Nephrotic Syndrome

Descriptive text is not available for this imageBASICS

DESCRIPTION

Nephrotic syndrome (NS) is characterized by the following:

  • Edema
  • Nephrotic range proteinuria (typically 3 to 4+ protein on the urine dipstick/urinalysis with spot urine protein-to-creatinine ratio ≥2 mg/mg or >40 mg/m2/h on a 24-hour urine sample)
  • Hypoalbuminemia
  • Hyperlipidemia

EPIDEMIOLOGY

  • Minimal change NS (MCNS) is the most frequent cause of NS in younger children:
    • Occurs mainly between 2 and 7 years of age, with a peak at 2.5 years old
    • In children <13 years old, boys are more commonly affected than girls (2 to 3.8:1).
  • Focal segmental glomerulosclerosis (FSGS) is the second most frequent cause of NS in childhood:
    • Children with FSGS are more likely than children with MCNS to have steroid-resistant NS (SRNS).
  • Less common than MCNS and FSGS is congenital NS (<3 months) and infantile NS (3 to 12 months).
  • Annual incidence 2 to 7 new cases of NS per 100,000 children
  • Prevalence is 16 cases per 100,000 children.

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 and membranous nephropathy.
  • SRNS and/or FSGS can be caused by inherited gene mutations in approximately 15% of cases. >60 genes have been identified to cause SRNS; most affect the podocyte.
  • Secondary causes of NS include infections, vasculitis, systemic lupus erythematosus (SLE), diabetes, drugs (e.g., NSAIDs), and hereditary disorders.
  • Congenital and infantile NS (presenting age <1 year old) are most often caused by genetic diseases.
    • The top 5 gene defects are LAMB2 (Pierson’s syndrome), NPHS1 (Finnish type congenital NS), NPHS2, PLCE1, and WT1 (Denys-Drash).
    • All are inherited in autosomal recessive fashion except for WT1 which is autosomal dominant
    • Histopathology of CNS includes diffuse mesangial sclerosis (DMS).
  • Congenital NS can also be caused by infections (toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, HIV, syphilis).

PATHOPHYSIOLOGY

  • NS occurs due to disruption of the glomerular filtration barrier (composed of podocytes, glomerular basement membrane, and fenestrated endothelial cells), which leads to proteinuria and low serum albumin.
  • Edema may result from either underfill or overfill.
    • Overfill: Albuminuria activates the kidney transporters responsible for sodium reabsorption, leading to sodium and water retention and edema.
    • Underfill: Low oncotic pressure from hypoalbuminemia leads to leakage of fluid into the interstitium and secondary fluid and sodium retention by the kidney, leading to edema.
    • Hypotension and low urine fractional excretion of sodium suggest underfill since they are intravascularly depleted.
    • Hypertension suggests overfill given their increased sodium and thereby water retention.
  • Hyperlipidemia occurs due to increased production, decreased metabolism, and decreased clearance of lipids.
  • Pathophysiology of MCNS is not fully understood but CD80 (B7-1), regulatory T-cell (Treg) dysfunction, and circulating factors such as cytokines and/or antibodies to nephrin may contribute.

COMMONLY ASSOCIATED CONDITIONS

  • Atopy and MCNS have an association.
  • Syndromes associated with NS include Denys-Drash, Frasier, (WT mutations), nail-patella (LMX1B mutations), Galloway-Mowat, and Pierson (LAMB2 mutations).

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