This action might not be possible to undo. Are you sure you want to continue?
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
1 3 3 4 4 5 6 6 6 7 8 8 9 9 10 11 12
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. Mohd Sham Kasim Consultant Paediatrician and Head Department of Paediatrics Hospital Kuala Lumpur 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. Kwan Geok lan Consultant Paediatrician Hospital Melaka Dr Pyar Kaur Consultant Paediatrician Hospital Pulau Pinang Dr. Lim Yam Ngo Consultant Paediatric Nephrologist Department of Paediatrics Hospital Kuala Lumpur Chairman: Dr. Wong Swee Lan Consultant Paediatrician Hospital Seremban Dr.CONSENSUS STATEMENT: MANAGEMENT OF IDIOPATHIC NEPHROTIC SYNDROME IN CHILDHOOD WORKING GROUP FOR INITIAL DRAFT Adivisor : Dr. Soo Thian Lian Consultant Paediatrician Hospital Queen Elizabeth Kota Kinabalu 2 .
Angeline Yeoh Paediatrician Hospital Seberang Jaya Dr Kamarul Azahar Paediatrician Hospital Seremban Dr. Ipoh Dr. Neoh Siew Hong Paediatrician Hospital Taiping Dr. Kelantan CONSENSUS STATEMENT: 3 . Nazeli Hamzah Paediatrician Klinik Perdana Kota Bharu.Dr. Wong See Chang Paediatrician Hospital Sibu Dr Tam Pui Ying Paediatrician Hospital Sultanah Aminah Johor Baru Dr. Christopher CC Chua Paediatrician/Lecturer University Hospital. Jamaluddin Hj Mohamad Paediatrician Hospital Tengku ampuan Afzan Kuantan Dr. 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. Nur Khatijah Nurani Paediatrician Hospital Kangar Dr. Hans Van Rulenberghe Paediatric Nephrologist Hospital University Sains Malaysia Kubang Kerian Dr. Margaret Kannimmel Paediatrician Hospital Tengku Ampuan Rahimah. Low Bin Hooi Paediatrician Tawau Hospital Representatives from the Universities Dr. Leow Poy Lee Paediatrician Hospital Muar Dr. Irene Cheah Consultant Paediatrician Hospital Kuala Lumpur Dr. Kelang Dr. David Manickam Consultant Paediatrician Ipoh Specialist Centre. S Tharam Consultant Paediatrician Hospital Ipoh Dr. Melaka Dr.
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. investigation and management of nephrotic syndrome in childhood. Oedema. hypoalbuminaemia and oedema.000 child population. 1. data suggests that Asians have a higher incidence at about 16 new cases per 100. 4 . Although said to be uncommon in the West at about 3 new cases per 100. 3.MANAGEMENT OF IDIOPATHIC NEPHROTIC SYNDROME IN CHILDHOOD Idiopathic nephrotic syndrome in childhood is diagnosed by the presence of significant proteinuria. the underlying cause of which is unknown. 2. complement levels depends on the clinical features and the physician in charge. Serum albumin. Urinalysis and quantification for urinary protein excretion. In addition. It is important to ensure that there is no known primary renal disorder that has led to the nephrotic syndrome. There are variations in the definition. Other investigations e. INVESTIGATIONS AT INITIAL PRESENTATION a) b) c) d) e) Full blood count. The obvious outcome of treatment of this condition is prolonged and sustained remission of the nephrotic syndrome with minimal side effects from treatment. 1. 4. This has occasionally led to dire consequences to the physical health of the child as well as the mental health of his/her parents. Hypercholesterolaemia is not needed in definition.g. more evidence is now available for a reasonable guideline to be formulated.1 Although there is no available local data. Hypoalbuminaemia of <25 g/l. 2. In general.000 child population . 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. the above list of investigations may suffice for children below 8 years of age presenting with nephrotic syndrome without any other clinical features. Renal profile. it is felt that the incidence in Malaysia is also higher than in the West.
