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Idiopathic Nephrotic Syndrome

Idiopathic Nephrotic Syndrome. David Hughes Consultant Paediatric Nephrologist RHSC, Glasgow Honorary Consultant Paediatric Nephrologist RHSC, Edinburgh. Idiopathic (Primary) Nephrotic Syndrome (INS). Definition Epidemiology The spectrum of Idiopathic NS Diagnosis and investigation

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Idiopathic Nephrotic Syndrome

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  1. Idiopathic Nephrotic Syndrome David Hughes Consultant Paediatric Nephrologist RHSC, Glasgow Honorary Consultant Paediatric Nephrologist RHSC, Edinburgh

  2. Idiopathic (Primary) Nephrotic Syndrome (INS) • Definition • Epidemiology • The spectrum of Idiopathic NS • Diagnosis and investigation • Management • First line • Second line

  3. Definition • Heavy Proteinuria • Consider if urine ‘stix’ protein > ++ • >50 mg/kg/day or 40 mg/m2/hr • Protein Creatinine Ratio>250 mg/mmol • Usually highly selective – albumin and low mol wt. • Low serum albumin (< 25g/L) • Generalised Oedema • Hyperlipidaemia

  4. Epidemiology of INS in childhood • Incidence • 2-7 per 100 000 child population • 19-66 new cases across Scotland • 188 new cases in 14 months in UK (‘95-’96) • (Evans, personal communication) • 6 x more common in Asians • Much rarer in Africans • Prevalence • 12-16 per 100 000 child population • 114-152 cases across Scotland

  5. Epidemiology of INS in childhood • Young age • 1-6 years old – median age 4 years • More common in boys • 2:1 m:f • 1:1 m:f (adolescents) • <5% family history • Minimal Change Disease commonest cause in childhood v. 25 % in adults

  6. Spectrum of INS – Histological types • Minimal Change Disease (MCD) • Focal Segmental Glomerulosclerosis (FSGS) • Membranoproliferative Glomerulonephritis • (Membranous Nephropathy)

  7. Idiopathic NS Spectrum: from MCD to FSGS 80-90 % MCD Non Infrequently Frequently Steroid Steroid Relapsing Relapsing Relapsing Dependent Resistant ~90 % Steroid Sensitive - PROGNOSTIC Multiple aetiologies

  8. Pattern of response to steroids in steroid sensitive nephrotic syndrome (ISKDC)

  9. Progress of INS in childhood • ~80% minimal change disease • >90% steroid responsive • >70% relapsing course • 80% long term remission during childhood • mortality rates • Published series1-7.2% • Sepsis • Vascular thrombosis • Currently much lower

  10. Presenting Features • Preceding URTI @ 1st episode (and relapses) • Generalised oedema • intermittent • scrotal • “allergic” • Infection • cellulitis • primary peritonitis • septicaemia • ‘Frothy’ urine

  11. Initial clinical assessment • Volume status • Perfusion • Heart rate and BP • Hypertension • Infection • Height, weight, surface area

  12. Initial investigation • Urine • stix testing • P:CR • Culture • Na+ (volume depletion) • Blood • U&E, Creatinine, Albumin, LFTs; FBC • C3/C4; VZV titre • At risk cases: HBV/HCV • Older and atypical: ASOT/antiDNaseB; lupus screen

  13. Initial management • Volume resuscitation • 4.5% albumin 5 – 20ml/kg • Hypertension • Paradoxical: volume resuscitation • Volume overload: diuretic • Ca+ channel blocker • Short acting nifedipine • Long acting amlodipine

  14. Initial management • Infection • Streptococcal and gram negative • Broad spectrum cover • Penicillin prophylaxis • Venous thrombosis • Rare • Specialist care

  15. Subsequent management • Steroid trial • Gastro-protection • Fluid restriction • Albumin and diuretics • Symptomatic oedema – skin compromise • Use with care • Monitoring progress • Daily weight • Fluid balance • Daily EMU ‘stix’/PC:R • BP

  16. Parent teaching disease information urine testing and recording Albustix for monitoring Dietician salt intake and fluid restriction limit calorie intake on steroids normal protein intake ‘healthy diet’ for all the family Subsequent management

  17. Pharmacist drug dosing and administration appropriate formulation steroid weaning regimen antibiotic prophylaxis gastro-protection Renal Medication Information Booklet Vaccination Pneumococcal Varicella status non-immune ZIG (passive immunity) for exposure prophylaxis IV aciclovir for active infection Active immunisation when off immunosuppressives Annual flu vaccination Subsequent management

  18. Atypical featuresEarly discussion with nephrologist • Age <12 months or >12 years • Persistent hypertension or impaired renal function • Gross haematuria • Low plasma C3 • HBV or HCV +ve • Failure to respond to steroids at 4 weeks

  19. Childhood Nephrotic Syndrome – Biopsy Indications • Systemic disease • Extremes of age • Under 1 year • Older child • Low complement • Gross haematuria • Persistent hypertension • Impaired renal function • Steroid unresponsive at 4-8 weeks

