Nephrotic Syndrome

Symptoms

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

Features

• 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
• Positive fatty casts

Diagnosis

• 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
• Hypoalbuminemia (<3.5 g/dL)
• Peripheral edema
• Hyperlipidemia

Differential Diagnosis/Work-Up

Primary Nephrotic Syndrome

• Minimal Change Disease
  • Generally idiopathic, but associated with Hodgkin Lymphoma, NSAIDs
  • Normal complement levels
  • Generally very responsive to steroids, especially in the younger population
• Focal Segmental Glomerulosclerosis (FSGS)
  • Associated with HIV, heroin use, African-Americans, Hispanics
  • Normal complement levels
• Membranous Glomerulonephritis
  • Associated with HBV, SLE (Lupus Nephritis Class V), adenocarcinomas
  • Associated with anti-phospholipase-A2-receptor antibodies (Anti-PLA2-R Ab)
  • Normal complement levels
  • 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
  • May also present with nephritic syndrome

Secondary Nephrotic Syndrome

• Diabetic Nephropathy
  • Blood glucose, Hemoglobin A1c
  • “Kimmelstiel-Wilson” lesions on biopsy
• Amyloidosis
  • SPEP, UPEP, serum free light chains, serum protein immunofixation
  • “Apple-green birefringence” with Congo Red stain on polarized light microscopy of renal biopsy
  • See Plasma Cell Dyscrasias
• 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
• Pregnancy
  • Pregnancy test
• Alport Syndrome
  • History (deafness), family history +/- genetic testing
• 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
  • Hemoglobin A1c
  • SPEP
  • UPEP
  • Serum FLC
  • Serum Protein Immunofixation
  • HBV serologies
  • HCV antibody
  • HIV testing
  • Anti-phospholipase-A2-receptor Antibody (Anti-PLA2-R Ab)
  • ANA (with Anti-dsDNA Antibody and Smith Antibody if positive)
• Consider obtaining based on clinical scenario:
  • Beta-hCG
  • CMV serology
  • TTE/TEE
  • Flow cytometry
  • Genetic testing