin  can be helpful in guiding management: intervention or expectant observation.

Patients often can be managed as an out patient with regular review while awaiting remission.  

Drug treatment 

Prednisolone 

Prednisolone treatment should be restarted once a relapse has been diagnosed. Traditionally treatment has been based on the ISKDC relapse regimen: 

  • 60 mg/m2/day (maximum 80 mg) until urinary remission: negative or trace only for protein in first morning urine for 3 consecutive days  
  • 40 mg/m2 (maximum 60 mg) on alternate days for 4 weeks then stop. Individual patient care plans can include a taper over 4 to 8 weeks. (Appendix 6 below for both 4 & 8 week taper regimens) 

Further modifications aimed at minimising steroid exposure (e.g. limiting maximum daily dose or tapering more rapidly the alternate day dose) may be used for individual patients at the recommendation of a supervising nephrologist.

Treatment plans should be clearly documented in case records and the patient RMIB. 

Antibiotic Prophylaxis – Penicillin V 

Antibiotic prophylaxis in relapse follows guidance for prophylaxis at presentation – above. While there is persistent proteinuria (> 2+) Penicillin V prophylaxis can be given. 

Penicillin V can be discontinued when the child goes into remission. 

Grossly oedematous children are at risk of cellulitis and should receive antibiotic prophylaxis. 

Pneumococcal vaccination is recommended for children with NS.  

Gastroprotection

Protection against steroid induced gastric irritation should be considered for the duration of steroid treatment.

  • Ranitidine o2 – 4 mg (max. 150 mg) twice daily
  • Omeprazole
    • For weight 10 – 20 kg 10mg once daily
    • For weight over 20 kg 20mg once daily 

Dietary and Fluid management 

Whilst there is proteinuria (> 2+) a no added salt diet is advised and advice on calorie control given. (Appendix 5 below).

Advise on avoiding an excessively large fluid intake while awaiting remission. A modest fluid restriction may also be helpful in the clinically well child. These restrictions can be lifted as soon as the child enters remission.  

Complications 

The main complications of nephrotic syndrome are hypovolaemia, hypertension, infection and thrombosis. See above.

Monitoring and Observations  

Admission is often not necessary with relapse. Early clinic review to monitor for complications and to assess the onset of remission is needed.

Parental support for the first relapse is often welcome and allows teaching to be reinforced.

Nursing

Role of nurse specialist link or CCNs in local paediatric service

Monitoring and clinical support of patients in relapse may be carried out by local paediatric nurse specialists or community children’s nurses with support from the paediatric clinical team.

  • Monitoring progress
  • Clinical assessment – fluid retention; complications
  • Weight
  • BP
  • Daily EMU Albustix (uP:CR – see below)
  • Fluid balance advice 

Laboratory 

Where clinical uncertainty on relapse status:

  • urine P:CR
  • Renal biochemistry including serum albumin. 
Further management of patients with Frequent Relapses or Steroid Dependency

Diagnosis of frequent relapse 

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 while 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. 

The Cochrane systematic review [6] concluded that eight-week courses of Cyclophosphamide or Chlorambucil and prolonged courses of Ciclosporin and Levamisole reduce the risk of relapse in children with relapsing SSNS compared with corticosteroids alone. Limited data indicate that Mycophenolate Mofetil and Rituximab are valuable additional medications for relapsing SSNS. 

Drug treatment 

Unfortunately, around 60% of steroid-responsive patients who relapse experience five or more relapses. Some can be successfully managed with lowdose alternate day steroids. Many will still relapse, often with intercurrent infections. Steroid-induced side-effects develop in a high proportion. Currently there are no data on the preferred second-line immunosuppression (IS). Use of cyclophosphamide, chlorambucil, ciclosporin, and levamisole to reduce the risk of relapses is supported by the Cochrane systematic review of randomised controlled trials and by evidence-based recommendations [6]. Limited data indicate that Mycophenolate Mofetil is a valuable additional medication and appears to have a more favourable side effect profile. Rituximab is a B cell depleting antibody which has been successfully used to achieve remission with reduced IS requirements [7]. It is approved for use in childhood nephrotic syndrome in NHSE [8]. 

Low Dose Alternate Day Prednisolone 

Low dose alternate day steroid treatment (< 0.5 mg/kg/alt days) may prevent relapses, and result in less steroid being given overall. (0.5 mg/kg/alt day = ~45mg/kg/year. 1 relapse of 14 days (60mg/m2/day and 4 weeks 40mg/m2/alt day) = ~46mg/kg/year)

Referral for discussion of second line therapy with a Paediatric Nephrologist is indicated in children with

  • Frequent relapses 
  • Steroid dependency 
  • Steroid toxicity  

Intercurrent viral URTI

For children controlled on low dose alternate day steroid the strategy of increasing alternate day steroid to daily steroid for a total 6 days treatment during viral URTIs may reduce the risk of relapse [4]. Clinical research in the UK on this intervention is ongoing (Prednos2) due to complete in 2018. Any use of this approach should be documented and reviewed at follow up.  

