Nephrotic syndrome

N04

DESCRIPTION

Nephrotic syndrome (NS) is a clinical syndrome associated with massive proteinuria due to increased permeability of the glomerular basement membrane. Most children have primary (idiopathic) nephrotic syndrome associated with minimal change nephrotic syndrome (MCNS) or focal segmental glomerulosclerosis (FSGS). In an undefined proportion of patients, the disease is caused by genetic mutations in podocyte specific genes. Main causes of secondary nephrotic syndrome include infections (HIV, Hepatitis C), Systemic lupus erythematosis (SLE) and reflux nephropathy.

Main complications:

  • Increased risk of infections with encapsulated organisms, S. pneumoniae, E coli. Chicken pox and measles are the main major viral infections.
  • Hypercoagulable state: increased risk of arterial and venous thrombosis. Aggressive investigation and treatment may be necessary to prevent fatal pulmonary embolism.

DIAGNOSTIC CRITERIA

Clinical

  • Massive proteinuria.
  • Hypo-albuminaemia.
  • Oedema.
  • Hyperlipidaemia (hypercholesterolaemia).
  • Usually normal blood pressure.
  • Transient microscopic haematuria and/or hypertension in 25% of children.
  • Usually normal renal function.

Investigations

  • Urine test strip: ≥ 3+ proteinuria; may have trace to 1+ haematuria.
  • Spot random urine sample protein:creatinine ratio: >0.2 g/mmol.
  • Urine microscopy: hyaline and lipid casts. May have occasional red and white blood cells.
  • Serum albumin: <25 g/L.
  • S-urea and creatinine and electrolytes usually normal.
  • S-cholesterol: increased.
  • Investigations to exclude secondary causes of nephrotic syndrome, including: ASO and Anti-DNAseB titre, hepatitis B s-antigen, hepatitis C antibody, RPR, HIV and CMV antibodies.
  • C3/C4
  • Antinuclear factor antibody and anti-dsDNA.

A presumptive diagnosis of MCNS can be made in children:

  • who are 2–6 years old and who have:
    • normal blood pressure,
    • normal renal function,
    • only a trace/1+ haematuria, but no red cell casts,
    • normal complement levels, and
    • in whom secondary causes have been excluded.

GENERAL AND SUPPORTIVE MEASURES

  • Monitor fluid balance.
  • Monitor urine output strictly and weigh daily (1 kg = 1 L of fluid).
  • Assess hydration status.
    • Suspect
      • Hypovolaemia: in the presence of hypotension, small pulse volume and cold extremities.
      • Normovolaemia: with normal moist mucosa and normal blood pressure with well perfused limbs.
    • Replace ongoing extra-renal losses as for dehydrated child e.g. oral rehydration for gut losses, etc.

Continued weight gain or anuria is an indication for referral.

  • Dietary measures:
    • Do not restrict oral fluid intake,
    • Restrict salt intake in all patients. No salt should be added during preparation of food and there should be no salt on the table during meals. Restrict all salt preserved foods.
    • Limit intake of saturated fat.
    • Normal energy intake.
    • Normal protein diet for all with normal renal function.

MEDICINE TREATMENT

Specific treatment of causative conditions where possible e.g.

  • HIV infection.
  • Syphilis infection.
  • SLE.
  • Streptococcal infection.

For hypovolaemia:

  • Sodium chloride 0.9%, IV, 20 mL bolus, immediately over 10 minutes.
    Replace ongoing extra-renal losses as for dehydrated child e.g. oral rehydration solution for gut losses, etc.

Note: Beware of intravascular volume depletion which can be induced by over aggressive diuresis. In patients with oedema, exclude hypovolaemia prior to the administration of furosemide.

For patients with oedema and hypervolaemia:

  • Furosemide, oral, 1 mg/kg/dose, 12 hourly.
    LoEIII [3]
    AND
  • Potassium chloride (100mg/ml), oral, 75 - 225 mg/kg/day (1-3 mmol/day or 0.75 -2.25 ml/kg/day) in divided doses.
  • Monitor serum potassium.

For patients with intractable oedema who fail to improve with furosemide treatment only:

ADD

  • Hydrochlorothiazide oral, 1 mg/kg, once daily.
    • Do not exceed 12.5 mg daily.

