Guideline for the Management of Nephrotic Syndrome

Scottish Paediatric Renal and Urology Network (SPRUN)

Please note: This guideline is to be assessed using the AGREE (Appraisal of Guidelines for Research and Evaluation) criteria.

Contents Page Number(s)

1. Guideline Development 1.1 Guideline Development Group 1.2 Patient population and target audience 1.3 Objectives and clinical questions 1.4 Methodology

2. Definition and diagnosis of idiopathic nephrotic syndrome

3. Initial assessment and investigation at presentation 4. Initial management 4.1 Drug treatment 4.1.1 Steroids 4.1.2 Antibiotic prophylaxis 4.1.3 Gastroprotection 4.1.4 Albumin infusion 4.2 Dietary and fluid management 4.3 Complications 4.3.1 Hypovolaemia 4.3.2 Hypertension 4.3.3 Infection 4.3.4 Thrombosis 4.4 Monitoring and Observations 4.4.1 Nursing 4.4.2 Laboratory 4.4.3 Response to treatment

5. Indications for referral to Paediatric Nephrology Service 5.1 Atypical features 5.2 Complications 5.3 Renal biopsy

6. Management of relapsing nephrotic syndrome 6.1 Diagnosis of relapse 6.2 Drug treatment 6.2.1 Steroids 6.2.2 Antibiotic prophylaxis 6.2.3 Gastroprotection 6.3 Dietary and fluid management 6.4 Complications 6.5 Monitoring and Observations 6.5.1 Nursing 6.5.2 Laboratory

7. Frequently relapsing nephrotic syndrome 7.1 Diagnosis of frequent relapse 7.2 Drug treatment 7.2.1 Alternate day steroids 7.2.2 Levamisole

7.2.3 Cyclophosphamide 7.2.4 CNI – Ciclosporin (or Tacrolimus) 7.2.5 Mycophenolate Mofetil 7.2.6 Rituximab IV 7.3 Diet and fluids 7.4 Monitoring and Observations 8. Dietary and Nutritional Management 9. Vaccination advice 9.1 Varicella 9.2 Pneumococcal 9.3 Live vaccines 9.4 Seasonal influenza and H1N1

10. Patient and Family Preparation 10.1 Patient and Family Education 10.2 Patient information provision and links

11. Pre-discharge Checklist 11.1 Parent training on urine monitoring 11.2 Pre-discharge education and planning checklist:

12. Outpatient Management and Follow-up 12.1 Monitoring 12.1.1 Growth 12.1.2 Blood pressure 12.1.3 Steroid side effects 12.1.4 Ophthalmology review 12.1.5 Varicella status 12.1.6 Second line therapy monitoring 12.2 Standards for laboratory and clinical indices 12.2.1 Urine P:CR 12.2.2 Drug level monitoring

13. Future Guideline Development Appendix 1 – Appendix 2 – References

1. Guideline Development

1.1 Membership of Guideline Development Group

Consultant Paediatrician Senior Staff Nurse/Paediatric Nurse Specialist Renal Nurse Specialist Consultant Paediatric Nephrologist Paediatric Renal Pharmacist Renal Dietician Consultant Microbiologist Parent Representative

1.2 Patient population and target 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.

1.3 Objectives and clinical questions Guideline objectives:

1. Describe typical and atypical presenting clinical features of idiopathic nephrotic syndrome of childhood likely to respond to treatment with steroids.

2. Provide guidance for the safe and effective clinical management of the initial presentation of children with typical idiopathic nephrotic syndrome to a general paediatric department.

3. Provide guidance for the safe and effective clinical management of subsequent relapses in children with typical idiopathic nephrotic syndrome to a general paediatric department.

4. Provide guidance on the clinical management of complications of idiopathic nephrotic syndrome.

5. Provide guidance on the indications for referral for specialist nephrology advice and review of complications of idiopathic nephrotic syndrome.

6. Provide guidance on the indications for referral for specialist nephrology advice and review of relapsing idiopathic nephrotic syndrome and its management.

7. Provide guidance on follow up in the general paediatric clinic setting.

8. Provide adequate information and training for children and their families on idiopathic nephrotic syndrome, its treatment (medication, dietary), home monitoring and planned follow up.

Clinical questions answered by the 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? a. Use of albumin infusion b. Management of hypertension c. Treatment of infection d. Venous thrombosis

6. What are the recommended management strategies for relapsing nephrotic syndrome?

7. What follow-up and monitoring do nephrotic syndrome patients require? 1.4 Methodology This guideline was based on the RHSC, Glasgow “Guidelines on the Management of Nephrotic Syndrome” (2005). Best evidence was used to inform recommendations including Cochrane Collaboration reviews, literature searches of PubMed, using the terms “paediatric” / “children”, “nephrotic syndrome”, and “steroid sensitive”. Evidence based on double blind randomised control trials was deemed to be the best level of evidence, and expert opinion where no other form of evidence was available. Only articles written in English were included. Recommendations were based on consensus of opinion from the working group. There were no areas of disagreement.