Levamisole 

Levamisole may be beneficial for children with frequent relapses. It is less useful if steroid dependent [6].

Dose 2.5 mg/kg/ on alternate days  rounded to 25mg doses to max. 150mg.

After treatment established for 4 weeks steroids can be tapered.

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

Side effects are rare and limited:

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

Monitoring:

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

This drug is not licensed in the UK, and is imported. Community pharmacists can access the drug by special order. Families are advised to give adequate notice for repeat prescriptions. 

Cyclophosphamide 

For children with frequently relapsing or steroid dependent NS, cyclophosphamide can induce longer lasting remissions [6].

  • Frequently relapsing SSNS: ~50% remission at 5 years
  • Steroid dependent: ~30% remission at 5 years

Dose 2.5 - 3 mg/kg/day for 8 weeks or equivalent. Maximum cumulative dose 168mg/kg. It is best to avoidcutting the tablets. Liquid extemporaneous preparations are available. Discuss with pharmacist re handling and disposal.

Side effects to be discussed:

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

Monitoring

FBC check weekly throughout treatment.

  • Reduce dose to 50-75% if neutrophils 1.0 – 1.5x109/L.
  • Stop if neutrophils <1.0x109/L and restart at 50-75% dose on neutrophil recovery >1.5x109/L. 

Calcineurin Inhibitors – Ciclosporin (or Tacrolimus)

Ciclosporin (CsA) (Neoral®) is useful as a steroid sparing agent [6].

Dose  2.5 mg/kg 12 hourly adjusted to achieve target trough level (see below).

If successful, treatment continued for at least 1 year initially.

It can be continued for up to 3 years before a trial off therapy if relapse free For children less than 5 yrs of age, three times daily dosing may be necessary. Parent advised to withhold morning dose until after trough level check.

Monitor BP, urine P:CR and renal biochemical function at review for features suggesting possible drug nephrotoxicity.

If successful, CsA treatment can be continued, with careful monitoring for 3 years, or more if clinically indicated [6].

When stable on treatment frequency of review can reduce to 2-3 monthly. 

Tacrolimus (Prograf®) has been used in similar manner, in preference to ciclosporin, in children with SSNS but less frequently. However, there are fewer data examining its efficacy and no controlled trials comparing it with ciclosporin. 

Monitoring:

12 hour trough level checked 1 week after treatment introduction.

Check 12 hour trough 1-2 weeks after any dose changes.

Therapeutic range for nephrotic syndrome is lower than for transplant patients. Aim for a 12 hour CsA trough of 50 – 100 nmol/l initially.

Higher CsA trough levels up to a maximum of 150 nmol/l. Consider in patients relapsing at lower trough levels where renal function, blood pressure remain normal. 

Mycophenolate Mofetil (MMF) 

MMF has been used successfully as a second line steroid sparing agent in frequently relapsing and steroid dependent NS [6]. Advantages include the absence of nephrotoxicity and no need for routine drug level monitoring.

Dose Up to 600mg /m2/dose twice daily. The GI intolerance may be reduced by a gradual introduction of MMF with stepwise dose increases over 4 – 8 weeks.

Side effects:

  • GI upset, mainly diarrhoea.
  • 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

Monitoring:

FBC monitored for leucopenia.

If successful, MMF treatment can be continued, with careful monitoring for 3 years, or more if clinically indicated.

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 [6]

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. 

Dietary and Nutritional management

Increased exposure to steroids of children with frequent relapses or steroid dependence may lead to problems with weight and blood pressure control. Dietary advice should be repeated where clinically indicated. 

Nephrotic Syndrome Dietetic Guidelines (Appendix 5).

Vaccination Advice

All children with NS should receive all routine childhood vaccinations. The timing of these may be interrupted if the child is treated with high dose steroids or immunosuppressant therapies; see Immunisation Guideline for Children with Chronic Kidney Disease for a list of vaccines that can be given safely. Vaccinations should be documented in the individual patient record. Refer DH ‘Green Book’ for further guidance on the administration of vaccines in nephrotic syndrome and in patients on immunosuppression.

Other vaccines required include:

Pneumococcal 

  • Confirm status
  • Recommended for all unvaccinated children with NS.
  • Repeat vaccination every 5 years
  • If not administered
    • Administer with first admission OR
    • Refer to GP to administer on discharge

Varicella

  • Varicella - active disease
  •         Consider repeat Varicella status 6 - 12 monthly in the non-immune child. 