However. Children with nephrotic syndrome are more prone to primary bacterial peritonitis.The International Study of Kidney Disease in Children (ISKDC) had found that at the initial presentation of children with minimal change nephrotic syndrome • 20. A. B. and haemoconcentration. 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. Salt intake should be reduced during the oedematous state.7% had microscopic haematuria • 32. 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.5 to 1. If salt poor albumin is not available. Children with nephrotic syndrome can present with hypovolemia.5% had transiently raised plasma creatinine concentration 3. B. Previous recommendations of high protein diet had not been shown to improve serum albumin concentration.1 MANAGEMENT OF THE OEDEMATOUS STATE. Pneumococcal vaccine can be considered. poor pulse volume. • 22. C. The treatment is to infuse salt poor albumin at 0. A. Hypovolaemia. the manisfestations of which include abdominal pain. hypotension.0 g/kg/dose over one to two hours. MANAGEMENT 3. Diet A normal protein diet with adequate calories is recommended.7% of children had systolic blood pressure above 98th percentile for age. plasma protein derivatives or human plasma can be used. 5 . Fluid restriction This is not usually recommended except in chronic oedematous states. Bed rest This is not required and usually not practical unless the child has gross oedema. Antibiotics. other volume expanders like 5% albumin. cold peripheries.
3. Infections. some units recommend giving a single dose of intravenous immunoglobulin. While the child is on corticosteroid treatment and within 6 weeks after its cessation. D. 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. Immunisation. Children with nephrotic syndrome are prone to infections particularly cellulitis & primary peritonitis. There is however. Diuretic therapy is not usually necessary in steroid responsive nephrotic syndrome but if required should be used with caution as it can precipitate hypovolemia. If varicella-zoster immunoglobulin (VZIG) is available. and if exposed should be treated like any immunocompromised child. it should be given within 72 hours after exposure to chickenpox. 2. the danger of fluid overload with salt poor albumin infusion and the child’s urine output and blood pressure should be closely monitored. Hypercholesterolaemia There is insufficient evidence for a recommendation to be made as yet. B.C. MANAGEMENT OF THE COMPLICATIONS OF NEPHROTIC SYNDROME A. If VZIG is not available. The parents and children should be advised and cautioned about contact with chickenpox and measles. Salt poor albumin of 20 . Diuretics. Live vaccines can be administered 6 weeks after cessation of corticosteroid therapy 6 .25% concentration can be used in symptomatic grossly oedematous states together with intravenous frusemide at 1-2 mg/kg to produce a diuresis. only killed vaccines may be safely be administered to the child. Should a child with nephrotic syndrome develop primary peritonitis.
Acute renal failure This is a rare complication in children with steroid responsive nephrotic syndrome.7 Main indication for renal biopsy • Steroid resistant nephrotic syndrome defined as failure to achieve remission despite 4 weeks of adequate corticosteroid therapy. INDICATIONS FOR RENAL BIOPSY A renal biopsy is not required for children presenting with idiopathic nephrotic syndrome for the following reasons. 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. 4. D.C. 7 .1 . The duration of anticoagulation required is still controversial. Thrombosis This complication if suspected should be thoroughly investigated and treated to prevent fatal complications. 91. A renal biopsy is also NOT required prior to cytotoxic therapy.97% of patients MCNS respond to corticosteroid therapy 3. Treatment consists of anticoagulation with the various anticoagulants available. Adequate cover with corticosteroids during these periods of stress is recommended to be given in 3 divided doses. 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. The actual cause is not known although hypovolemia has been implicated. E.8% of steroid responders have minimal change disease1.3. 3.4. Intrarenal factors have also been postulated to play a role. • About 80% of children 1to 12 years of age with idiopathic have minimal change • • nephrotic syndrome. 93.6.
