IDIOPATHIC NEPHROTIC SYNDROME
 
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IDIOPATHIC NEPHROTIC SYNDROME

 

DEFINITION:

A syndrome characterized by proteinuria, hypoalbuminemia, edema, and hyperlipidemia.

EPIDEMIOLOGY:

  • incidence: accounts for 90% of nephrosis in childhood
  • age of onset:
    • most common between 2-6 years
  • risk factors:
    • M > F (2:1)
    • not hereditary

PATHOGENESIS:

1. Pathology

1. Major types (90%)

  • most common in children between ages 1-8 years

1. Minimal-Change (85%)

  • LM - glomeruli are normal or show a minimal increase in mesangial cells and matrix
  • EM - retraction of epithelial foot processes
  • IFM - negative

2. Focal Sclerosis (10%)

  • LM - glomeruli
    • most normal or have mesangial proliferation
    • others show segmental scarring in one or more lobules
    • eventually all glomeruli involved

3. Mesangial Proliferative (5%)

  • LM - diffuse increase in mesangial cells & matrix
  • IFM - negative

2. Minor types (10%)

  • more common in children greater than 8 years
  • membranous and membranoproliferative GN

2. Proteinuria

  • due to an increase in glomerular capillary wall permeability perhaps due to a loss of negatively-charged glycoproteins within the capillary wall or an abnormality in T-cell function which results in a factor that increases vascular permeability -> proteinuria

3. Edema

  • appears when albumin less than 25 g/L -> decreased oncotic pressure -> transudation of fluid to interstitial space -> decreases intravascular volume -> increased reabsorption of salt and water via the renin-angiotensin-aldosterone system and ADH, respectively

4. Hyperlipidemia

  • elevated serum lipids (cholesterol and triglycerides) and lipoprotein levels via:
    • hypoalbuminemia -> generalized decrease in hepatic protein synthesis -> reduced levels of lipoprotein lipase -> diminished lipid catabolism

CLINICAL FEATURES:

1. Prodrome

  • initial episode and subsequent relapses may follow an upper respiratory tract infection

2. Renal Manifestations

1. Proteinuria

  • symptomatic
  • pitting edema
    • usual initial feature
    • eyes, lower extremities -> generalized -> ascites, pleural effusion -> weight gain with decreased urine output
    • fluid accumulates in dependent areas and may shift from face & back to abdomen, perineum, and legs as the day progresses
  • hypertension uncommon

3. Other Manifestations

  • abdominal pain, anorexia, diarrhea

4. Complications

1. Infections

  • increased susceptibility to bacterial infections during relapses
  • peritonitis most common infection
    • S. pneumoniae most common cause
    • also caused by gram negative bacteria
  • other infections include sepsis, pneumonia, cellulitis, UTI
  • s/s of infection may be minimal if on steroid therapy
  • all patients should receive a single injection of polyvalent pneumococcal vaccine while in remission

2. Arterial and Venous Thrombosis

  • due to an increase in:
    • certain coagulation factors
    • inhibitors of fibrinolysis
    • platelet aggregation
    • - (decreased antithrombin III)

3. Others

  • deficiencies of coagulation factors IX, XI, & XII
  • reduced levels of vitamin D

INVESTIGATIONS:

1. Urinalysis

  • proteinuria - 3+ to 4+
  • 24 hour protein excretion >40 mg/m2/hr
  • low creatinine clearance (due to decreased intravascular volume)
  • microscopic hematuria (gross hematuria rarely)

2. Serum

  • elevated serum cholesterol and triglyceride levels
  • albumin usually <20 g/L
  • decreased calcium (due to decreased albumin)
  • normal C3
  • normal or reduced renal function

3. Renal Biopsy

  • see Pathology

MANAGEMENT:

1. Edema

1. Mild-Moderate

  • salt-free diet
  • chlorothiazide 10-40 mg/kg/d po bid with KCl supplement or
  • spironolactone 3-5 mg/kg/d po qid

2. Severe

  • salt-free diet
  • fluid restriction
  • elevate swollen scrotum with pillows
  • lasix 1-2 mg/kg/d po qid and
  • metolazone 0.2-0.4 mg/kg/d po bid
  • 25% albumin 1 gm/kg/d IV

2. Proteinuria

1. Prednisone

1. Initial Therapy

  • 60 mg/m2/d po tid (max. dose of 60 mg/d) for 4-6 weeks
  • response time:
    • 50% of cases respond within 8 days
    • 80% of cases respond within 1 month - (a majority respond within 2 weeks)
  • treatment goals:
    • protein-free urine for 5 consecutive days
    • normalization of albumin (complete remission)
  • steroid-responsive:
    • 95% of those with minimal-change
    • 55% of those with mesangial proliferative
    • 20% of those with focal sclerosis

2. 'Weaning' Therapy

  • 60 mg/m2/d po od on alternate days for
    • 4 weeks (standard protocol)
    • 6 weeks (long protocol)
  • begin once complete remission achieved
  • long protocol may decrease the number of subsequent relapses per year from 60% (standard) to 30% - patient may need corticosteroid supplementation for severe illness or surgery for up to 1 year after com-pleting prednisone therapy
  • treatment goal:
    • avoidance of relapse

3. Relapse Therapy

  • 60 mg/m2/d po tid until proteinuria resolves for 3 consecutive days then 40 mg/m2/d po alt day for 4 weeks - 60% will experience at least one relapse:
    • 1/3 of these will have infrequent relapses
    • 2/3 of these will have frequent relapses; (2 in the 1st month or 4 in 1 year)
  • frequent relapsers usually remain steroid-responsive
  • Steroid-resistant: persistent proteinuria (2+ or greater) after 1 month of continuous prednisone therapy - Steroid-dependent: relapse shortly after switching to or after terminating alternate-day therapy

2. Alternate Therapy

1. Alkylating Agents

  • cyclophosphamide, chlorambucil, nitrogen mustard
  • indications:
    • failure of steroid therapy
    • severe corticosteroid toxicity
    • repeated relapses
  • cyclophosphamide
    • 3 mg/kg/d po od for 8 weeks
    • may be given with alternate day steroid therapy
    • side effects:
      • leukopenia (monitor WBC count weekly & if <5,000, discontinue cyclophosphamide)
      • disseminated varicella infection
      • hemorrhagic cystitis
      • alopecia
      • sterility

3. Prognosis

  • majority with steroid-dependent variety will have repeated relapses until spontaneous resolution of the disease toward the end of the 2nd decade
  • relapse is defined as the recurrence of edema
  • response to 1 month steroid therapy:

1. Responders (78%)

  • 92% minimal-change
  • 8% other (3% of these will be focal sclerosis)

2. Nonresponders (22%)

  • 25% minimal-change
  • 25% focal sclerosis
  • 25% mesangial proliferative
  • 25% other
  • poor prognosticators
    • hematuria
    • hypertension
    • hypocomplementemia
    • focal sclerosis (usually progress to ESRD)

 

 

 

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