CONSENSUS STATEMENT: MANAGEMENT OF IDIOPATHIC NEPHROTIC SYNDROME IN CHILDHOOD

Contents
Working group and workshop participants 1. Definition of nephrotic syndrome 2. Investigations at initial presentation 3. Management 3.1. Management of oedematous state 3.2. Management of complications of nephrotic syndrome 3.3. Indications for renal biopsy 3.4. Corticosteroids in nephrotic syndrome 3.4.1. At initial diagnosis 3.4.2. Relapse 3.4.3. Frequent relapses and steroid dependence 3.5. Cyclophosphamide 3.6. Relapses post cyclophosphamide 3.7. Urine albumin monitoring 4. Schema of treatment of idiopathic nephrotic syndrome 5. Definitions 6. References

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CONSENSUS STATEMENT: MANAGEMENT OF IDIOPATHIC NEPHROTIC SYNDROME IN CHILDHOOD WORKING GROUP FOR INITIAL DRAFT
Adivisor : Dr. Mohd Sham Kasim Consultant Paediatrician and Head Department of Paediatrics Hospital Kuala Lumpur Dr. Lim Yam Ngo Consultant Paediatric Nephrologist Department of Paediatrics Hospital Kuala Lumpur

Chairman:

Dr. Indon Lajin Consultant Paediatric Nephrologis Subang Jaya Medical Centre Subang Jaya Dr. Susan Pee Consultant Paediatric Nephrologist Department of Paediatrics Hospital Sultanah Aminah Johor Baru Dr. Amir Hamzah Paediatric Clinical Specialist Department of Paediatrics Hospital Kuala Lumpur Dr. Lynster Liaw Trainee in Paediatric Nephrology Department of Paediatrics Hospital Kuala Lumpur

WORKSHOP PARTICIPANTS Representatives from the Ministry of Health

Dr. Wong Swee Lan Consultant Paediatrician Hospital Seremban Dr. Kwan Geok lan Consultant Paediatrician Hospital Melaka Dr Pyar Kaur Consultant Paediatrician Hospital Pulau Pinang Dr. Soo Thian Lian Consultant Paediatrician Hospital Queen Elizabeth Kota Kinabalu

Dr. S Tharam Consultant Paediatrician Hospital Ipoh Dr. Leow Poy Lee Paediatrician Hospital Muar Dr. Jamaluddin Hj Mohamad Paediatrician Hospital Tengku ampuan Afzan Kuantan Dr. Margaret Kannimmel Paediatrician Hospital Tengku Ampuan Rahimah, Kelang Dr. Angeline Yeoh Paediatrician Hospital Seberang Jaya Dr Kamarul Azahar Paediatrician Hospital Seremban

Dr. Irene Cheah Consultant Paediatrician Hospital Kuala Lumpur Dr. Nur Khatijah Nurani Paediatrician Hospital Kangar Dr. Neoh Siew Hong Paediatrician Hospital Taiping Dr. Wong See Chang Paediatrician Hospital Sibu Dr Tam Pui Ying Paediatrician Hospital Sultanah Aminah Johor Baru Dr. Low Bin Hooi Paediatrician Tawau Hospital

Representatives from the Universities

Dr. Hans Van Rulenberghe Paediatric Nephrologist Hospital University Sains Malaysia Kubang Kerian Dr. Christopher CC Chua Paediatrician/Lecturer University Hospital, Kuala Lumpur Assoc Prof Zulkifli Ismail Department of Paediatrics Universiti Kebangsaan Malaysia Assoc Prof Ong Lai Choo Department of Paediatrics Universiti Kebangsaan Malaysia

Representatives from Private Sector

Dr Gnanambai Athi Consultant Paediatrician Medical Specialist Centre Air Keroh, Melaka Dr. David Manickam Consultant Paediatrician Ipoh Specialist Centre, Ipoh Dr. Nazeli Hamzah Paediatrician Klinik Perdana Kota Bharu, Kelantan