For Severe ascites:

Add

  • Spironolactone, oral 1.5 – 2.5 mg/kg/dose, 12 hourly.

For short term treatment of congenital nephrotic syndrome and for patients with oedema (anasarca), volume contraction and oliguria:

  • Albumin, human 20% (salt poor solution), IV, 1 g/kg (i.e. 5 mL/kg) administered over 5 hours on 2 consecutive days.
    AND
  • Furosemide, IV, 2 mg/kg, slow IV infusion over 5 hours, i.e. 0.4 mg/kg/hour.

For all children with non-remitting nephrotic syndrome:

  • Multivitamin, oral, 5 mL daily. (Formulation to include pyridoxine, other B vitamins, vitamin C 30 mg and vitamin D 400 IU)
  • Folic acid, oral, 5 mg daily.
  • Calcium (elemental), oral, 10–15 mg/kg/dose, 12 hourly.
    • Maximum dose: 1 000 mg (1 g) daily.
    • Calcium carbonate 420 mg = 168 mg elemental calcium.

Give all children with non-remitting nephrotic syndrome renoprotective treatment as for patients with chronic renal failure.

IMPORTANT:

Renoprotective strategies are not indicated in children with steroid responsive nephrotic syndrome.

  • ACE inhibitor
    An ACE inhibitor is given to decrease proteinuria, irrespective of presence or absence of systemic hypertension. Begin with low dosage and titrate against response and blood pressure.
  • Enalapril, oral, 0.1 mg/kg once daily.
    • Increase dose to 0.5 mg/kg/day, as a single dose or two divided doses.
    • Monitor for adverse effects: hyperkalaemia (increased risk when potassium sparing diuretic is used simultaneously) and acute renal failure (increased risk in children with impaired renal function or volume depletion).
    • Do not use if estimated CrCl <30 mL/minute.

Cholesterol lowering drugs

For children >8 years who have non-remitting nephrotic range proteinuria and persistent cholesterol levels >7 mmol/L:

  • HMGCoA reductase inhibitors (statin), e.g.:
  • Simvastatin, oral, 10 mg at night.

Immunisation

Do not give live vaccines to patients receiving steroid and other immunosuppressive treatment.

Once in remission

Provide all other EPI vaccines according to the schedule.

In children >2 years who received conjugate pneumococcal vaccine 13:

  • Pneumococcal vaccine (polysaccharide), IM, 0.5 mL as a single dose

Give Varicella-zoster vaccine, 0.5mL, SC, 2 doses 6 weeks apart.

Check Hepatitis B immunity. In the absence of any immunity

  • Hepatitis B vaccine, IM, 1 mL, 3 doses one month apart.
    • If the antibody level is considered non-protective or insufficient, give 2 booster doses one month apart.

Antibiotics

For patients with anasarca who have an increased risk for spontaneous pneumococcal peritonitis:

  • Phenoxymethylpenicillin, oral, 125–250 mg, 12 hourly.

For severe penicillin allergy:

Corticosteroids

Initiate corticosteroid treatment only in consultation with a specialist.

In the absence of a histological diagnosis, empiric steroid treatment should only be given to children with presumed minimal change disease where a rapid response is expected.

In patients with initial macroscopic haematuria, persistent hypertension, persistent low C₃ and renal function impairment a diagnosis other than MCNS is suggested. These cases should be referred for kidney biopsy before steroid treatment is given.

Initial treatment (first course of steroid treatment)

  • Prednisone, oral, 2 mg/kg/dose as a single dose in the morning for 4 weeks.
    • Maximum dose: 60 mg daily. If in remission
    • Taper dose over next 16 weeks as follows:
      • 2 mg/kg/dose as a single dose on alternate mornings for 4 weeks.
      • 1.5 mg/kg/dose as a single dose on alternate mornings for 4 weeks.
      • 1 mg/kg/dose as a single dose on alternate mornings for 4 weeks.
      • 0.5 mg/kg/dose as a single dose on alternate mornings for 4 weeks.

A shorter initial treatment course i.e. 8 weeks vs. 20 weeks is associated with more frequent relapses.

