What are the diagnostic criteria for Lupus Nephritis in Systemic Lupus Erythematosus (SLE)?

Diagnostic Criteria for Lupus Nephritis in SLE

Lupus nephritis is diagnosed when a patient with SLE presents with persistent proteinuria >0.5 g/day (or spot urine protein/creatinine ratio >0.5) and/or active urinary sediment (>5 RBC/hpf, >5 WBC/hpf without infection, or cellular casts), with definitive diagnosis requiring kidney biopsy showing immune complex-mediated glomerulonephritis classified by ISN/RPS criteria. 1, 2

Clinical and Laboratory Criteria

The diagnostic approach begins with identifying clinical and laboratory abnormalities in patients with established or suspected SLE:

Urinary Abnormalities (ACR Criteria)

• Proteinuria: Persistent proteinuria >0.5 g/24 hours or dipstick ≥2+ 1, 2
• Alternative measurement: Spot urine protein/creatinine ratio >0.5 can substitute for 24-hour collection 1, 2
• Active urinary sediment: >5 RBC/hpf, >5 WBC/hpf (without infection), or presence of RBC casts, WBC casts, hemoglobin casts, granular casts, or tubular casts 1, 2
• Acanthocytes: ≥5% on urine microscopy 1

Renal Function Abnormalities

• Decreased or decreasing eGFR: Below expected level for age and clinical history with no attributable cause other than SLE 1
• Rising serum creatinine: Without compelling alternative explanation 2

Serologic Markers

• Anti-dsDNA antibodies: Present in most but not all cases; some patients with membranous lupus nephritis remain anti-dsDNA negative long-term 1
• Low complement levels: C3 and C4 typically decreased 1
• Anti-C1q antibodies: Found in nearly 100% of patients with active lupus nephritis, with critical negative predictive value 1

Critical caveat: ANA-negative or seronegative lupus nephritis exists and should not exclude the diagnosis when clinical suspicion is high and biopsy findings are compatible 3

Kidney Biopsy: The Gold Standard

All patients with clinical evidence of active lupus nephritis should undergo kidney biopsy unless strongly contraindicated. 1, 2

Indications for Biopsy (Highest Priority)

• Confirmed proteinuria ≥1.0 g/24 hours 2
• Proteinuria ≥0.5 g/24 hours plus hematuria or cellular casts 2
• Increasing serum creatinine without alternative explanation 2
• Any clinical evidence of active nephritis in previously untreated patients 1, 2

Biopsy Processing Requirements

• Light microscopy (LM): Minimum 10 glomeruli for adequate evaluation 2
• Immunofluorescence (IF): Essential for identifying immune complex deposition patterns 2, 4
• Electron microscopy (EM): Recommended where available for ultrastructural details and immune deposit localization 1, 2

Pathologic Features Diagnostic of Lupus Nephritis

The most specific pathologic findings include 4:

• "Full-house" staining: IgG, IgM, IgA, C3, and C1q on immunofluorescence (specificity 0.80-0.96) 4
• Intense C1q staining: Particularly characteristic 4
• Extraglomerular deposits: In tubular basement membranes or interstitium 4
• Combined subendothelial and subepithelial deposits: On electron microscopy 4
• Endothelial tubuloreticular inclusions: On electron microscopy 4

The presence of at least 2 of these 5 features has 92% sensitivity and 89% specificity; 3 features have 80% sensitivity and 95% specificity for lupus nephritis. 4

ISN/RPS Classification System

Biopsy must be classified according to ISN/RPS criteria (Classes I-VI), which directly guides treatment decisions 1, 2:

• Class I (Minimal mesangial): Mesangial immune deposits by IF/EM only
• Class II (Mesangial proliferative): Mesangial hypercellularity
• Class III (Focal): <50% of glomeruli with active or inactive lesions
• Class IV (Diffuse): ≥50% of glomeruli with active or inactive lesions
• Class V (Membranous): Subepithelial immune deposits
• Class VI (Advanced sclerosis): ≥90% globally sclerosed glomeruli

Biopsies should be read by experienced kidney pathologists and include assessment of both activity and chronicity indices to inform prognosis and treatment reversibility. 1, 2

Diagnostic Algorithm

1. Screen all SLE patients regularly for proteinuria (dipstick ≥2+) and abnormal urinary sediment 1
2. If positive screening: Quantify proteinuria with spot urine protein/creatinine ratio or 24-hour collection 1
3. If proteinuria ≥0.5 g/day or active sediment: Check serum creatinine, anti-dsDNA, complement levels, and anti-C1q 1
4. Proceed to kidney biopsy if proteinuria ≥0.5 g/day with hematuria/casts, or ≥1.0 g/day alone, or rising creatinine 1, 2
5. Ensure biopsy includes LM, IF, and EM (where available) with ISN/RPS classification 1, 2

Important pitfall: Clinical findings do not always correlate with severity of kidney involvement; proteinuria can appear "insignificant" even in severe active nephritis, requiring holistic assessment and serial monitoring. 1, 5