CONSENSUS STATEMENT:
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MANAGEMENT OF IDIOPATHIC NEPHROTIC SYNDROME IN CHILDHOOD Idiopathic nephrotic syndrome in childhood is diagnosed by the presence of significant proteinuria, hypoalbuminaemia and oedema, the underlying cause of which is unknown. Although said to be uncommon in the West at about 3 new cases per 100,000 child population, data suggests that Asians have a higher incidence at about 16 new cases per 100,000 child population .1 Although there is no available local data, it is felt that the incidence in Malaysia is also higher than in the West. There are variations in the definition, investigation and management of nephrotic syndrome in childhood. This has occasionally led to dire consequences to the physical health of the child as well as the mental health of his/her parents. In addition, more evidence is now available for a reasonable guideline to be formulated. The obvious outcome of treatment of this condition is prolonged and sustained remission of the nephrotic syndrome with minimal side effects from treatment. 1. DEFINITION OF NEPHROTIC SYNDROME: A clinical syndrome of massive proteinuria defined by: Urine protein excretion greater than 40 mg/m2/hour on a timed urine collection or an early morning urine protein creatinine index of >200 mg/mmol; 2. Hypoalbuminaemia of <25 g/l, 3. Oedema. 4. Hypercholesterolaemia is not needed in definition.
1.

It is important to ensure that there is no known primary renal disorder that has led to the nephrotic syndrome, in particular that associated with post infectious glomerulonephritis as the treatment for the nephrotic syndrome then depends on the treatment of the primary renal disease. 2. INVESTIGATIONS AT INITIAL PRESENTATION a) b) c) d) e) Full blood count, Renal profile, Serum albumin, Urinalysis and quantification for urinary protein excretion. Other investigations e.g. complement levels depends on the clinical features and the physician in charge.

In general, the above list of investigations may suffice for children below 8 years of age presenting with nephrotic syndrome without any other clinical features.

The International Study of Kidney Disease in Children (ISKDC) had found that at the initial presentation of children with minimal change nephrotic syndrome 20.7% of children had systolic blood pressure above 98th percentile for age; 22.7% had microscopic haematuria 32.5% had transiently raised plasma creatinine concentration 3. MANAGEMENT 3.1 MANAGEMENT OF THE OEDEMATOUS STATE. A. Bed rest This is not required and usually not practical unless the child has gross oedema. B. Diet A normal protein diet with adequate calories is recommended. Previous recommendations of high protein diet had not been shown to improve serum albumin concentration. Salt intake should be reduced during the oedematous state. C. Antibiotics. Children with nephrotic syndrome are more prone to primary bacterial peritonitis. Prophylactic oral penicillin at doses of 125 mg BD or 250 mg BD depending on the size of the child is recommended during relapse particularly with gross oedema in view of the lack of home albuminuria monitoring and long distance from the hospital. Pneumococcal vaccine can be considered. However, it must be cautioned that the vaccine does not cover all strains of pneumococci and some children with nephrotic syndrome have been shown to be poor responders to this vaccine.
A.

Hypovolaemia. Children with nephrotic syndrome can present with hypovolemia, the manisfestations of which include abdominal pain, cold peripheries, poor pulse volume, hypotension, and haemoconcentration. The treatment is to infuse salt poor albumin at 0.5 to 1.0 g/kg/dose over one to two hours. If salt poor albumin is not available, other volume expanders like 5% albumin, plasma protein derivatives or human plasma can be used.

B. Fluid restriction This is not usually recommended except in chronic oedematous states.

C. Diuretics. Diuretic therapy is not usually necessary in steroid responsive nephrotic syndrome but if required should be used with caution as it can precipitate hypovolemia. Salt poor albumin of 20 - 25% concentration can be used in symptomatic grossly oedematous states together with intravenous frusemide at 1-2 mg/kg to produce a diuresis. There is however, the danger of fluid overload with salt poor albumin infusion and the childs urine output and blood pressure should be closely monitored. D. Hypercholesterolaemia There is insufficient evidence for a recommendation to be made as yet. 3. 2. MANAGEMENT OF THE COMPLICATIONS OF NEPHROTIC SYNDROME
A.

Infections. Children with nephrotic syndrome are prone to infections particularly cellulitis & primary peritonitis. Should a child with nephrotic syndrome develop primary peritonitis, the antibiotics recommended is parenteral penicillin and a third generation cephalosporin as it has been found that about half of primary peritonitis is due to Streptococcal pneumoniae and the other half to gram negative bacilli. The parents and children should be advised and cautioned about contact with chickenpox and measles, and if exposed should be treated like any immunocompromised child. If varicella-zoster immunoglobulin (VZIG) is available, it should be given within 72 hours after exposure to chickenpox. If VZIG is not available, some units recommend giving a single dose of intravenous immunoglobulin.

