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Nephrotic Syndrome

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Definition

A clinical syndrome characterised by heavy proteinuria, hypoalbuminaemia (albumin < 25g/l), oedema and hypercholesterolemia. Nephrotic range proteinuria is >40mg/hr/m2 or a first morning urine protein/creatinine ratio >200mg/mmol (normal <20).

Nephrotic syndrome may be primary/idiopathic (INS)

  • minimal change disease (MCD)
  • focal segmental glomerulosclerosis(FSGS)
  • membranoproliferative glomerulonephritis (MPGN)
  • membranous glomerulophritis (MGN)

or secondary  to infections, medications or systemic disease (eg lupus or malignancy).

Epidemiology

INS has its peak incidence in early childhood, median age of diagnosis 2.5 years for MCD and 6 for FSGS.  Male to female ratio 3:2 in young children. MCD and FSGS may be familial.

Clinical Features

  • Proteinuria occurs first, followed by oedema which develops either slowly over a few weeks, or rapidly over a few days.
  • Accumulation of fluid in body cavities also occurs.
  • Hypertension occurs in 15% at onset of MCD and in 33% of FSGS patients.
  • Microscopic haematuria is present in up to 70% of MCD and 48% of FSGS. Macroscopic haematuria is common in FSGS.

Laboratory Features

  • Serum albumin < 25g/l.
  • Haematocrit may be elevated because of intravascular volume contraction.
  • Urine microscopy - waxy casts, fat droplets, few red cells.
  • Plasma creatinine is usually normal but may be transiently raised in MCD at presentation or in the setting of severe intravascular volume contraction.
  • Hypercholesterolaemia.
  • If atypical features present (e.g. age <12 months or >12 years, persistent hypertension, impaired renal function, macroscopic haematuria, signs of systemic illness) measure complement C3, C4 and ANA

Complications

Hypovolaemia

  • Occurs early in relapse as oedema is accumulating.
  • May be precipitated by sepsis, aggressive diuretic usage, drainage of ascites.
  • May present as acute abdomen, tachycardia, raised haemoglobin/haematocrit, hypertension, or hypotension as a late sign. Postural blood pressure change should be assessed.
  • A very low fractional excretion of sodium (<1%) is a supporting laboratory finding.
  • These patients require treatment with 20% albumin (see Management Table below) without frusemide, or 4% albumin bolus 10-20ml/kg.

Infection
Children with INS are at increased risk of infection with encapsulated bacterial organisms (Pneumococcus, H. Influenzae). Infection with gram negative organisms and Varicella zoster may be more severe in those on steroids.

Thrombosis
Deep veins of legs, pulmonary emboli, renal vein thrombosis. Increased risk during relapses, especially with hypovolaemic episodes.

Acute renal failure
Usually due to hypovolaemia. Other causes are renal vein thrombosis and interstitial nephritis secondary to diuretics, and some antibiotics.

Chronic renal failure
Up to 30% FSGS progress to end stage renal failure within 5 years of diagnosis.

Definitions of Response to Treatment 

Remission Urine protein excretion <4mg/hr/m2 or albustix is negative/trace for 3 consecutive days.
Relapse Proteinuria on dipstick 3+ for 3 consecutive days after having been previously in remission. This is common, occurring in up to 75% of patients.
Frequent Relapse 2 more relapses within 6 months or > 4 relapses in 12 months.
Steroid Dependence 2 consecutive relapses occurring during steroid treatment or within 14 days of its cessation.
Steroid Resistance Failure to achieve response after 28 days of steroid at 60mg/m2/day followed by 3 pulses of intravenous methylprednisolone (10mg/kg/dose to maximum 700mg on alternate days).

NOTE - some experts define steroid resistance after 8 weeks of daily high dose prednisone. Discussion with Nephrology should be made if no response at 28 days to arrange for biopsy within 8 weeks from onset. They will advise regarding continued steroid therapy whilst awaiting biopsy on a case by case basis.

Management 

Diet Normal protein intake.
Salt restriction during relapses.
Antibiotics Oral penicillin should be given during both initial illness and relapses.  Pneumoccoccus is the most common bacteria causing infection.  If peritonitis suspected, cover gram negative organisms as well.
Diuretics Careful use of frusemide, only in the absence of hypovolaemia, if fluid restriction (e.g. 70% maintenance) and salt restriction alone not effective in controlling oedema formation.
IV Albumin Only for clinical evidence of hypovolaemia or severe oedema. Maximum dose 1g/kg of 20% albumin over minimum of 4 hours.
If given for severe oedema, follow with IV frusemide 2-3 mg/kg/dose.
Complications: hypertension, hyponatraemia, hypokalaemia, pulmonary oedema.
If patient has evidence of renal impairment discuss with Nephrology prior to IV albumin use.
Steroid Therapy

This is the mainstay of treatment and should be commenced once the diagnosis is established.  If there are concerns of the possibility of secondary nephrotic syndrome please discuss with nephrology prior to commencing steroid therapy.
Many patients require the addition of gastroprotective medication whilst on high dose daily steroids.

