How to differentiate between persistent Class V Lupus Nephritis (LN) and Chronic Kidney Disease (CKD) causing persistent proteinuria on a renal biopsy?

Distinguishing Persistent Class V Lupus Nephritis from CKD-Related Proteinuria on Renal Biopsy

A repeat kidney biopsy is the definitive method to distinguish between persistent active Class V lupus nephritis and chronic kidney disease causing proteinuria, as it directly assesses for ongoing inflammatory activity versus irreversible scarring. 1

Key Histologic Features to Differentiate Active LN from CKD

Evidence of Active Lupus Nephritis (Class V)

• Immune complex deposits: Look for subepithelial, mesangial, or subendothelial immune deposits on immunofluorescence (IgG, IgA, IgM, C3, C1q in "full house" pattern) 1
• Active glomerular lesions: Presence of endocapillary hypercellularity, wire loop deposits, cellular crescents, or fibrinoid necrosis indicates ongoing inflammatory activity 1
• Tubulointerstitial inflammation: Active interstitial infiltrates with lymphocytes and plasma cells suggest active disease rather than chronic scarring 1
• Absence of significant chronicity: Minimal glomerulosclerosis, interstitial fibrosis, or tubular atrophy 1

Evidence of Chronic Kidney Disease (Scarring)

• Glomerulosclerosis: Global or segmental sclerosis without active inflammatory changes 1
• Interstitial fibrosis and tubular atrophy (IFTA): Extensive fibrosis indicates irreversible damage 1
• Vascular sclerosis: Arteriosclerosis and arteriolosclerosis without active vasculitis 2
• Absence of immune deposits: Minimal or no immune complex deposition on immunofluorescence suggests "burned out" disease 1
• High chronicity index: Scoring systems that quantify chronic changes help distinguish from active disease 1

Clinical Context Supporting the Biopsy Decision

When to Perform Repeat Biopsy

KDIGO guidelines explicitly recommend repeat kidney biopsy when there is uncertainty whether worsening kidney function and/or persistent proteinuria represents disease activity versus chronicity. 1

Specific indications include:

• Persistent nephrotic-range proteinuria despite adequate immunosuppressive therapy 1
• Rising serum creatinine with unclear etiology 1
• Consideration of tapering immunosuppression in patients with incomplete remission 1
• Suspected class transformation (e.g., Class V evolving to proliferative classes) 1

Complementary Clinical and Laboratory Markers

While biopsy is definitive, these markers provide supporting evidence:

Favoring Active Lupus Nephritis:

• Elevated anti-dsDNA antibodies and low complement (C3, C4) levels 2
• Positive anti-C1q antibodies 2
• Active extrarenal lupus manifestations (arthritis, rash, serositis) 3
• Active urinary sediment with dysmorphic RBCs, RBC casts, or WBC casts 1
• Recent onset or increasing proteinuria 3, 4

Favoring CKD/Chronic Scarring:

• Stable or normalized serologic markers (anti-dsDNA, complement) despite persistent proteinuria 1
• Bland urinary sediment without cellular casts 1
• Long-standing proteinuria without fluctuation 1
• Small, echogenic kidneys on ultrasound 5
• Gradual decline in GFR over years rather than acute changes 2

Critical Pitfalls to Avoid

Do not rely solely on proteinuria levels to distinguish active disease from chronic scarring. Studies demonstrate that proteinuria can persist due to chronic glomerular damage without active inflammation, and treating this with immunosuppression exposes patients to unnecessary toxicity. 1, 6

Do not assume that improving serologic markers (complement, anti-dsDNA) indicate absence of active renal disease. Protocol biopsy studies show discordance between clinical/serologic remission and histologic activity in up to 30-40% of cases. 1

Do not delay repeat biopsy indefinitely in patients with persistent proteinuria after 12-24 months of therapy. While KDIGO acknowledges that complete remission may take 18-24 months, persistent nephrotic-range proteinuria beyond this timeframe warrants histologic reassessment to guide further management. 1

Practical Algorithm for Decision-Making

1. Assess clinical trajectory: Is proteinuria stable, improving, or worsening? Is kidney function stable or declining? 1

2. Review serologic activity: Check anti-dsDNA, C3, C4, anti-C1q antibodies 2

3. Examine urinary sediment: Active sediment (casts, dysmorphic RBCs) suggests ongoing inflammation 1

4. Consider timing: If >12-24 months post-treatment initiation with persistent nephrotic proteinuria, strongly consider repeat biopsy 1

5. Perform repeat biopsy when uncertainty exists, as worsening kidney function and persistent proteinuria may occur in the absence of inflammatory activity and should not be treated with immunosuppressive therapies 1

6. Interpret biopsy in context: Correlate histologic findings with clinical picture—presence of active lesions warrants continued/escalated immunosuppression, while predominant chronicity indicates conservative management 1

The 2021 KDIGO guidelines emphasize that repeat biopsy studies have shown many patients achieving only partial clinical remission have no remaining histologic activity, making biopsy essential for determining whether to continue, escalate, or discontinue immunosuppression. 1