Nephrotic syndrome


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    This guideline has been adapted for statewide use with the support of the Victorian Paediatric Clinical Network

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    Background

    • Nephrotic syndrome is a clinical disorder characterised by heavy proteinuria, hypoalbuminaemia and oedema
    • 90% of children will have Idiopathic Nephrotic Syndrome, either minimal change disease (85%), or Focal Segmental Glomerulosclerosis (10-15%)
      • Idiopathic Nephrotic Syndrome (INS) – 90% of children(for which this guideline applies)
        • Minimal change disease (MCD)
        • Focal segmental glomerulosclerosis (FSGS)
      • Non-idiopathic Nephrotic Syndrome - rare (discuss with nephrology if features)
        • Secondary
          • Systemic Lupus Erythematosis (SLE), Henoch Schonlein Purpura (HSP), Membranoproliferative Glomerulonephritis (MPGN)
        • Membranous nephropathy
        • Congenital nephrotic syndrome
      • The key acute complications of nephrotic syndrome are hypovolemia, infection and thrombosis
      • Although in 80-90% of cases INS will respond to initial steroid therapy (hence called ‘steroid-sensitive nephrotic syndrome’, SSNS), children with SSNS have an 80% chance of having one or more relapses and approximately 50% of these children will have frequent relapses.
        • Thus, the first admission is an important opportunity to educate families about home monitoring and management (see ‘Family Education’, below), knowing that they will be likely to have one or more relapses

      Assessment

      • Oedema is the primary presenting feature. History can also include weight gain, poor urine output, dizziness, or discomfort as a result of the oedema (including abdominal pain).  
      • Degree of oedema ranges from:
        • Mild (subtle peri-orbital region, scrotum or labia)
        •  Moderate with peripheral pitting oedema of the limbs and sacrum.
        •  Severe with gross limb oedema, ascites and pleural effusions.
      •  In the child with oedema, confirm the diagnosis of nephrotic syndrome with
        •  Heavy proteinuria (dipstick 3-4+ or urine protein/creatinine ratio >0.2g/mmol)
        •  Hypoalbuminaemia (<25g/L).
        •  Other causes of generalised oedema include liver disease or protein losing enteropathy (leading to hypoalbuminaemia) or congestive cardiac failure.
      •  Assess for features suggesting not INS
        •  Age <1y or >12y
        •  Systemic symptoms of fever, rash, joint pains (SLE).
        •  Persistent hypertension (can have mild hypertension first 1-2 days)
      •  Rule out any nephritic features (requiring entirely different management)
        •  Macroscopic haematuria (INS may have microscopic haematuria)
        •  Hypertension
        •  Raised serum creatinine (INS may have mild elevation with mod-severe volume depletion)
      •  Assess for severity and complications of INS
        •  Intravascular volume depletion
          •  Although patients are invariably oedematous, they can be concurrently intravascular volume deplete
          •  Clinically
            •  Dizziness, abdominal cramps
            •  Peripheral hypoperfusion (cold hands or feet, mottling, capillary refill time > 2 seconds), tachycardia, oligoanuria, low urinary sodium, hypotension (late sign)
        •  Severe/symptomatic oedema – potential skin breakdown/cellulitis, gross scrotal/vulval oedema, increased work of breathing from pleural effusion
        •  Infection (at increased risk in nephrotic state)
          •  Cellulitis from gross oedema with skin compromise
          •  Spontaneous bacterial peritonitis – abdominal pain, fever, nausea/vomiting, rebound tenderness
        •  Thrombosis (at increased risk in nephrotic state)
          •  Deep vein thrombosis, pulmonary embolus
          •  Renal vein thrombosis – macroscopic haematuria, palpable kidney, loin tenderness, raised creatinine, hypertension
          •  Cerebral vein thrombosis - headache, vomiting, impaired conscious state or focal neurology

      Investigations:

      • Urine
        • Dipstick (proteinuria)
        • Microscopy (quantify any haematuria)
        • Spot protein: creatinine ratio
          • For quantification of proteinuria with correction for urinary concentration
          • Also useful if lack of response to steroids (compare initial result to later results for trend)
        • Sodium if required (to confirm intravascular volume depletion if clinically unclear. Less than 10mmol/L consistent with volume depletion)
      • Blood
        • FBC
        • UECr, LFT (albumin)
        • Immunology
          • C3 and 4 (low in SLE and MPGN)
          • ANA (SLE)
      • Hep B if risk factors on history (secondary cause of membranous nephropathy)
      • Varicella serology (so serostatus known while immunosuppressed in case of contact)

      Management

      Admitting unit based on hospital policy. Paediatric nephrology consultation recommended if:

      • Age <12 months or >12 years
      • Persistent hypertension +/- persistent microscopic hematuria
      • Elevated creatinine despite correction of any hypovolemia
      • C3 or 4 below normal range
      • Unclear if nephrotic versus mixed nephritic-nephrotic (e.g. macroscopic haematuria, intravascular fluid overload with hypertension, renal impairment)
      • Steroid resistance (Failure to achieve remission despite 4 weeks of prednisolone)