Seasonal Influenza and H1N1

  • Annual seasonal flu vaccination should be administered
    • Inform GP of recommendation in clinic letter  
Patient and Family Preparation

Discharge planning and parent education should begin soon after admission and diagnosis.

This should include family support needs. Local psychology support can be sought. Information is also available on the SPRUN Managed Knowledge Network for children, siblings and parents. This can be adapted according for local arrangements.

Patient and Family Education  

Corticosteroid use in nephrotic syndrome

Children with nephrotic syndrome lose excessive amounts of protein from their blood stream into their urine. This loss of protein causes tissue swelling, especially in the face, stomach and legs. The risk of infection also increases because important proteins used by their immune system have been lost.  When it is untreated, children can often die from infections. Corticosteroid drugs (steroids) such as prednisolone are used to induce a remission of the nephrotic syndrome and so reduce the risk of these infections. Steroids can have a number of serious side effects. A review of trials found that increasing the use of steroids for several months after the first episode reduces the risk of relapses, without an increase in serious side effects.

Second line treatment in nephrotic syndrome

Most children who experience this syndrome do have repeat episodes - relapses. Steroids such as prednisolone can stop the protein leak but the leak frequently recurs and further steroids can have adverse effects of poor growth, cataracts, osteoporosis and high blood pressure. Loss of protein in children with nephrotic syndrome can also be reduced with non-corticosteroid drugs. These drugs can reduce relapses and the need for more steroids.

A review of trials compared several drugs and found that cyclophosphamide, ciclosporin and levamisole are more effective than prednisolone alone in preventing relapses of the nephrotic syndrome. Newer drugs have also been used. There is less evidence of their benefit but they may be considered for individual children. 

Patient and Family Information Provision and Links 

Web links for patient information on Nephrotic Syndrome (NS)

InfoKid providing information for parents and carers about kidney conditions in babies, childen and young people. Information can be downloaded on http://www.infokid.org.uk/nephroticsyndrome and http://www.infokid.org.uk/nephrotic-syndrome-frequentlyrelapsing 

There are links to the Medicines for Children website regarding medications used in Nephrotic Syndrome: http://www.medicinesforchildren.org.uk/search-for-aleaflet  

EdREN Info- Edinburgh Renal Unit’s website information on NS.

Pre-discharge checklist

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 8 below).  

Nephrotic Syndrome Discharge Planning Checklist

 

Date complete 

Nephrotic syndrome info sheet/website links

 

Renal Medication Information Booklet 

  • Prednisolone dose and reducing regimen
  • Steroid card
  • Penicillin prophylaxis regimen
  • Omeprazole/Ranitidine regimen

· 

 

 

Urinalysis

  • Parent/carer education complete
  • Diary record
  • Albustix® provided

 

 

Dietetic referral

  • Diet information sheet
  • Fluid restriction during relapse discussed

 

Infection

  • Pneumococcal vaccination confirmed/arranged
  • Varicella status:    positive □     negative □ ·Advice given for VZ seronegative

 

 

 

Information

  • InfoKid download and website details provided

 

 

Follow up

  • Out patient appointment issued
  • Contact number/details issued

 

 

 

Out-patient management and follow-up

In a natural-history study of 398 children, the proportion that became nonrelapsers rose from 44% at 1 year to 69% at 5 years, and 84% at 10 years [10].

The frequency of follow up will be dictated by the clinical course. For patients first presenting or having only an infrequent relapse a suggested course might comprise:

Follow up

Comment

4 weeks after starting steroids

Confirm steroid reduction plan. Review side effects. Information giving

3 mo. after starting steroids

Confirm steroid completion. Review side effects. Vaccine advice - influenza. Varicella status (see clinical monitoring below)

6 mo. from presentation/last relapse

Review. Information giving. Vaccine advice – influenza; VZ vaccine if seronegative

12 mo. from presentation/last relapse

Review. Vaccine advice - influenza.

24 mo. from presentation/last relapse

Review. Discharge to see again if relapse. Intermittent monitoring of urine up to 5 years.

For patients with a history of  frequent relapses or previously treated with second line therapy and no longer relapsing, follow up is suggested for 2 years from last relapse or from completion of second line therapy without further relapse. A suggested course might comprise: 

Follow up

Comment

1-2 mo. from completion of 2nd line treatment or last relapse.

Review. Confirm relapse free.

3-6 mo. from completion of 2nd line treatment or last relapse.

Confirm relapse free. Vaccine advice - influenza.

6-12 mo. from completion of 2nd line treatment or last relapse.

Review. Confirm relapse free. Vaccine advice - influenza. VZ vaccine if seronegative.

12-24 mo. from completion of 2nd line treatment or last relapse.

Review. Vaccine advice - influenza.

24 mo. from completion of 2nd line treatment or last relapse.

Review. Discharge to see again if relapse. Intermittent monitoring of urine up to 5 years.