If the patient fails to achieve remission after 4 weeks of treatment, continue with the high dose for another 4 weeks (maximum of 8 weeks). Patients who go into remission must then the tapering regimen above. Patients who fail to go into remission after 8 weeks of steroid treatment are considered steroid resistant and should be referred for kidney biopsy.

IMPORTANT

Long-term corticosteroid treatment suppresses adrenal function. Therefore, additional steroids or steroid supplementation is necessary during periods of acute stress, e.g. surgery or septic shock.

Assessment of treatment response

For practical reasons a dipstick test is usually performed on a spontaneously voided urine sample instead of a 24-hour urine sample.

  • Test urine every morning during corticosteroid treatment.
  • Dipstick test should be negative for minimum of 3 consecutive mornings before decreasing the dose.
  • If proteinuria recurs, go back one step in the suggested dose for a few more days before again attempting to decrease the dose.
  • Some patients do not understand alternate day treatment schedules in which case daily dose of prednisone is given instead of alternate days.

Classifying treatment responses

  • Remission: No/trace protein on urine test strip test for 3 consecutive days (spot sample urine protein:creatinine ratio <0.02 g/mmol).
  • Steroid-sensitive NS: No/trace protein on urine test strip for 3 consecutive days within 4 weeks after start of standard oral prednisone therapy.
  • Steroid-dependent NS: Relapse develops during tapering of steroid treatment or within 2 weeks after stopping treatment.
  • Steroid-resistant NS: Failure to achieve remission in spite of maximum 8 weeks’ treatment with prednisone 2 mg/kg/day. (Spot sample urine protein:creatinine ratio >0.02 g/mmol).
  • Relapse of NS: 3+ proteinuria on urine test strip or urine protein:creatinine ratio >0.2 g/mmol for 3 consecutive days.
  • Frequently-relapsing NS: two or more relapses per 6 months or ≥ 4 per 12-month period.

Schedule for relapse: similar as initial course, but for shorter period:

  • Prednisone, oral, 2 mg/kg/dose as a single daily dose for minimum of one week. Urine test strip should be negative for minimum of 3 consecutive mornings before the dose is decreased.
  • Then taper dose as follows:
    • 2 mg/kg/dose as a single dose on alternate mornings for 2 weeks.
    • 1.5 mg/kg/dose as a single dose on alternate mornings for 2 weeks.
    • 1 mg/kg/dose as a single dose on alternate mornings for 2 weeks.
    • 0.5 mg/kg/dose as a single dose on alternate mornings for 2 weeks.
      • If proteinuria recurs, go back one step in the suggested dose for a few more days before again attempting to decrease the dose.

Second-line immunosuppressive treatment

  • Second line immunosuppressive treatment is indicated in children with steroid sensitive nephrotic syndrome with frequently-relapsing NS, steroid-dependent NS and in those with steroid toxicity.
  • It should only be prescribed after consultation with a paediatric nephrologist. It remains the prescriber’s responsibility to monitor the patient at regular intervals for side effects of treatment.
    • Full blood count, urea, creatinine, electrolytes and albumin needs to be done every 10–14 days throughout the course of treatment.
  • Second line immunosuppressive treatment for steroid sensitive nephrotic syndrome should only be started when the urine dipstick test is negative.
  • It is always given in combination with steroid treatment.
  • Kidney biopsy is preferably done before second line immunosuppressive treatment is started due to the risks associated with this treatment.
  • Immunosuppressive Therapy - nephrologist initiated
    • Cyclophosphamide, oral, 2mg/kg/dose once daily for 12 weeks.
    • Ensure adequate fluid intake to avoid haemorrhagic cystitis.

IMPORTANT

Children with steroid resistant nephrotic syndrome do not benefit from treatment with cyclophosphamide and should be referred to a paediatric nephrologist.

REFERRAL

  • All with congenital nephrotic syndrome.
  • All with clinical features and/or laboratory results, which suggest a diagnosis other than MCNS, e.g. initial macroscopic haematuria, persistent hypertension, persistent low C₃ and renal function impairment.
  • Patients with steroid resistant nephrotic syndrome.
  • All patients before second line immunosuppressive treatment is prescribed.