Steroid therapy for first presentation:
The most recent systematic analysis (Cochrane library 2015) recommends 3 months of corticosteroid therapy. 
- Prednisone or Prednisolone - start at 60mg/m2/day (max 80mg) in a single daily dose to complete a total of 28 days.
- This is followed by alternate day therapy at 40mg/m2/day (max 60mg) for further 28 days.
-Then wean steroid dose gradually over the next 4-6 weeks and stop.
-Total treatment duration of first presentation should be approximately 3 months.

Steroid therapy for relapses:
Infrequent Relapses
Prednisone or prednisolone - start at 60mg/m2/day (max 80mg) until in remission. Then give alternate day prednisone or prednisolone at 40mg/m2/day (max 60mg) for total of 28 days, then stop.
Children having <2-3 relapses per year can be managed with repeated courses of prednisone, providing they have a complete response to treatment each time.

Frequently relapsing or Steroid Dependent
Consider alternate day prednisone 0.3-0.75mg/kg for 4-6 months, at the lowest dose to avoid side effects.  After 4-6 months therapy, slow taper to attempt cessation of steroid therapy. Consider non-steroid immunosuppressive therapy earlier if the patient is already exhibiting significant steroid side effects.
For patients whose relapses are precipitated by URTI or other infections whilst on alternate day steroid, increasing the alternate day dose to daily for 5 days at the onset of the illness will reduce the risk of relapse by up to 60%. This strategy is supported by a number of randomised controlled trials.

If relapses continue despite alternate day steroids >0.75mg/kg or steroid related adverse effects develop, referral to Nephrology is indicated for consideration of alternative immunosuppressive therapy.

 Vaccinations Recommend updating routine vaccination schedule if not up to date (in particular pneumococcal) and assessment of Varicella serology. 

Pneumococcal
Children with nephrotic syndrome under the age of 5 years are currently eligible for funded pneumococcal vaccines PCV13 and 23PPV (high risk condition listed under Ministry of Health Immunisation Schedule 2014).
Use of steroids has not been found to alter the serological response to pneumococcal vaccine in these children, therefore there is no reason to delay this or other non-live vaccinations.

Varicella Zoster
If non-immune to Varicella and have a chickenpox contact whilst actively nephrotic and/or on steroid therapy recommend consideration of immunoglobulin. Do not give live vaccinations whilst on long term or high dose corticosteroids (refer to NZ Immunisation Handbook).

Seasonal Influenza vaccine
Recommended for frequently relapsing or Steroid Dependent patients. 

Indications for Renal Biopsy

  • Steroid resistance.
  • Impaired renal function with normal volume status.
  • Initial macroscopic haematuria.
  • Persistent microscopic haematuria if associated with hypertension.
  • Onset less than 6 months of age.
  • Low C3.

Information for Families

http://www.kidneys.co.nz/resources/file/nephrotic_syndrome_in_children_03.pdf

http://www.medicinesforchildren.org.uk/search-for-a-leaflet/cyclophosphamide-for-nephrotic-syndrome/

http://www.medicinesforchildren.org.uk/search-for-a-leaflet/ciclosporin-for-nephrotic-syndrome/

References 

  1. Hahn et al, 2015.  Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database of Systematic Reviews. 
  2. Larkins N, Kim S, Craig J, Hodson E.  Steroid-sensitive nephrotic syndrome: an evidence based update of immunosuppressive treatment in children. Arch Dis Child 2016, 101:404-408
  3. Avner ED, Haromn WE, Niaudet P, Yoshikawa N. (editors)  Pediatric Nephrology 6th edition, Volume 1, Springer 2009
  4. Ministry of Health Immunisation Handbook 2014. Wellington: Ministry of Health.

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Document Control

  • Date last published: 05 August 2016
  • Document type: Clinical Guideline
  • Services responsible: Paediatric Nephrology
  • Author(s): William Wong, Chanel Prestidge
  • Owner: William Wong
  • Editor: Greg Williams
  • Review frequency: 2 years

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