What is lupus nephritis and what are the indications for renal biopsy in patients with systemic lupus erythematosus?

What is Lupus Nephritis and Indications for Renal Biopsy

Definition of Lupus Nephritis

Lupus nephritis is immune complex-mediated glomerulonephritis occurring in patients with systemic lupus erythematosus (SLE), characterized by proteinuria, active urinary sediment, and/or declining kidney function. 1

The American College of Rheumatology defines lupus nephritis by the following clinical criteria 1:

• Persistent proteinuria >0.5 g/24 hours (or spot urine protein/creatinine ratio >0.5)
• Active urinary sediment (>5 RBC/hpf, >5 WBC/hpf without infection, or cellular casts including red cell, hemoglobin, granular, tubular, or mixed casts)
• Unexplained decline in glomerular filtration rate

The lifetime incidence of lupus nephritis among SLE patients ranges from 20-60%, varying by race and ethnicity, with higher rates in Asian, African/Caribbean, and Hispanic populations. 1 Childhood-onset SLE carries particularly high risk for severe lupus nephritis. 1

Indications for Renal Biopsy

Absolute Indications

All patients with clinical evidence of active lupus nephritis who are previously untreated should undergo renal biopsy unless strongly contraindicated. 1

Specific clinical scenarios requiring biopsy include 1, 2:

• Proteinuria ≥0.5 g/24 hours (or UPCR ≥500 mg/g), especially with glomerular hematuria and/or cellular casts
• Unexplained decrease in GFR with no alternative cause
• Proteinuria ≥1.0 g/24 hours confirmed on repeat testing
• Proteinuria ≥0.5 g/24 hours plus hematuria or cellular casts

Critical Nuance: Low-Level Proteinuria

Do not dismiss low-grade proteinuria—patients with proteinuria <500 mg/24 hours can harbor severe Class III/IV lupus nephritis requiring aggressive immunosuppression. 3, 4 A 2020 study found that 76% of SLE patients with isolated proteinuria below 1000 mg/24 hours had histologic lupus nephritis, including 14 patients with Class III/IV disease. 4 Another 2023 study confirmed that 20% of patients with Class III/IV lupus nephritis presented with proteinuria below 0.5 g/24 hours. 3

Why Biopsy is Indispensable

Clinical, serological, and laboratory parameters cannot accurately predict renal biopsy findings—biopsy remains the only definitive diagnostic tool. 1, 2 The biopsy serves multiple essential purposes 1:

• Classification: Determines ISN/RPS class (I-VI), which directly dictates treatment intensity
• Activity vs. Chronicity: Distinguishes reversible inflammatory lesions from irreversible fibrosis, guiding immunosuppression decisions
• Alternative diagnoses: Identifies non-lupus pathology (focal segmental glomerulosclerosis, acute interstitial nephritis, thrombotic microangiopathy) present in 11.5% of suspected lupus nephritis cases 3
• Prognosis: Activity and chronicity indices predict treatment response and long-term kidney outcomes 1, 5

Technical Requirements for Adequate Biopsy

The biopsy must include 1, 2:

• Minimum 10 glomeruli for light microscopy evaluation
• Light microscopy with H&E, PAS, Masson's trichrome, and silver stains
• Immunofluorescence for IgG, IgA, IgM, C3, C1q, and κ/λ light chains
• Electron microscopy to determine location of immune deposits and assess podocyte injury

When NOT to Delay Biopsy

Even with advanced kidney dysfunction (GFR <30 mL/min), biopsy should proceed if kidney size is normal and there is evidence of active disease. 2 The presence of chronic kidney disease does not preclude biopsy if acute-on-chronic deterioration is suspected. 1

Treatment Implications Based on Biopsy Classification

The ISN/RPS classification directly determines management 1, 2:

• Class I-II: Generally no immunosuppression required
• Class III (focal proliferative, <50% glomeruli) and IV (diffuse proliferative, ≥50% glomeruli): Require aggressive therapy with glucocorticoids plus mycophenolate mofetil or cyclophosphamide 1
• Class V (membranous): When combined with III/IV, treat as proliferative disease; pure Class V with nephrotic-range proteinuria requires immunosuppression 1
• Class VI (≥90% glomerular sclerosis): Prepare for renal replacement therapy rather than immunosuppression 1

Common Pitfalls to Avoid

• Do not wait for proteinuria to exceed arbitrary thresholds—significant lupus nephritis can exist with minimal proteinuria 3, 4
• Do not rely on serologies alone—anti-dsDNA and complement levels do not reliably predict biopsy findings 4
• Do not delay biopsy for advanced age or reduced GFR if kidneys are normal size and active disease is suspected 2
• Do not assume all urinary abnormalities in SLE represent lupus nephritis—11.5% have alternative diagnoses requiring different management 3