      Treatment for INS

      1. Admit to hospital on first presentation.
      2. Manage the oedematous state
        1. No added salt diet
        2. Daily weights, daily urine dipstick
        3. Strict fluid balance with close attention to volume status
          •  Discuss with nephrology if severe, difficult to control oedema
        4. Intravenous 20% albumin (with Frusemide)
          1.  There are 2 indications (see above for details)
            1.  Intravascular volume depletion
            2.  Severe or symptomatic oedema
          2.  It should only be given in consultation with the treating consultant, and ideally in daytime hours (risk of hypertension and pulmonary oedema), unless severe oedema or depletion – very rarely indicated. 
          3. 20% albumin 5ml/kg (1g/kg) over 4-6hrs IV.
            1.  Give frusemide 1mg/kg (max 40mg) mid infusion
            2. If giving for severe/symptomatic oedema, repeat frusemide 1mg/kg (max 40mg) at end of infusion, unless already has had brisk diuresis or signs of peripheral hypoperfusion
            3. Larger doses of frusemide are sometimes given if poor response
        1. Prophylaxis against complications
          • Oral penicillin V (phenoxymethylpenicillin) at a prophylactic dose 125mg/dose 12 hrly if under 5 years, or 250mg/dose 12hrly if over 5 years. Phenoxymethylpenicillin is to continue until oedema subsides.
            •  i.    If the child is profoundly ill or appears to have sepsis use IV Ceftriaxone 50 mg/kg/dose 24 hrly (max 2g)
          • Ranitidine 2-4mg/kg/dose 12 hrly (max 150mg per dose) or a proton pump inhibitor as prophylaxis for prednisolone induced gastritis  
        2. Prednisolone: to induce remission, followed by a slow wean to reduce risk of relapse. Consult with paediatric nephrology if remission not achieved after 4 weeks of prednisolone.
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          • 60 mg/m2/day (max 80 mg) for 4 weeks
          • then 40 mg/m2/on alternate days (max 60mg) for 4 weeks
          • then  20 mg/m2/on alternate days for 10 days
          • then  10 mg/m2/on alternate days for 10 days
          • then  5 mg/m2/on alternate days for 10 days
          • then cease

        1. Family Education
          1. The family should be taught to test urine protein each morning
            1. These can be documented in the booklets produced by the nephrology department, which also contain information on INS. Printable forms for documentation are available here:
              NEPH DEPT BOOKLET (PDF)
              DIARY FOR ENTERING PROTEIN LEVEL
          2. After remission, the urine protein should still be checked and documented daily (for at least 1-2 years), in order to identify a relapse (defined as 3+ or 4+ protein for 3 consecutive days), at which point the family should contact their treating clinician
            1. This allows for re-institution of prednisolone prior to the onset of oedema, thus avoiding the associated consequences (admission, risk of sepsis, thrombosis).
            2. Weight should also be checked daily while nephrotic (as a sign of fluid accumulation).
          3.  It is important to convey that, though their child will likely respond to therapy, they will likely have relapses (80% chance)
          4.  The most common relapse trigger is intercurrent infection. In patients on weaning or maintenance alternate day prednisolone, the risk of relapse can be reduced by temporarily increasing the dose from alternate to every day for 3-5 days.

        Treatment of relapses

        • A relapse is defined as proteinuria 3+ or 4+ for 3 consecutive days, and should prompt re-introduction of full dose prednisolone:
          •  Prednisolone 60 mg/m2 per day until urine protein is 0, trace or + for 3 consecutive days.
            • Then weaning regimen:
              • 40 mg/m2 alternate day for 2 weeks.
              • 20 mg/m2 alternate day for 2 weeks.
              • 15 mg/m2 alternate day for 2 weeks.
              • 10 mg/m2 alternate day for 2 weeks.
              • 5 mg/m2 alternate day for 2 weeks.
          • The total time of weaning regimen can be shortened if the patient relapses infrequently (2 – 3 relapses in any 12 month period) and responds to treatment quickly
          • If oedema recurs, penicillin prophylaxis should also be restarted.

          Additional issues with relapsing or steroid dependant disease

          • Increased infection
            • Children with relapsing or persistent nephrotic syndrome qualify for the additional booster Prevenar® (pneumococcal conjugate vaccine), and the Pneumovax® (23-valent pneumococcal polysaccharide vaccine), timing as per schedule.
          • Vitamin D deficiency (loss in urine)
          • Hyperlipidaemia
          • Hypothyroidism (loss in urine)
          • Bone density and eye examination for cataracts should be monitored in patients on prolonged maintenance steroid therapy.
            • Consider if >12m continuous therapy

          Ongoing reasons for referral to nephrology

          • Frequent relapses (2 or more in first 6 months or 4 or more in any 12 month period)
          • Steroid dependant (relapses while taking steroids – or within 2 weeks of cessation)
          • Steroid toxicity prompting consideration of alternative agent. 

            For emergency advice and paediatric or neonatal ICU transfers, call the Paediatric Infant Perinatal Emergency Retrieval (PIPER) Service: 1300 137 650.

          Parent information sheet: Nephrotic Syndrome booklet

          Information Specific to RCH – Including who to consult for inpatients.

          Specimen collection and results