What is the diagnostic workup for primary Focal Segmental Glomerulosclerosis (FSGS)?

Diagnostic Workup for Primary Focal Segmental Glomerulosclerosis (FSGS)

A thorough evaluation to exclude secondary forms of FSGS is essential before diagnosing primary FSGS, as this distinction significantly impacts treatment decisions and patient outcomes. 1

Initial Classification Approach

Primary FSGS should be distinguished from secondary causes through a systematic approach:

Clinical Presentation Assessment

• Nephrotic syndrome features:
  • Proteinuria ≥3.5 g/day
  • Serum albumin <3.0 g/dL
  • Edema
  • Hyperlipidemia 1

Laboratory Evaluation

1. Quantitative proteinuria measurement:

   • 24-hour urine collection or spot urine protein-to-creatinine ratio (UPCR)

2. Basic laboratory tests:

   • Complete blood count
   • Serum creatinine and electrolytes (sodium, potassium)
   • Serum albumin
   • Lipid profile
   • Urinalysis (for hematuria, lipiduria, cellular elements) 1, 2

3. Serological testing to exclude secondary causes:

   • Hepatitis B and C serology
   • HIV testing
   • Antinuclear antibody (ANA)
   • Complement levels (C3, C4)
   • Anti-PLA2R antibodies (to exclude membranous nephropathy)

Kidney Biopsy Evaluation

Kidney biopsy is crucial for diagnosis and should include:

1. Light microscopy: Identify FSGS lesion pattern (collapsing, tip, cellular, perihilar, or NOS variants)

2. Electron microscopy: Critical for distinguishing primary from secondary FSGS

   • Primary FSGS: Diffuse foot process effacement (≥80%, mean 96%)
   • Secondary FSGS: Segmental foot process effacement (typically 20-60%, mean 48%) 3

3. Immunofluorescence: Usually negative or showing non-specific IgM and C3 in sclerotic areas

Genetic Testing

• Indicated for:

  • Patients with familial kidney disease
  • Syndromic features
  • Steroid-resistant FSGS
  • Early-onset disease 1

• Benefits of genetic testing:

  • Identifies patients unlikely to respond to immunosuppression
  • Predicts risk of recurrence post-transplantation
  • Enables family screening
  • May guide enrollment in clinical trials 1

Imaging Studies

• Renal ultrasound to assess kidney size and rule out structural abnormalities

Classification of FSGS

Based on the 2021 KDIGO guidelines, FSGS should be classified into four categories:

1. Primary FSGS: Immunologically mediated, responsive to immunosuppression
2. Genetic FSGS: Associated with genetic mutations
3. Secondary FSGS: Due to viral injury, medications, or adaptive changes
4. FSGS of undetermined cause (FSGS-UC) 1

Clinical Pearls and Pitfalls

Key Diagnostic Clues for Primary FSGS

• Nephrotic-range proteinuria (>3.5 g/day)
• Hypoalbuminemia (<3.0 g/dL)
• Diffuse foot process effacement on electron microscopy (≥80%)
• Absence of secondary causes 3

Key Diagnostic Clues for Secondary FSGS

• Non-nephrotic proteinuria or nephrotic proteinuria with albumin >3.0 g/dL
• Segmental foot process effacement on electron microscopy (20-60%)
• Presence of risk factors (obesity, reduced nephron mass, viral infections, medications) 1, 3

Common Pitfalls

• Failure to distinguish between primary and secondary FSGS leads to unnecessary immunosuppressive treatment
• Overlooking genetic causes in patients with atypical presentations
• Not considering history of prematurity as a potential etiology for secondary FSGS due to reduced nephron number 1

By following this systematic diagnostic approach, clinicians can accurately identify primary FSGS and distinguish it from secondary forms, leading to appropriate treatment decisions and improved patient outcomes.