Description

Nephrotic syndrome (NS) is defined by nephrotic-range proteinuria, hypoalbuminemia, edema, and hypercholesterolemia. Nephrotic-range proteinuria is typically found when there is 3 to 4+ protein on the urine dipstick and is defined as >40 mg/m²/h or a spot protein-to-creatinine ratio >2 mg protein/mg creatinine.

Epidemiology

• Minimal change nephrotic syndrome (MCNS) is the most frequent cause of NS in younger children:
  • Occurs mainly between 2 and 8 years of age, with a peak at 3 years
  • Boys are more commonly affected than girls (3:2).
• Focal segmental glomerulosclerosis (FSGS) is the 2nd most frequent cause of NS in childhood:
  • Children with FSGS are more likely than children with MCNS to have steroid-resistant nephrotic syndrome (SRNS).
• Less common than MCNS and FSGS are congenital NS (<3 months) and infantile NS (3 to 12 months).

Pathophysiology

• Disruption of podocyte architecture composing the glomerular filtration barrier leads to proteinuria, hypoalbuminemia, and subsequently edema.
• Hypercholesterolemia occurs due to increased liver production of cholesterol in response to hypoalbuminemia as well as to loss of lipoprotein lipase in urine.
• MCNS pathology
  • Minimal histologic changes on light microscopy
  • The glomerular tuft size is normal.
  • Mesangial expansion is absent or minimal.
  • Immunofluorescence is usually negative, although mild staining for C3, IgM, and IgA may occasionally be found.
  • Electron microscopy reveals diffuse effacement of the podocyte foot processes.

Etiology

• Most pediatric cases are primary; 5–10% are secondary to other diseases.
• The most common primary cause of NS in childhood is MCNS.
• Other causes of primary NS include FSGS, membranous nephropathy, and membranoproliferative glomerulonephritis (GN).
• Secondary causes of NS include infections, vasculitis, diabetes, drugs (e.g., NSAIDs), and hereditary disorders.
• Examples of congenital NS include Finnish type caused by NPHS1 mutations, diffuse mesangial sclerosis (DMS), and infections (toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, HIV, syphilis).
• NS can be caused by inherited mutations in proteins involved in the podocyte cytoskeleton, which often results in SRNS and FSGS (up to 20–30% of SRNS).

Commonly Associated Conditions

• Atopy and MCNS have an association.
• Syndromes associated with NS include Denys-Drash, nail-patella, Lowe, Galloway-Mowat, Frasier, and Pierson.