A relapse is defined by urine albumin excretion of > 40 mg/m 2/hour or urine dipstix of 2+ or more for 3 consecutive days. 8 . and the so called longer initial steroid induction regime proposed and studied by Ueda et al8 and Ksiazek and Wysznska9.1 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 1940’s.4. 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. Various regimes of corticosteroids have been used. 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. • Reduced by 25% monthly over the next 4 months The choice of using either regime was left to the individual attending paediatrician.4.3% for the modified ISKDC regime. The two regimes discussed were the modified ISKDC regime.4. 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. 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. 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 .3.2 Relapse The majority of children with idiopathic nephrotic syndrome will relapse 11. 3.12. CORTICOSTEROIDS IN NEPHROTIC SYNDROME 3. who showed a 2 year relapse free rate of 50% for the long initial prednisolone dose versus 27.
the child should be re-induced as for a relapse.4. This low dose alternate day prednisolone should preferabley not exceed 0.It has not been shown that giving more corticosteroids for treatment of relapses results in longer period of remission. The rate of tapering depends on the patient and the paediatrician in charge. showed no difference.4. Breakthrough proteinuria may occur with intercurrent infection and usually does not require corticosteroid therapy if the child has no oedema and remains well. 2 mg/kg/day for 12 weeks or 3 9 .4.13 Various dose and duration of oral cyclophosphamide have been used. The prednisolone is then kept on as low an alternate day dose as possible for 6 months. Various trials have shown the superiority of cyclophosphamide with prednisolone versus prednisolone alone in maintaining prolonged remission. striae.5.6. Cyclophosphamide should be considered if the nephrotic syndrome is steroid dependent and the child shows signs of steroid toxicity 3. cataracts. Prednisolone at 60 mg/m2/day (maximum 80 mg) until urine dipstix is nil/trace for 3 consecutive days.2 on relapse i. 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.7. Cyclophosphamide therapy is indicated for the treatment of steroid dependent nephrotic syndrome with signs of steroid toxicity like stunting of growth. Should a child relapse while on low dose alternate day prednisolone. severe cushingoid features and osteoporosis and should be started when the child is in remission following induction with corticosteroids.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. after which the prednisolone dose is reduced to 40 mg/m2/48 hours for 4 weeks .12. Concern was expressed about the side effects of cyclophosphamide particularly on the gonads. the prednisolone is again tapered to low dose alternate day prednisolone.e.e.The prednisolone is now tapered instead of discontinued at the end of the re-induction regime.5 mg/kg/dose. Re-induction of any relapse with corticosteroids is as described in the section 3. 3. A total cumulative dose of cyclophosphamide of 168 mg/kg was adopted for the treatment of steroid dependent nephrotic syndrome i. CYCLOPHOSPHAMIDE A renal biopsy is not needed prior to cyclophosphamide therapy. Ueda et al 15 in a later paper comparing the 8 week versus 12 week duration of cyclophosphamide however.
Regular fortnightly review with full blood counts and urinalysis should be carried out while the child is on oral cyclophosphamide.mg/kg/day for 8 weeks. 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.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. or the child again becomes steroid toxic after multiple relapses.6. prednisolone therapy which can be further reduced and discontinued once the child completes the cyclophosphamide therapy and remains in remission. 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. While the child is on cyclophosphamide. Options available here are not many but fortunately this group of patients make up only about 10 – 20% of children with nephrotic syndrome. 3. then a paediatric nephrology opinion should be sought. Should the relapse occur soon after a course of cyclophosphamide when the child is still steroid toxic. • Levamisole which is not available in this country 3. 10 .
If steroid toxic.1 . refer paediatric nephrologist to consider a). 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. 4.0.4. then 40 mg/m2/48 hours for 4 weeks and discontinue. Relapses post cyclophosphamide As for (2) and (3) if not steroid toxic. consider cyclophosphamide (cumulative dose 168 mg/kg) if steroid toxic. Relapse on prednisolone As for (3) if not steroid toxic. Relapse Prednisolone 60 mg/m2/day (max 80 mg/day) till remission.5 mg/kg/dose for 6 months. * choice depends on attending paediatrician. Frequent Relapses Reinduce as for (2) above. then taper and keep low dose alternate day prednisolone at 0. 11 . second course cyclophosphamide or b). SCHEMA OF TREATMENT OF IDIOPATHIC NEPHROTIC SYNDROME 1. cyclosporine therapy. 5. 3.
