exp date isn't null, but text field is
Clinical questions answered by this guideline:
Children with idiopathic nephrotic syndrome.
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.
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
Initial presenting clinical features Onset of oedema may be insidious. Features include
|
The findings of fluid retention and heavy proteinuria in a child should lead to an urgent referral to the local general paediatric department.
For further reviews see:
Confirm diagnostic and presenting features (see above).
Initial clinical assessment to include:
|
Investigations to be performed in all children
|
Investigations to be performed in selected children
|
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.
Drug treatment in children with nephrotic syndrome can prove challenging.
Pharmacy advice is helpful in many aspects of appropriate drug treatment in NS:
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.
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.
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.
Protection against steroid induced gastric irritation should be considered for the duration of steroid treatment.
Clinical indications for albumin include
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.
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.
The main complications of nephrotic syndrome are hypovolaemia, infection and thrombosis.
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 is unusual in the acute setting and if persistent should lead to reconsideration of other possible underlying glomerulonephritis.
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.
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.
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.
Paediatric Nursing Care Plan
Discharge planning (see Parent & family preparation & Pre-discharge checklist below)
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.
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.
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.
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.
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
If uncertain whether there is a ‘full’ relapse
Patients often can be managed as an out patient with regular review while awaiting remission.
Prednisolone
Prednisolone treatment should be restarted once a relapse has been diagnosed. Traditionally treatment has been based on the ISKDC relapse regimen:
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.
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.
The main complications of nephrotic syndrome are hypovolaemia, hypertension, infection and thrombosis. See above.
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.
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.
Where clinical uncertainty on relapse status:
Frequent relapses are defined as:
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.
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 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
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 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.
For children with frequently relapsing or steroid dependent NS, cyclophosphamide can induce longer lasting remissions [6].
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:
Monitoring
FBC check weekly throughout treatment.
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.
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:
Monitoring:
FBC monitored for leucopenia.
If successful, MMF treatment can be continued, with careful monitoring for 3 years, or more if clinically indicated.
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.
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).
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
Varicella
Seasonal Influenza and H1N1
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.
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.
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.
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
· |
□ □ □ □ |
|
|
Urinalysis
|
□ □ □ |
|
|
Dietetic referral
|
□ □ □ |
|
|
Infection
|
□
□ |
|
|
Information
|
□ |
|
|
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. |
For children on long-term steroids monitor for side effects:
Last reviewed: 22 March 2017
Next review: 30 May 2021
Author(s): David Hughes
Approved By: Clinical Effectiveness
Reviewer Name(s): Paediatric Clinical Effectiveness & Risk Committee