B. Immunisation. While the child is on corticosteroid treatment and within 6 weeks after its cessation, only killed vaccines may be safely be administered to the child. Live vaccines can be administered 6 weeks after cessation of corticosteroid therapy

C. Acute renal failure This is a rare complication in children with steroid responsive nephrotic syndrome. The actual cause is not known although hypovolemia has been implicated. Intrarenal factors have also been postulated to play a role. D. Thrombosis This complication if suspected should be thoroughly investigated and treated to prevent fatal complications. Treatment consists of anticoagulation with the various anticoagulants available. The duration of anticoagulation required is still controversial. E. Acute Adrenal Crisis This may be seen in children who have been on long term corticosteroid therapy (equivalent to 18 mg/m2 of cortisone daily) when they undergo situations of stress. Adequate cover with corticosteroids during these periods of stress is recommended to be given in 3 divided doses. 3.3. INDICATIONS FOR RENAL BIOPSY A renal biopsy is not required for children presenting with idiopathic nephrotic syndrome for the following reasons.

About 80% of children 1to 12 years of age with idiopathic have minimal change

nephrotic syndrome. 93.1 - 97% of patients MCNS respond to corticosteroid therapy 3,4. 91.8% of steroid responders have minimal change disease1.

A renal biopsy is also NOT required prior to cytotoxic therapy. 4,6,7 Main indication for renal biopsy Steroid resistant nephrotic syndrome defined as failure to achieve remission despite 4 weeks of adequate corticosteroid therapy.

Other indications This would depend on the associated features of the nephrotic syndrome and shall be left to the discretion of the attending paediatrician in consultation with the paediatric nephrologist.

3.4. CORTICOSTEROIDS IN NEPHROTIC SYNDROME 3.4.1 At Initial diagnosis A paediatrician should be consulted before initiation of therapy in a child with newly diagnosed nephrotic syndrome Corticosteroids was found to be effective in inducing remission of nephrotic syndrome from the 1940s, and has since then been used as first line therapy in the treatment of idiopathic nephrotic syndrome although no controlled trial was ever conducted about its efficacy Controversy lies in the dosage and duration of corticosteroids used at initial diagnosis of the nephrotic syndrome. Various regimes of corticosteroids have been used. The two regimes discussed were the modified ISKDC regime; and the so called longer initial steroid induction regime proposed and studied by Ueda et al8 and Ksiazek and Wysznska9, who showed a 2 year relapse free rate of 50% for the long initial prednisolone dose versus 27.3% for the modified ISKDC regime. Modified ISKDC regime Prednisolone dosage at: 60 mg/m2/day (maximum 80 mg/day) for 4 weeks 40 mg/m2/48 hours for 4 weeks only. Long initial prednisolone regime: Prednisolone dosage at: 60 mg/m2/day (maximum 80 mg/day) for 4 weeks 40 mg/m2/48 hours for 4 weeks. Reduced by 25% monthly over the next 4 months The choice of using either regime was left to the individual attending paediatrician. A child with nephrotic syndrome who fails to respond to an initial four week treatment with corticosteroids should be referred to a paediatric nephrologist for a renal biopsy. 3.4.2 Relapse The majority of children with idiopathic nephrotic syndrome will relapse 11,12. A relapse is defined by urine albumin excretion of > 40 mg/m2/hour or urine dipstix of 2+ or more for 3 consecutive days. Treatment of relapse Prednisolone at 60 mg/m2/day (maximum 80 mg) is to be given until remission defined as urine dipstix is trace or nil for 3 consecutive days after which the prednisolone dose is reduced to 40 mg/m2/48 hours for 4 weeks .