Clinical monitoring 

For children on long-term steroids monitor for side effects: 

  1. Monitor BP at each clinic visit and chart against ‘casual’ BP centile chart. 
  2. Monitor growth (including bone age and pubertal stage where appropriate
  3. Monitor weight – dietetic review where appropriate 
  4. Glycosuria / HbA1c if clinical concerns about glycaemic control. 
  5. Monitor Varicella status 6 - 12 monthly if seronegative. Consider vaccination if still seronegative and having completed immunosuppressive therapy.
  6. Patients who receive prolonged steroid treatment (continuously for over 12 months) 
  • consider modified Synacthen test to identify risk of adrenal suppression on stopping treatment [11].
  • consider ophthalmology review
  1. Patients on second line therapy require monitoring as specified for treatment regimen above

 

References
  1. Eddy and Symons. Nephrotic syndrome in childhood (Seminar) Lancet. 2003. 
    An excellent review article of nephrotic syndrome.
  1. Rees L, Webb NJA, Brogan PA. Paediatric Nephrology. Chapter 17, Nephrotic Syndromes. Oxford Medical Publications. Oxford University Press, 2007.
    An excellent and concise resource providing practical management advice.
  1. Hodson et al. Evidence-based management of steroid-sensitive nephrotic syndrome.  Pediatr Nephrol (2005) 20:1523–1530.
    Meta-analysis indicates prolonged courses of steroid therapy should be administered in the first episode of SSNS to reduce the risk of early relapse and that this regimen, by reducing relapses, may result in a net reduction in steroid exposure compared with shorter courses.
  1. Abeyagunawardena et al. Increasing the dose of prednisolone during viral infections reduces the risk of relapse in nephrotic syndrome: a randomised controlled trial Arch. Dis. Child. 2008; 93; 226-228.
    In children with steroid-dependent NS, a viral URTI triggers a relapse in nearly 50% of cases. A short-term modest increase in the dose of prednisolone during viral URTI can reduce this risk significantly.
  1. Hahn D, Hodson EM, Willis, Narelle S, Craig JC. Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database of Systematic Reviews, 2015.
    This review updates information previously published in 2000, 2003, 2005 and 2007. The addition of three new studies evaluating different durations of prednisone in the first episode of nephrotic syndrome has changed the conclusions expressed in previous versions of this review. Studies at low risk of bias found no significant differences in the risk of relapse or the development of FRNS between prednisone given for three to six months compared with two or three months. Therefore there is no benefit of increasing the duration of prednisone beyond two or three months in the initial episode of SSNS.
  1. Pravitsitthikul N, Willis NS, Hodson EM, Craig JC. Non-corticosteroid immunosuppressive medications for steroidsensitive nephrotic syndrome in children. Cochrane Database of Systematic Reviews, 2013
    Updated Cochrane review
  1. Guigonis et al. Rituximab treatment for severe steroid- or cyclosporine dependent  nephrotic syndrome: a multicentric series of 22 cases. Pediatr Nephrol (2008) 23:1269–1279.
    First prospective, open series on the effective use of RTX in patients with severe SDNS.
  1. NHS England. Clinical Commissioning Policy: Rituximab for the treatment of relapsing steroid sensitive nephrotic syndrome
  1. Alpay et al. Varicella vaccination in children with steroid-sensitive nephrotic syndrome Pediatr Nephrol (2002) 17:181–183.
    A study in 20 patients reports that immunization with a single dose of VZV vaccine is safe and effective in children with SSNS in remission.

  2. P Tarshish, JN Tobin, J Bernstein and CM Edelmann Jr, Prognostic significance of the early course of minimal change nephrotic syndrome: report of the International Study of Kidney Disease in Children, J Am Soc Nephrol 8 (1997), pp. 769–776
    A natural-history study of 398 children.

  3. Abeyagunawardena AS, Hindmarsh P, Trompeter RS Adrenocortical suppression increases the risk of relapse in nephrotic syndrome Arch Dis Child. 2007;92(7):585.
    A study of 32 children with NS receiving alternate day prednisolone therapy for >12 months shown to be at risk of developing HPA suppression and should be evaluated using the modified synacthen test. Children with evidence of HPA suppression are at a greater risk of relapse

  4. Improving the standard of care of children with kidney disease through paediatric nephrology networks (RCPCH 2011)
    The RCPCH in collaboration with NHS KidneyCare and the British Association of Paediatric Nephrology. A report on paediatric nephrology networks, setting out the core requirements for success and standards for commissioning and provision of services. 
Editorial Information

Last reviewed: 22 March 2017

Next review: 31 March 2020

Author(s): David Hughes

Approved By: Clinical Effectiveness

Reviewer Name(s): Paediatric Clinical Effectiveness & Risk Committee