What is the recommended approach for managing adult onset nephrotic syndrome, including the role of renal biopsy and subsequent treatment options?

Renal Biopsy for Adult-Onset Nephrotic Syndrome

In adults with nephrotic syndrome, renal biopsy is strongly recommended before initiating immunosuppressive therapy to establish the specific histologic diagnosis, guide treatment selection, and predict prognosis—except in cases where serum anti-phospholipase A2 receptor antibodies are positive, which is diagnostic of membranous nephropathy. 1, 2

When Renal Biopsy is Indicated

Perform kidney biopsy in the following scenarios:

• All adults ≥12 years presenting with nephrotic syndrome (proteinuria ≥3.5 g/24 hours, hypoalbuminemia <3.0 g/dL, edema) to determine the underlying cause 1, 2

• Exception: Positive anti-PLA2R antibodies - biopsy may be deferred as this is diagnostic of membranous nephropathy 1, 2

• Steroid-resistant cases in children - if initial glucocorticoid trial fails, biopsy becomes necessary 1, 2

• Atypical presentations including:

  • Non-nephrotic range proteinuria (<3.5 g/day) with hypoalbuminemia 1
  • Nephrotic-range proteinuria but serum albumin >3.0 g/dL 1
  • Severe hypertension or diminished renal function at presentation 3
  • Age >60 years with acute renal failure 3

Why Biopsy Matters for Outcomes

The histologic diagnosis fundamentally changes management and predicts long-term outcomes:

• Focal segmental glomerulosclerosis (FSGS) requires classification into primary, genetic, secondary, or undetermined cause—each with distinct treatment approaches 1

• Membranous nephropathy carries higher venous thromboembolism risk (especially when albumin <2.9 g/dL) requiring consideration of prophylactic anticoagulation 1, 2

• Minimal change disease in adults responds to corticosteroids in 81% of cases by 16 weeks, but the time-course differs from children 3

• Secondary causes (diabetes, amyloidosis, lupus, malignancies, infections) require treatment of the underlying disease rather than immunosuppression 2, 4

Pre-Biopsy Evaluation

Complete the following workup before proceeding to biopsy:

• Confirm nephrotic syndrome: 24-hour urine protein or UPCR, serum albumin (note assay type: BCG vs BCP), lipid profile 1

• Screen for secondary causes:

  • Fasting glucose and HbA1c (diabetic nephropathy) 4
  • ANA, complement levels (C3, C4) if lupus suspected 1
  • Hepatitis B and C serologies 1
  • HIV testing in high-risk populations 1
  • Serum and urine protein electrophoresis (amyloidosis/myeloma) 4
  • Anti-PLA2R antibodies (membranous nephropathy) 1, 2

• Renal ultrasound: Assess kidney size and echogenicity before biopsy 1

• Genetic testing consideration: Family history of kidney disease, syndromic features, or steroid-resistant FSGS 1

Biopsy Timing and Technical Requirements

Optimal biopsy approach:

• Perform within the first month after nephrotic syndrome onset, preferably before starting immunosuppressive treatment 5

• Adequate sample: ≥8 glomeruli for light microscopy with H&E, PAS, Masson's trichrome, and silver stain 5

• Immunofluorescence required: IgG, C3, IgA, IgM, C1q, κ and λ light chains 5

• Electron microscopy recommended: Facilitates recognition of proliferative and membranous lesions 5

When to Consider Empiric Treatment Without Biopsy

The pediatric approach (empiric steroids) is NOT recommended for adults, despite older data suggesting equivalence:

• A 1982 decision analysis suggested empiric corticosteroids in adults yielded similar remissions with fewer complications than routine biopsy 6

• However, current guidelines strongly favor biopsy in adults because:

  • Adult nephrotic syndrome has more diverse etiologies than children 2, 4
  • FSGS and membranous nephropathy (most common in adults) have different treatment algorithms than minimal change disease 2, 7
  • Secondary causes are far more prevalent in adults and require disease-specific therapy 4, 7

The only scenario for empiric treatment in adults:

• Children <12 years: Initial glucocorticoid trial (prednisone 60 mg/day for 8 weeks with taper) without biopsy is appropriate, as minimal change disease accounts for the majority of cases 1, 2, 3

Special Considerations for Advanced CKD

Biopsy decisions when GFR <30 mL/min/1.73 m²:

• Proceed with biopsy if: Kidney size >9 cm length AND evidence of active disease (proteinuria, active urinary sediment with dysmorphic RBCs, WBCs, or cellular casts) 5, 8

• Avoid biopsy if: Small kidneys suggesting chronic irreversible disease without active features 8

• GFR thresholds are not absolute contraindications - clinical context determines safety and utility 8

Common Pitfalls to Avoid

• Delaying biopsy for empiric steroid trial in adults - this approach lacks current guideline support and delays definitive diagnosis 1, 2

• Assuming all nephrotic syndrome in adults is minimal change disease - FSGS and membranous nephropathy are actually more common 2, 7

• Failing to check anti-PLA2R antibodies - positive results can spare patients an invasive biopsy 1, 2

• Overlooking secondary causes - diabetes is the most common secondary cause in adults and requires different management 2, 4, 7

• Starting immunosuppression before biopsy in non-urgent cases - histologic changes may be obscured by treatment 5

• Using GFR alone to exclude biopsy candidacy - active disease with normal kidney size warrants biopsy even with reduced GFR 5, 8