Nephrotic Syndrome

Snapshot

A 6-year-old boy is brought to the emergency department by his mother due to swelling around his eyes and legs. The mother reports that the patient recently recovered from an upper respiratory tract infection. Physical exam is significant for periorbital and lower extremity edema. Laboratory testing is significant for hypoalbuminemia and normal complement levels. Urinalysis demonstrates 4+ protein. A presumptive diagnosis of minimal change disease is made and the patient is started on steroid therapy.

Introduction

Clinical definition
- a type of kidney disease that results in proteinuria, peripheral edema, hyperlipidemia, and hypoalbuminemia
Epidemiology
- incidence
  - annually there are 3 cases per 100,000 adults
Etiology
- primary glomerular disease
  - focal segmental glomerulosclerosis
  - membranous nephropathy
  - minimal change disease
- secondary causes
  - diabetic nephropathy
  - systemic lupus erythematosus
  - amyloidosis
Pathogenesis
- the glomerulus becomes permeable to large molecules (e.g., albumin)
  - this loss of albumin (proteinuria) results in hypoalbuminemia and edema
  - associated with a hypercoagulable state
    - pathophysiology unclear but may be due to loss of antithrombin and plasminogen proteins
  - increased lipid synthesis secondary to proteinuria
    - this in turn results in hypercholesterolemia and hyperlipidemia
Associated conditions
- chronic kidney disease
Prognosis
- depends on the underlying cause
e.g., patients with minimal change disease typically respond well to steroid therapy

Presentation

Symptoms
- edema
  - periorbital, lower extremity, and genital edema
- frothy urine
- ascites
- weight gain
- fatigue
- shortness of breath
Physical exam
- hypertension
- edema
- leukonychia
suggestive of a low albumin state and presents as white streaking on the fingernails

Studies

Labs
- hypoalbuminemia (serum albumin of < 2.5 g/dL)
- hyperlipidemia
Urine studies
- proteinuria > 3-3.5 g/day
  - or > 300-350 mg/mmol on spot urine protein to creatinine ratio
fatty casts with “maltese cross” sign

Nephrotic Syndrome
Type	Pathophysiology	Renal Biopsy	Treatment and Notes
Focal segmental glomerulosclerosis	Podocyte injury or decreased glomerular filtration barrier integrity	Light microscopy segmental scarring	Treat underlying etiology in secondary causesSteroid therapyCan be secondary to HIVsickle cell diseaseheroin abuseinterferon treatment
Minimal change disease	Unclear but may be due to an immune-related mechanism	Light microscopynormal appearingElectron microscopyeffacement of the foot processes	Steroid therapyMost common in childrenMay follow recent infection, immunizations, or may be idiopathic
Membranous nephropathy	Antibody-immune complex depositionIgG antibodies target podocyte antigens or antigens in close proximity to the podocytesComplement-mediated podocyte injury	Light microscopyglomerular basement membrane thickeningImmunofluoresenceimmune complex deposition leading to granular appearanceElectron microscopy”spike and dome” subepithelial deposits	Immunosuppressive therapy in primary casessteroids and cyclophosphamideMost common cause of primary nephrotic syndrome in Caucasian adultsPrimary causesantibodies targeting phospholipase A2 receptors Secondary causesmedicationssystemic lupus erythematosusnonsteroidal anti-inflammatory drugsgoldpenicillaminehepatitis B and C infection
Amyloidosis	Amyloid deposits in the mesangium	Electron microscopy apple-green birefringence on Congo red stain under polarized light	Treatment involves addressing the plasma cell dyscrasia
Diabetic glomerulonephropathy	Glomerular hyperperfusion and hyperfiltration result in albumin leakingunder these conditions the glomerulus responds viaglomerular basement membrane thickeningdue to non-enzymetic glycosylationhypertrophysclerosingpodocyte injury	Light microscopy expansion of the mesangiumKimmelstiel-Wilson lesions	Angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) Adequately controlling diabetes

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