Guideline for the Management of Nephrotic Syndrome
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1 Guideline for the Management of Nephrotic Syndrome Renal Unit Royal Hospital for Sick Children Yorkhill Division Please note: the following guideline has not been assessed according to the AGREE (Appraisal of Guidelines for Research and Evaluation) criteria. This will take place at the next guideline review. Nephrotic Syndrome Version: 1.1 Page 1 of 8
2 Contents Page(s) 1. Introduction 2 2. Definition of Nephrotic Syndrome Initial Investigation 3 4. Referral to Paediatric Nephrology 3 5. Complications Hypovolaemia Infection Thrombosis 4 6. Treatment of Initial Presentation of Nephrotic 4 Syndrome 6.1 Prednisolone Albumin Penicillin Prophylaxis Salt/Fluid Restriction Vaccination 5 7. Relapse of Nephrotic Syndrome 6 8. Treatment of Relapse of Nephrotic Syndrome Prednisolone Albumin Salt Restriction Penicillin Vaccination 6 9. Treatment of Frequent Relapses Low Dose Alternate Day Prednisolone Levamisole Cyclophosphamide Cyclosporin Mycophenylate Mofitil (MMF) Follow Up Future Guideline Review 8 1. Introduction This guideline represents our current practice within the Renal Unit and are intended for use by clinicians. These guidelines are based on previous recommendations reviewed in the light of recent literature and will be update regularly. They cover many aspects of the management of typical nephrotic syndrome, but they are not exhaustive, and many not be relevant for children with atypical nephrotic syndrome. There is always a paediatric nephrology consultant on call for the unit who will be happy to discuss difficult or unusual cases. 2. Definition of Nephrotic Syndrome Nephrotic range proteinuria (> 1g/m 2 /day) Hypoalbuminaemia (<25 g/l) Oedema Nephrotic Syndrome Version: 1.1 Page 2 of 8
3 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 a renal biopsy, were it performed, would be likely to show minimal change nephrotic syndrome. Those with atypical features are more likely to be unresponsive to steroid treatment, and a biopsy more likely to show FSGS or one of the other forms of nephrotic syndrome. Therefore children with typical features are started on steroids without recourse to renal biopsy. Those with atypical features should therefore undergo renal biopsy before receiving steroid treatment. Nephrotic Syndrome Typical Features Atypical Features Age 1-10 years <1yr, >10years Normotensive Hypertensive Normal Adrenal Function Elevated Creatinine +/- microscopic haematuria Macroscopic Haematuria 3. Initial Investigation 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 andurinary protein/creatinine ratio 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. Referral to Paediatric Nephrology Age < 1 yr Age > yrs Persistent hypertension Macroscopic haematuria Low C3/C4 Failure to respond to steroids within 4 weeks Nephrotic Syndrome Version: 1.1 Page 3 of 8
4 5. Complications The main complications of nephrotic syndrome are hypovolaemia, infection and thrombosis. 5.1 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 > 2 o C, 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. 5.2 Infection Loss of complement components and possibly immunoglobulins results in an increased risk of infection. Consider antibiotic prophylaxis whilst patients have significant proteinuria. 5.3 Thrombosis Loss of proteins such as anti-thrombin III contributes to a pro-coagulant state. This might be exacerbaterd by hypovolaemia. 6. Treatment of Initial Presentation of Nephrotic Syndrome 6.1 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 referred to paediatric nephrology for consideration of renal biopsy. There is increasing evidence that longer initial courses of prednisolone are associated with a lower incidence of relapse, and therefore a 12-week initial course is recommended. The dose of prednisolone is based on surface area. 60 mg/m 2 /day for 4 weeks (maximim 80 mg) 40 mg/m 2 /on alternate days for 4 weeks (maximum 60mg) Reduce dose by 5-10mg/m 2 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. Patients should be issued with a steroid warning card, and they should be aware of the side effects and risks of steroid treatment. Varicella status should be documented clearly in the casenotes and on HISS. If Nephrotic Syndrome Version: 1.1 Page 4 of 8