6. DEFINITIONS14 1. 5. serum albumin < 25 g/l. STEROID DEPENDENCE: Two consecutive relapses occurring during the period of steroid taper or within 14 days of its cessation. 3. 12 . 4. FREQUENT RELAPSES: Two or more relapses within 6 months of initial response or four or more relapses within any 12 month period.5. proteinuria > 40 mg/m2 /hour or urine protein creatinine ratio > 200 mg/mmol. REMISSION: Urinary protein excretion < 4 mg/m2/hour or urine dipstix nil/trace for 3 consecutive days. STEROID RESISTANCE: Failure to achieve remission in spite of 4 weeks of standard prednisolone therapy. 2. RELAPSE: Urinary protein excretion > 40 mg/m2/hour or urine dipstix ++ or more for 3 consecutive days. NEPHROTIC SYNDROME: Oedema.
Applying decision analysis to the management of adolescent idiopathic nephrotic syndrome. lancet 1974 I. Poulton J. Srinivasan R. Kidney Int. The primary nephrotic syndrome in children. Lewis MA. Chihara M. A Report of the ISKDC. Koskimies O. Houston IB. Baidom EM. Glasgow EF. Predicting the response to cytotoxic therapy for childhood nephrotic syndrome: Superiority of response to corticosteroid therapy over histopathologic patterns. Acta Paediatr 1995. Long term outcome of primary nephrotic syndrome.6. 84:889-93 10. Intermittent versus long-term tapering prednisolone for intial therapy in children with idiopathic nephrotic syndrome. Nephrotic syndrome: From toddlers to twenties. Pediatr Nephrol 1994. 8:660664 6. 82:607-613 13. White RHR. Pediatr 1981. Wyszynska T. Hallamn N. 60:1014-1017 2. J Pediatr 1973. Nephrotic syndrome in children. minimal lesion nephrotic syndrome in childhood. Arch Dis Child 1985. Polinsky MS. Kaiser BA. Baluarte HJ. J Pediatr 1988. Prospective controlled trial of cyclophosphamide therapy in children with the nephrotic syndrome. Ksiazek J. 112:122-6 9. Sharples PM. Pediatr Nephrol 1991. Davis N. References 1. Matoo T. Kawaguchi S et al.Ueda N. Prediction of histopathology from clinical and laboratory characteristics at time of diagnosis. 1978. a controlled prospective study of cyclophosphamide in relapsing corticosteroid responsive. Postlethwaite RJ. lancet 1989 I: 255-259 12. Clinicopathological study of nephrotic syndrome in childhood. Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. White RHR. Kidney biopsy prior to cyclophosphamide therapy in primary nephrotic syndrome. Steroid responsive nephrotic syndrome is more common in Asians. McLain PN. 57:544-48 11. 113:996-1001 7. Feld LG. Lancet 1970 I:1353-1359 5. Mills RJ. Vilska J. Short versus long initial prednisone treatment in steroid sensitive nephrotic syndrome in children. A Report of the ISKDC. 5:617-619 8. Bruder-Stapleton F. 13:159-165 3. J. Schulman SL. Moxey-Mims MM. Chiu J. 423-427 13 . J Pediatr 1988. 98:561-564 4. Rapola J. Drummond KN. Arch Dis Child 1982. A report of the ISKDC.
35 Suppl 1:S31-36 17. Arch Dis Child. Cyclophosphamide treatment of steroid dependent nephrotic syndrome: comparison of l8 weeks with twelve weeks. Arch Dis Child 1987. Lancet 1991. Kuno K. 1990. Report of APN. Ueda N. Eight and 12 week courses of cyclophosphamide in nephrotic syndrome. Clin Nephrol 1991. Ito S. Niaudet P. 65:1147-50 16. Treatment of idiopathic nephrotic syndrome with cyclosporin A in children. I:555 14 . Broyer M. British Association for Paediatric Nephrology. 62:1102-06 15.14. Levamisole for corticosteroid dependent nephrotic syndrome in childhood. Habib R.