2. Definition of Nephrotic Syndrome • Nephrotic range proteinuria (uProtein:Creatinine P:CR >200mg/mmol

Creatinine> 1g/m2/day;)

• Hypoalbuminaemia (<25 g/l) • Generalised oedema

Classification

• Idiopathic (primary) nephrotic syndrome o Minimal change (80-90%) o Focal segmental glomerulosclerosis (FSGS) (10-20%)

• Secondary nephrotic syndrome (HSP, SLE, MPGN) • Congenital nephrotic syndrome

This document relates only to the management of idiopathic nephrotic syndrome. Children who present with the typical features of nephrotic syndrome (see below) are generally responsive to steroid treatment and are likely to show minimal changes on histology, although biopsy is not usually indicated. Therefore children with typical features are started on steroids without recourse to renal biopsy. Those 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.

Nephrotic Syndrome Typical Features Atypical Features

Age 1-10 years <1yr, >10years Normotensive Hypertensive

Normal Renal Function Elevated Creatinine +/- microscopic haematuria ( in xx%) Macroscopic Haematuria

systemic disease symptoms

3. Initial Assessment and Investigation at presentation • Hypovolaemia

• The initial examination of children with nephrotic syndrome needs to include an assessment of their intravascular volume. Whilst these children may be very oedematous, they may also be intravascularly depleted. Signs of intravascular depletion are cool peripheries (capillary refill time >

2 secs), a core-peripheral temperature gap of > 2oC, and tachycardia.

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

• If clinically shocked give 10ml/kg 4.5% albumin. Children should be closely monitored during an albumin infusion, and unless needed for emergency management it should be administered when medical support readily available.

• If there is evidence of hypovolaemia, give 1 g/kg 20% albumin (5ml/kg) over 4 - 6 hours. Give 2mg/kg of iv frusemide mid-infusion.

• Hypertension

• Paradoxical: volume resuscitation • Volume overload: diuretic • Ca+ channel blocker

• Short acting nifedipine • Long acting amlodipine

• Infection

• Loss of complement components and immunoglobulins results in an increased risk of infection. For antibiotic prophylaxis whilst patients have significant proteinuria.

• Renal vein thrombosis

• Loss of proteins such as anti-thrombin III contributes to a pro-coagulant state. This might be exacerbated by hypovolaemia.

• Renal Doppler USS and specialist referral if suspicion. The following investigations should be performed in all children:

• Blood: FBC, U+E’s; Creatinine; LFT’s; ASOT; C3/C4; Varicella titres • Urine: Urine culture and Urinary protein:creatinine ratio (uPCR) • BP • Urinalysis including glucose • A urinary sodium concentration can be helpful in those at risk of

hypovolaemia. • Varicella status should be known in all children commencing steroids. • Hepatitis B status may be appropriate in children at high risk.

4. Initial Management of First Presentation of Typical Idiopathic Nephrotic Syndrome

4.1 Drug Treatment

4.1.1 Prednisolone When the diagnosis of nephrotic syndrome has been made, prednisolone treatment can be started in children with typical features. Children with atypical features should be discussed with a paediatric nephrologist when renal biopsy may be considered first (see above/below). There is increasing evidence that longer initial courses of prednisolone are associated with a lower incidence of relapse. Further studies are in progress to identify any increase in side effects with longer initial courses. Also it is not clear whether increased initial treatment leads to a reduction in the use of second line treatments for relapsing steroid sensitive nephrotic syndrome. Currently a 12-week initial course is recommended. The dose of prednisolone is based on surface area.

• 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 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. Varicella status should be documented clearly in the case notes and on any electronic patient record.

4.1.2 Antibiotic Prophylaxis – Penicillin V Whilst nephrotic, children are at increased risk of infection, particularly with encapsulated organisms such as pneumococcus. There is no evidence that antibiotic prophylaxis is of benefit, and some centres do not use prophylaxis. Penicillin V can be given while there is proteinuria and discontinued when the child goes into remission. Grossly oedematous children are at risk of cellulitis and may benefit from antibiotic prophylaxis. Pneumococcal vaccination is recommended for children with NS. Consider giving at the time of diagnosis.