5 prednisolone causes gastric irritation, start ranitidine 2mg/kg bid for the duration of steroid treatment. 6.2 Albumin As discussed above the clinical indications for albumin are Clinical hypovolaemia Symptomatic oedema 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. 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. 6.3 Penicillin Prophylaxis 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. Dose: Under 5 yrs 5yrs or above 125 mg bid 250 mg bid 6.4 Salt/Fluid Restriction 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. 6.5 Vaccination Pneumococcal vaccination is recommended for children with NS. Consider giving at the time of diagnosis. Varicella vaccination is only available on a named patient basis. Response To Treatment Most children with nephrotic syndrome will respond to steroid treatment within 2-4 weeks. A remission is defined as 3 or more days of trace or negative on dipstick testing. Treatment is continued for a total of 12 weeks as outlined above. If proteinuria persists beyond the first 4 weeks of steroid treatment, then children should be referred for renal biopsy. Nephrotic Syndrome Version: 1.1 Page 5 of 8
6 7. Relapsing Nephrotic Syndrome Up to % of children with nephrotic syndrome may have one or more relapse. 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. 8. Treatment of Relapse Nephrotic Syndrome 8.1 Prednisolone Prednisolone treatment should be restarted once a relapse has been diagnosed. 2mg/kg daily (maximum 80 mg) until the urine is negative or trace for 3 days 40 mg/m 2 (maximum 60 mg) on alternate days for 4 weeks then stop or taper the dose over 4-8 weeks 8.2 Albumin The indications for albumin infusion are as for the initial presentation. It is less likely to be needed during a relapse. 8.3 Salt Restriction Whilst there is proteinuria (>++) a no added salt diet is advised. 8.4 Penicillin Whilst there is proteinuria (>++) penicillin can be given. 8.5 Vaccination Consider giving varicella vaccine between relapses in children who are varicella seronegative. Referral to/discussion with Paediatric Nephrology Frequent relapsers Steroid dependency Steroid toxicity 9. Diagnosis and Treatment of Frequent Relapses Frequent relapsers are diagnosed if there is: 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 are occurring during steroid tapering. Varicella status should be repeated 6 monthly in those who are nonimmune. Nephrotic Syndrome Version: 1.1 Page 6 of 8
7 If children have frequent relapses, strategies should be adopted to try to reduce the amount of steroid required. 9.1 Low Dose Alternate Day Prednisolone Low dose alternate day steroid treatment (< mg/alt days) may prevent relapses, and result in less steroid being given overall. 9.2 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 for 6 months to a year in the first instance. Reversible neutropenia is a rare but recognised side-effect. A FBC should be checked monthly for the first 3 months. This drug is not licensed in the UK, and has to be imported. 9.3 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. 9.4 Cyclosporin Cyclosporin 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 nmol/l ( ug/l). For children under 5 yrs of age, tid dosing may be necessary. Monitor BP and renal function. 9.5 Mycophenylate Mofitil (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 /m 2 /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. Nephrotic Syndrome Version: 1.1 Page 7 of 8
8 10. Follow Up GENERAL CONSIDERATIONS DURING FOLLOW UP For children on long-term steroids:- 1) Monitor BP 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) VACCINATION Pneumococcal: recommended for all children with NS. Varicella: consider in varicella negative children with frequent relapses. Aim to administer vaccine when prednisolone dose is low. 11. Future Guideline Development Should any aspect of this guideline change before the planned review (i.e. new technology or procedural change) then this guideline should be updated accordingly. Future review of this guideline should make use of the AGREE document to ensure that up-to-date evidence and best clinical practice has been used to inform this guideline. For further information regarding guideline development, please contact the Chairperson of the Multi-Professional Clinical Practice Committee. Nephrotic Syndrome Version: 1.1 Page 8 of 8
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