It has not been shown that giving more corticosteroids for treatment of relapses results in longer period of remission. Breakthrough proteinuria may occur with intercurrent infection and usually does not require corticosteroid therapy if the child has no oedema and remains well. 3.4.3 Frequent relapses and steroid dependence An initial responder who has 2 or more relapses within 6 months of initial response or 4 or more relapses in any 12 month period is said to have frequent relapses. Re-induction of any relapse with corticosteroids is as described in the section 3.4.2 on relapse i.e. Prednisolone at 60 mg/m2/day (maximum 80 mg) until urine dipstix is nil/trace for 3 consecutive days, after which the prednisolone dose is reduced to 40 mg/m2/48 hours for 4 weeks .The prednisolone is now tapered instead of discontinued at the end of the reinduction regime. The rate of tapering depends on the patient and the paediatrician in charge. The prednisolone is then kept on as low an alternate day dose as possible for 6 months. This low dose alternate day prednisolone should preferabley not exceed 0.5 mg/kg/dose. Should a child relapse while on low dose alternate day prednisolone, the child should be reinduced as for a relapse; the prednisolone is again tapered to low dose alternate day prednisolone. Cyclophosphamide should be considered if the nephrotic syndrome is steroid dependent and the child shows signs of steroid toxicity 3.5. CYCLOPHOSPHAMIDE A renal biopsy is not needed prior to cyclophosphamide therapy.4,6,7. Cyclophosphamide therapy is indicated for the treatment of steroid dependent nephrotic syndrome with signs of steroid toxicity like stunting of growth, cataracts, striae, severe cushingoid features and osteoporosis and should be started when the child is in remission following induction with corticosteroids. Various trials have shown the superiority of cyclophosphamide with prednisolone versus prednisolone alone in maintaining prolonged remission.12,13 Various dose and duration of oral cyclophosphamide have been used. The report by APN14 demonstrated a 2 year remission rate of 67% for cyclophosphamide at 2 mg/kg/day for 12 weeks against 22% for 8 weeks given for children with steroid dependent nephrotic syndrome. Ueda et al 15 in a later paper comparing the 8 week versus 12 week duration of cyclophosphamide however, showed no difference. Concern was expressed about the side effects of cyclophosphamide particularly on the gonads. A total cumulative dose of cyclophosphamide of 168 mg/kg was adopted for the treatment of steroid dependent nephrotic syndrome i.e. 2 mg/kg/day for 12 weeks or 3 mg/kg/day for
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8 weeks. While the child is on cyclophosphamide, prednisolone therapy which can be further reduced and discontinued once the child completes the cyclophosphamide therapy and remains in remission. Regular fortnightly review with full blood counts and urinalysis should be carried out while the child is on oral cyclophosphamide. 3.6. RELAPSES POST CYCLOPHOSPHAMIDE Relapses after a course of cyclophosphamide is treated as for relapses after the initial diagnosis of nephrotic syndrome if the child does not exhibit any further signs of steroid toxicity. Should the relapse occur soon after a course of cyclophosphamide when the child is still steroid toxic, or the child again becomes steroid toxic after multiple relapses, then a paediatric nephrology opinion should be sought. Options available here are not many but fortunately this group of patients make up only about 10 20% of children with nephrotic syndrome. The available options available include: A second course of cyclophosphamide Cyclosporine can also be used on a very selective basis by paediatric nephrologists and has been shown to maintain remission in 80% of these patients. Levamisole which is not available in this country 3.7 URINE ALBUMIN MONITORING It is advocated that monitoring of urine albumin excretion be done regularly either at home with urinary dipstix or at the nearest health centre.

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4. SCHEMA OF TREATMENT OF IDIOPATHIC NEPHROTIC SYNDROME 1. Nephrotic Syndrome Initial Diagnosis Prednisolone 60 mg/m2/day (max 80/day) for 4 weeks

Response Prednisolone 40 mg/m2/48 hours for 4 weeks

No Response

Renal Biopsy *Discontinue *Steroid taper at 25% monthly over 4 months

2. Relapse Prednisolone 60 mg/m2/day (max 80 mg/day) till remission, then 40 mg/m2/48 hours for 4 weeks and discontinue. 3. Frequent Relapses Reinduce as for (2) above, then taper and keep low dose alternate day prednisolone at 0.1 - 0.5 mg/kg/dose for 6 months. 4. Relapse on prednisolone As for (3) if not steroid toxic, consider cyclophosphamide (cumulative dose 168 mg/kg) if steroid toxic. 5. Relapses post cyclophosphamide As for (2) and (3) if not steroid toxic. If steroid toxic, refer paediatric nephrologist to consider a). second course cyclophosphamide or b). cyclosporine therapy.