4.1.3 Gastroprotection Protection against steroid induced gastric irritation should be considered.

• Ranitidine 2mg/kg twice daily for the duration of steroid treatment. • Omeprazole - dose

4.1.4 Albumin Infusion Clinical indications for albumin include • Clinical hypovolaemia (see earlier) • Symptomatic oedema

• skin compromise • cellulitis

• Primary peritonitis • Respiratory compromise – pleural effusions

A low serum albumin alone is not an indication for intravenous albumin. If there is evidence of hypovolaemia, give 1 g/kg 20% albumin (5ml/kg) over 4 - 6 hours. Give 2mg/kg of iv frusemide mid-infusion and repeat at end unless good diuretic response in progress. If clinically shocked give 10ml/kg 4.5% albumin. Children should be closely monitored during albumin infusions, and where possible they should be administered during working hours.

4.2 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. These restrictions are lifted once the child goes into remission. Dietetic advice re calorie control while on steroids.

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

4.3.1 Hypovolaemia The initial examination of children with nephrotic syndrome needs to include an assessment of their intravascular volume. Whilst these children may be very oedematous, they may also be intravascularly depleted. Signs of intravascular depletion are cool peripheries (capillary refill time > 2 secs), a core-peripheral

temperature gap of > 2oC, and tachycardia. Hypotension is a late sign of

hypovolaemia, but paradoxical hypertension may be present. A urinary sodium of < 10 mmol/l is a useful investigation to confirm hypovolaemia. If there is evidence of hypovolaemia, give 1 g/kg 20% albumin (5ml/kg) over 4 - 6 hours. Give 2mg/kg of iv frusemide mid-infusion.

4.3.2 Hypertension • Paradoxical: volume resuscitation • Volume overload: diuretic • Steroid induced • Ca+ channel blocker

• Short acting nifedipine • Long acting amlodipine

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

4.3.3 Infection Loss of complement components and immunoglobulins results in an increased risk of infection. Consider antibiotic prophylaxis whilst patients have significant proteinuria. Cellulitis History of recent VZ exposure Primary Varicella Zoster infection Herpes Zoster infection (Shingles)

4.3.4 Thrombosis Loss of proteins such as anti-thrombin III contributes to a pro-coagulant state. This might be exacerbaterd by hypovolaemia. Information here on clinical features to watch for.

4.4 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

4.4.1 Nursing At admission During in patient admission Discharge preparation??

4.4.2 Laboratory 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.

4.4.3 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. Treatment is continued for a total of 12weeks as outlined above. If proteinuria persists beyond the first 4 weeks of steroid treatment, then children should be referred for renal biopsy.

5. Indications for Referral to Paediatric Nephrology Service

5.1 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

5.2 Complications Severe ‘pre-renal’ renal failure Renal vein thrombosis

5.3 Renal Biopsy Renal biopsy is considered mandatory in children unresponsive to steroids following at least 28 days treatment with Prednisolone at a dose of 60

mg/m2/day (maximum 80 mg). 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.

6. Management of Relapsing Nephrotic Syndrome Up to 60 - 70 % of children with nephrotic syndrome may have one or more relapse. Typically relapses are triggered by intercurrent illnesses, particularly viral upper respiratory infections. Families should be aware to be more vigilant at such times. Low grade proteinuria may occur transiently (up to 2+) and may subside without steroid as the intercurrent illness settles.

6.1 Diagnosis of Relapse Nephrotic Syndrome These are diagnosed if there is +++ or ++++ proteinuria for 3 or more days. Urine should be checked initially twice weekly, then weekly after the first episode, and the families instructed to get in contact should a relapse of proteinuria occur, or if there is ++ for more than 1 week. If there is uncertainty whether there is a ‘full’ relapse clinical assessment (weight, BP) for fluid retention, quantitative uPCR and 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.

6.2 Drug treatment

6.2.1 Prednisolone Prednisolone treatment should be restarted once a relapse has been diagnosed. • 2mg/kg daily (maximum 80 mg) until the first morning urine is negative or

trace for 3 consecutive days

• 40 mg/m2 (maximum 60 mg) on alternate days for 4 weeks then stop or taper

the dose over 4-8 weeks

6.1.2 Antibiotic Prophylaxis – Penicillin V While there is persistent proteinuria (>++) Penicillin V prophylaxis can be given. Penicillin V can be given while there is proteinuria and discontinued when the child goes into remission. Grossly oedematous children are at risk of cellulitis and may benefit from antibiotic prophylaxis. Pneumococcal vaccination is recommended for children with NS. Check that this has been administered.

6.2.3 Gastroprotection Protection against steroid induced gastric irritation should be considered.

• Ranitidine 2mg/kg twice daily for the duration of steroid treatment. • Omeprazole - dose

6.3 Dietary and Fluid management Whilst there is proteinuria (>++) a no added salt diet is advised. It is also advisable to advise on avoiding an excessively large fluid intake while awaiting remission. A modest fluid restriction may also be helpful. These restrictions are lifted once the child goes into remission. Dietetic advice re calorie control while on steroids.