  20. SSNS - management • Corticosteroid therapy • Cochrane review • Non-corticosteroid therapy • Cochrane review • Newer arrivals

  21. What's the best initial steroid regimen to use? • Prednisone for at least three months • Six months of therapy v. three months of therapy • The reduction in risk for relapse is associated with both an increase in duration and an increase in dose. • Prednisone is as effective when administered as a single daily dose compared with divided doses. • Alternate-day therapy is more effective than intermittent therapy

  22. SSNS – diagnosisScotland’s health on the web – SHOW http://www.show.scot.nhs.uk/

  23. What is the best approach to relapses? • Information on relapse definition • Confirm relapse if in doubt • Treat to remission and taper steroid • Gastro-protection on high dose steroid • Penicillin prophylaxis until remission

  24. When should I consider asking about second line therapy? • Frequent relapsers • How often? • Twice in first 6 months • Four times in any 12 months • Steroid dependence • How dependent? • > 0.5mg/kg alternate day • Or steroid toxic side effects

  25. What approaches will be considered? • Low dose alternate day steroid • Increase to daily over 6 days for viral URTI • A choice of second line agents • Discuss pros and cons of each • Need for monitoring • Trial of treatment • Duration of treatment if successful • Work through the list if not successful

  26. Non-corticosteroid therapy • 20 trials included • 923 children

  27. Cochrane review • >3 months steroid therapy at disease presentation have higher relapse-free rate at 12 months BUT • Trial quality? • Was there a clinically useful reduction • in steroid dependent disease? • use of second-line immunosuppressive agents? • Side effects?

  28. Levamisole • 4 trials – one excluded from analysis • 50% reduction in risk of relapse while on treatment • No benefit over steroids at 6-12 months when treatment ceased for 3 months • Cochrane review – 2005

  29. Levamisole • Action • Immunomodulatory - ? Stimulate T-cell function • Dose • 2.5mg/kg/alternate day • Adverse effects • Very low incidence • Neutropenia – idiosyncratic and reversible • GI upset • Rash

  30. Alkylating agents • Cyclophosphamide • 2-3mg/kg/day for 8 weeks • Chlorambucil • 0.2mg/kg/day for 8 weeks • No difference in effect between both agents • 50% reduction in risk of relapse for one to two years after treatment • Greater effect in FRSSNS than SDNS • Cochrane review – 2005

  31. Alkylating agents • Action • Bind to purine bases and impair normal DNA transcription • Short and long term adverse effects

  32. Ciclosporin • 2 trials of alkylating agents v. 6 months and 12 months Ciclosporin therapy • Both treatments equally effective at maintaining remission at 6 and 9 months • Ciclosporin effective during treatment but not sustained on cessation: 50% reduction in risk of relapse while on treatment • Cochrane review – 2005

  33. Ciclosporin • Action • Inhibition of IL-2 production by activated T-cells • Dose • 3-6mg/kg/day in 2 divided doses (12 hourly) • Adjusted for blood trough level ~50-125μg/L • Adverse effects • Short and log term

  34. Ciclosporin • Longer term adverse effects • Chronic nephrotoxicity

  35. Cochrane review conclusions • Effective second line therapy • Alkylating agents • Levamisole • Cyclosporin • No data to support one agent over another • Ineffective therapies • Azathioprine • Mizoribine

  36. Mycophenolate Mofetil (MMF) • Action • Inhibition of de novo purine synthesis • Inhibits T- and B-lymphocyte proliferation • Dose • 600-1200mg/m2 daily in 2 divided doses to max. 1g. b.d. • Adverse effects • Bone marrow suppression – FBC monitoring • GI upset – severe diarrhoea • Pulmonary fibrosis

  37. Mycophenolate Mofetil (MMF) • No RCTs reported yet • Small, uncontrolled, retrospective studies • Variable doses and duration of treatment • FRSSNS; SDNS; SRNS; CsA dependent NS. • Steroid sparing • Ciclosporin sparing • Improved GFR • Reduction in relapse rate: 40-70% • Increase in relapse rate on MMF cessation • Well tolerated

  38. Future therapy • Rituximab • chimeric human-murine monoclonal antibody • binds specifically to the CD20 antigen located on pre-B and mature B lymphocytes, thus mediating B-cell lysis • not directed against plasma cells.

  39. Rituximab • FRSSNS & SDNS • Response rate >75% • Relapse on B cell repopulation

  40. Rituximab • Give in remission • >75% good initial response • Side effects – acute reactions • ~75% relapse with B-cell repopulation • Responsive to repeat Rituximab treatment • Re-treat at first relapse • Further treatment on B cell re-population • Allows withdrawal of CNI, MMF and steroids

  41. Summary • The acute management of nephrotic syndrome can be optimally managed in a general paediatric setting with multi-disciplinary team support • Awareness of atypical and complicating features allows early discussion with specialist centres • Various second line therapies are available with no single optimal treatment • Following specialist discussion most treatments can be administered locally with shared/joint clinic review • Novel therapies requires detailed counselling, careful administration and close follow-up

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