* choice depends on attending paediatrician.

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5. DEFINITIONS14 1. NEPHROTIC SYNDROME: Oedema, serum albumin < 25 g/l, proteinuria > 40 mg/m2 /hour or urine protein creatinine ratio > 200 mg/mmol. 2. REMISSION: Urinary protein excretion < 4 mg/m2/hour or urine dipstix nil/trace for 3 consecutive days. 3. RELAPSE: Urinary protein excretion > 40 mg/m2/hour or urine dipstix ++ or more for 3 consecutive days. 4. FREQUENT RELAPSES: Two or more relapses within 6 months of initial response or four or more relapses within any 12 month period. 5. STEROID DEPENDENCE: Two consecutive relapses occurring during the period of steroid taper or within 14 days of its cessation. 6. STEROID RESISTANCE: Failure to achieve remission in spite of 4 weeks of standard prednisolone therapy.

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6. References 1. Sharples PM, Poulton J, White RHR. Steroid responsive nephrotic syndrome is more common in Asians. Arch Dis Child 1985; 60:1014-1017 2. A report of the ISKDC. Nephrotic syndrome in children. Prediction of histopathology from clinical and laboratory characteristics at time of diagnosis. Kidney Int. 1978; 13:159165 3. A Report of the ISKDC. The primary nephrotic syndrome in children. Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. J. Pediatr 1981; 98:561-564 4. White RHR, Glasgow EF, Mills RJ. Clinicopathological study of nephrotic syndrome in childhood. Lancet 1970 I:1353-1359 5. Moxey-Mims MM, Bruder-Stapleton F, Feld LG. Applying decision analysis to the management of adolescent idiopathic nephrotic syndrome. Pediatr Nephrol 1994; 8:660664 6. Schulman SL, Kaiser BA, Polinsky MS, Srinivasan R, Baluarte HJ. Predicting the response to cytotoxic therapy for childhood nephrotic syndrome: Superiority of response to corticosteroid therapy over histopathologic patterns. J Pediatr 1988; 113:996-1001 7. Matoo T. Kidney biopsy prior to cyclophosphamide therapy in primary nephrotic syndrome. Pediatr Nephrol 1991; 5:617-619 8.Ueda N, Chihara M, Kawaguchi S et al. Intermittent versus long-term tapering prednisolone for intial therapy in children with idiopathic nephrotic syndrome. J Pediatr 1988; 112:122-6 9. Ksiazek J, Wyszynska T. Short versus long initial prednisone treatment in steroid sensitive nephrotic syndrome in children. Acta Paediatr 1995; 84:889-93 10. Koskimies O, Vilska J, Rapola J, Hallamn N. Long term outcome of primary nephrotic syndrome. Arch Dis Child 1982; 57:544-48 11. Lewis MA, Baidom EM, Davis N, Houston IB, Postlethwaite RJ. Nephrotic syndrome: From toddlers to twenties. lancet 1989 I: 255-259 12. Chiu J, McLain PN, Drummond KN. a controlled prospective study of cyclophosphamide in relapsing corticosteroid responsive, minimal lesion nephrotic syndrome in childhood. J Pediatr 1973; 82:607-613 13. A Report of the ISKDC. Prospective controlled trial of cyclophosphamide therapy in children with the nephrotic syndrome. lancet 1974 I; 423-427

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14. Report of APN. Cyclophosphamide treatment of steroid dependent nephrotic syndrome: comparison of l8 weeks with twelve weeks. Arch Dis Child 1987; 62:1102-06 15. Ueda N, Kuno K, Ito S. Eight and 12 week courses of cyclophosphamide in nephrotic syndrome. Arch Dis Child. 1990; 65:1147-50 16. Niaudet P, Broyer M, Habib R. Treatment of idiopathic nephrotic syndrome with cyclosporin A in children. Clin Nephrol 1991; 35 Suppl 1:S31-36 17. British Association for Paediatric Nephrology. Levamisole for corticosteroid dependent nephrotic syndrome in childhood. Lancet 1991; I:555

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