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• Nephrotic syndrome


  A syndrome of nephrotic range proteinuria, hypoalbuminemia, edema, and hyperlipidemia
• Introduction to a child with proteinuria

  1. Definition of nephrotic syndrome

  2. Etiology & Epidemiology

  3. Pathophysiology & pathology

  4. Clinical manifestation

  5. Diagnosis

  6. Treatment

  7. Complications & prognosis
• Proteinuria


  Clinically significant when urine protein dipstick >trace (10-29 mg/dL) in a urine sample with specific gravity <1.010, or ≥1+ if specific gravity >1.015
• Urine dipstick readings


  • Trace (10-20mg/dL)
  • +1 (30mg/dL)
  • +2 (100mg/dL)
  • +3 (300mg/dL)
  • [phone]mg/dL)
• Spot urine protein:creatinine ratio

  Suggests nephrotic range proteinuria if >2
• 24-hour urine collection


  Abnormal is 4-40mg/m2/hr, nephrotic range is >40mg/m2/hr
• Types of proteinuria


  • Transient
  • Orthostatic (postural)
  • Fixed (glomerular or tubular disorders)
• Nephrotic syndrome


  Nephrotic range proteinuria plus triad of hypoalbuminemia, edema, and hyperlipidemia
• Incidence of nephrotic syndrome

  • 2-3 cases/100,000 children per year in western countries, higher in underdeveloped countries due to malaria
  • Usually in age 2-6 years, some adults
  • 2:1 male to female ratio
• Etiologies of nephrotic syndrome


  • Primary (idiopathic)
  • Secondary to infections, malignancies, drugs, or immunologic causes
• Pathophysiology of nephrotic syndrome

  1. Increased permeability of glomerular capillary wall leads to massive proteinuria and hypoalbuminemia

  2. Immune system disturbances, especially T cell-mediated immunity

  3. Hypoalbuminemia causes decreased plasma oncotic pressure and fluid transudation

  4. Reduced intravascular volume activates renin-angiotensin-aldosterone system and antidiuretic hormone release

  5. Elevated serum lipids due to increased hepatic lipoprotein synthesis and decreased lipid catabolism
• Pathology of nephrotic syndrome

  • 90% of children have idiopathic nephrotic syndrome
  • Minimal change nephrotic syndrome (85% of cases) has normal or minimally increased glomeruli
  • Mesangial proliferation (50% respond to steroids)
  • Focal segmental glomerulosclerosis (20% respond to steroids)
• Clinical manifestations


  Mild edema initially around eyes and lower extremities, progressing to generalized edema with ascites, pleural effusions, and genital edema<|>Anorexia, irritability, abdominal pain, and diarrhea are common
• Differential diagnosis of marked edema

  • Protein-losing enteropathy
  • Hepatic failure
  • Heart failure
  • Acute or chronic glomerulonephritis
  • Protein malnutrition
• Indications for renal biopsy

  • Gross hematuria
  • Hypertension
  • Renal insufficiency
  • Hypocomplementemia
  • Age <1 yr or >8 yr
  • Steroid resistant nephrotic syndrome
• Treatment of nephrotic syndrome

  1. Outpatient management for first episode with mild to moderate edema

  2. Inpatient admission for severe symptomatic edema

  3. Prednisone 60 mg/m2/day for 4-6 weeks, then taper

  4. Salt restriction

  5. Fluid restriction for hyponatremia

  6. IV albumin and furosemide for severe edema

  7. Steroid resistant, dependent, or frequent relapsers may require alternate therapies
• Alternate therapies


  • Cyclophosphamide
  • Cyclosporine or tacrolimus
  • Mycophenolate
  • Levamisole
  • ACE inhibitors and angiotensin II blockers
• Complications of nephrotic syndrome

  • Infection (spontaneous bacterial peritonitis, sepsis, pneumonia, cellulitis, UTI)
  • Thromboembolic events (renal vein thrombosis, pulmonary embolus, sagittal sinus thrombosis, catheter thrombosis)
• Prognosis


  Steroid-responsive nephrotic syndrome unlikely to develop chronic kidney disease<|>Steroid-resistant nephrotic syndrome, often due to FSGS, has poor prognosis with progressive renal insufficiency and end-stage renal disease
• Causes of secondary nephrotic syndrome

  • Infections (hepatitis B/C, HIV, malaria, syphilis, toxoplasmosis)
  • Drugs (penicillamine, gold, NSAIDs, interferon, mercury, lithium, heroin)
  • Immunologic/allergic disorders (Castleman disease, Kimura disease, bee sting, food allergens)
  • Malignant diseases (lymphoma, leukemia)
  • Glomerular hyperfiltration (oligomeganephronia, morbid obesity, adaptation to nephron reduction)
• Congenital nephrotic syndrome


  Nephrotic syndrome manifesting at birth or within first 3 months of life<|>Can be primary or secondary to in-utero infections, infantile SLE, or mercury exposure<|>Primary congenital nephrotic syndrome due to mutations in genes encoding components of the glomerular filtration barrier (NPHS1, NPHS2, WT1, LAMB2)
• The Finnish type of congenital nephrotic syndrome is caused by mutations in the NPHS1 or NPHS2 genes, encoding nephrin and podocin
• Denys-Drash syndrome is caused by mutations in the WT1 gene, resulting in abnormal podocyte function, early-onset nephrotic syndrome, progressive renal insufficiency, ambiguous genitalia, and Wilms' tumors
• Pierson syndrome is caused by mutation in the LAMB2 gene, leading to abnormalities of β2 laminin and presenting with congenital nephrotic syndrome and bilateral microcoria (fixed narrowing of the pupil)