6.4 Complications The main complications of nephrotic syndrome are hypovolaemia, infection and thrombosis. Their management is same as at presentation (see above: section 4.3)

6.5 Monitoring and Observations Admission is often not necessary with relapse. Early review to monitor for complications and to assess the onset of remission is needed. Parental support for first relapses is often welcome and allows teaching to be reinforced.

6.5.1 Nursing Role of nurse specialist in local teams?

• Monitoring progress • Clinical assessment – fluid retention; complications • Weight • BP • Daily EMU ‘stix’ (uPC:R – see below) • Fluid balance advice

6.5.2 Laboratory Where clinical uncertainty on relapse status: urine P:CR Renal biochemistry including serum albumin.

7. Further management of patients with Frequent Relapses

7.1 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 the relapses while still on steroids or within 2 weeks of ceasing steroids. If children have frequent relapses, strategies should be adopted to try to reduce the amount of steroid required.

7.2 Drug treatment

7.2.1 Low Dose Alternate Day Prednisolone Low dose alternate day steroid treatment (< 10-15 mg/alt days) may prevent relapses, and result in less steroid being given overall. Referral for discussion of second line therapy with a Paediatric Nephrologist is indicated in children with • Frequent relapses • Steroid dependency • Steroid toxicity

7.2.2 Levamisole Levamisole may be beneficial for children who have occasional relapses. It is less useful for children who are steroid dependent. The dose is 2.5 mg/kg/ on alt days . Wean steroid regiment when treatment established for at least 4 weeks. If successful it can be continued of periods up to 3 years. Reversible ‘idiosyncratic’ neutropenia is a rare but recognised side-effect. Also rash (erythema multiforme like) and GI intolerance may rarely limit use. A FBC should be checked monthly for the first 3 months. This drug is not licensed in the UK, and has to be imported.

7.2.3 Cyclophosphamide For children with frequent relapses or those who are steroid dependent consider a course of Cyclophosphamide 3 mg/kg/day for 8 weeks or equivalent. It is best to avoid cutting the tablets. FBC should be monitored for the first few weeks of treatment.

7.2.4 Calcineurin Inhibitors – Ciclosporin (or Tacrolimus) Ciclosporin at a dose of 2.5 mg/kg bid usually for 1 year may be useful as a steroid sparing agent. Levels should be checked after 1-2 weeks; aim for a 12 hour trough of 70 – 120 nmol/l. For children under 5 yrs of age, three times daily dosing may be necessary. Monitor BP and renal function.

7.2.5 Mycophenylate Mofetil (MMF) There is some experience of using MMF in children with difficult to treat NS. It may be useful for those children showing signs of cyclosporin toxicity. Doses of

600mg /m2/bid have been used. FBC should be monitored for leucopenia. The

use of MMF is associated with gastro-intestinal intolerance, mainly diarrhoea. This is an unlicensed indication for MMF.

7.2.6 Rituximab New experimental therapy.

8. Dietary and nutritional management

9. Vaccination Advice – Pneumococcal

– Confirm status – Recommended for all unvaccinated children with NS. – If not administered

– Administer with first admission OR – Refer to GP to have Prevenar/Pneumovax. –

– Varicella status non-immune

– Consider giving varicella vaccine between relapses in children with frequent relapses who are varicella seronegative. Aim to administer vaccine when prednisolone dose is low.

– ZIG (passive immunity) for exposure prophylaxis as per DH guidelinesImmunisation against Infectious Disease - DH Green Book

– Active disease – admission for IV aciclovir then p.o. valaciclovir when no new crops of vesicles.

– Active immunisation when off immunosuppression – Varicella status should be repeated 6 monthly in those who

are non-immune. –

– Annual seasonal flu vaccination recommended – Inform GP

– – H1N1 vaccination as recommended by Chief Medical Officer for high risk

groups – Inform GP

10. Patient and Family Preparation

10.1 Patient and Family Education

10.2 Patient and Family Information Provision and Links

11. Pre-discharge checklist

12. Out-patient management and follow-up

12.1 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 5) Bone mineral density / calcium supplements 6) Ophthmology review 7) Varicella status should be repeated 6 monthly in those who are non-immune. 8) Patients on second line therapy require monitoring as specified for treatment regimen above (section 7).

12.2 Standards for laboratory monitoring

13. Future guideline development Future review of this guideline is due every 2 years (insert date) or at an earlier date to incorporate clinically significant changes in practice. This guideline will be audited prior to its review to assess the impact of implementation of the guideline, and to determine changes required to improve patient outcomes. Audit of the guideline may cover:

Appendix 1 Appendix 2 etc. Reference list