Nephrotic Syndrome


  • Edema
  • Foamy urine
  • Weight gain
  • Fatigue
  • Blood clots (hypercoagualability due to antithrombin III loss in urine)


  • Insidious onset
  • Relatively normal blood pressure
  • Heavy proteinuria (4+ on dipstick, or ≥3.5 g/day on 24-hour urine collection)
  • Decreased serum albumin level
  • +/- hematuria
  • Negative RBC casts


  • Classic triad
    1. Protein excretion ≥ 3.5 g/24h
      • Order a 24-hour urine protein measurement
      • Random urine protein-to-creatinine ratio of ≥ 3.5 is a close surrogate
    2. Hypoalbuminemia (<3.5 g/dL)
    3. Peripheral edema

Differential Diagnosis/Work-Up

Primary Nephrotic Syndrome

  • Minimal Change Disease
    • Generally idiopathic, but associated with Hodgkin Lymphoma, NSAIDs
    • Normal complement levels
  • Focal Segmental Glomerulosclerosis (FSGS)
    • Associated with HIV, heroin use, African-Americans, Hispanics
  • Membranous Glomerulonephritis
    • Associated with HBV, SLE, adenocarcinomas
    • Generally a normal C3, C4
    • Associated with anti-phospholipase-A2-receptor antibodies (Anti-PLA2-R Ab)
    • Management:
      • First 6 months (if no kidney failure, anasarca, or deep vein thrombosis), treat conservatively (ACEIs, ARBs), statins (if cholesterol is above goal), and diuretics (for edema). Many will spontaneously go into remission
      • 6 to 12 months: If proteinuria increases, consider a course of immunosuppression (alternating glucocorticoids and alkylating agents)
  • Membranoproliferative Glomerulonephritis (MPGN)
    • Associated with HBV, HCV
    • Low C3, C4

Secondary Nephrotic Syndrome

  • Infection
    • HIV, CMV, HBV, HCV, endocarditis
    • Can test viral serologies, TTE/TEE if enough suspicion for endocarditis
  • Drugs
    • Interferon, Pamidronate, NSAIDs, Captopril, Lithium, gold, mercury, penicillamine, venoms
    • Based on history and medical record review
  • Other
    • Diabetic Nephropathy
      • Blood glucose, Hemoglobin A1c
    • Amyloidosis
      • SPEP, UPEP, serum free light chains, serum protein immunofixation
    • Pregnancy
      • Pregnancy test
    • Alport Syndrome
      • History (deafness), family history +/- genetic testing
    • Lupus
      • ANA, anti-dsDNA, Smith Antibody
    • Leukemia
      • CBC with diff, flow cytometry

Work-Up, summarized

First and foremost, these patients generally need a nephrology consult and usually a renal biopsy. The following labs can be obtained in the meantime to help guide the diagnosis ahead of time:

  • Generally obtain:
    • CBC with differentiation
    • CMP
    • C3, C4
    • HBV serologies
    • HCV antibody
    • HIV testing
    • Anti-phospholipase-A2-receptor Antibody (Anti-PLA2-R Ab)
    • Hemoglobin A1c
    • ANA
    • Anti-dsDNA Antibody
    • Smith Antibody
    • SPEP
    • UPEP
    • Serum FLC
    • Serum Protein Immunofixation
  • Consider obtaining based on clinical scenario:
    • Beta-hCG
    • CMV serology
    • TTE/TEE
    • Flow cytometry
    • Genetic testing

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