How should lupus nephritis be evaluated and managed, including diagnosis, classification, and treatment?

Lupus Nephritis: Evaluation and Management

Diagnostic Approach

All patients with systemic lupus erythematosus (SLE) require active and regular monitoring for kidney involvement, as lupus nephritis can remain clinically silent for extended periods, particularly in high-risk populations including Asian, African/Caribbean, and Hispanic patients, as well as those with childhood-onset SLE. 1

Initial Screening Parameters

• Monitor for proteinuria ≥0.5 g/24 hours (or spot urine protein-to-creatinine ratio >0.5) as the primary threshold for further investigation 1, 2
• Check for dipstick protein ≥2+ on urinalysis 1
• Evaluate urine sediment for acanthocytes (≥5%), red blood cell casts, or white blood cell casts 1
• Assess for active urinary sediment: >5 RBC/hpf, >5 WBC/hpf without infection, or RBC/WBC casts 2
• Measure eGFR to identify abnormal or decreasing kidney function below expected levels for age 1

When to Proceed with Kidney Biopsy

Kidney biopsy is the definitive diagnostic test and should be performed in all patients with clinical evidence of active lupus nephritis unless strongly contraindicated. 2, 3

Specific indications for biopsy include: 2

• Proteinuria ≥1.0 g/24 hours
• Proteinuria ≥0.5 g/24 hours plus hematuria or cellular casts
• Increasing serum creatinine without alternative explanation
• Even with eGFR <30 ml/min per 1.73 m² if kidney size is normal and active disease is evident 2

Biopsy Requirements and Processing

An adequate biopsy must contain a minimum of 10 glomeruli and be processed for light microscopy (with H&E, PAS, Masson's trichrome, and silver stains), immunofluorescence (for IgG, C3, IgA, IgM, C1q, κ and λ light chains), and electron microscopy. 1, 2

• Biopsies should be read by an experienced kidney pathologist and classified according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification 1, 4
• Timing is critical: perform biopsy within the first month after disease onset, preferably before starting immunosuppressive treatment 2

ISN/RPS Classification and Clinical Implications

• Class I (minimal mesangial) and Class II (mesangial hypercellularity): No immunosuppressive treatment required 2
• Class III (focal proliferative, <50% glomeruli) and Class IV (diffuse proliferative, ≥50% glomeruli): Require aggressive immunosuppression 2
• Class V (membranous): When combined with Class III or IV, treat as proliferative disease; pure membranous may be approached differently 2
• Class VI (advanced sclerosis in ≥90% glomeruli): Prepare for renal replacement therapy rather than immunosuppression 2

Critical pitfall: Clinical, serological, and laboratory parameters do not reliably predict histological findings or severity—maintain a low threshold for biopsy. 1, 2

Treatment Strategy

Universal Baseline Therapy

All patients with lupus nephritis must receive hydroxychloroquine (or equivalent antimalarial) at a dose not exceeding 5 mg/kg/day (adjusted for GFR) unless contraindicated, as this reduces flare rates, slows kidney disease progression, and decreases cardiovascular and thrombotic events. 1, 3, 5

Initial Induction Therapy for Class III/IV Lupus Nephritis

For active Class III or IV lupus nephritis (with or without membranous component), choose one of four equally effective first-line regimens, all combined with glucocorticoids: 1, 5

1. Mycophenolic acid analogs (MPAA) at target dose 2-3 g/day 1, 5
2. Low-dose intravenous cyclophosphamide 1, 5
3. Belimumab plus either MPAA or low-dose IV cyclophosphamide 1, 5
4. MPAA plus calcineurin inhibitor (CNI) when eGFR ≥45 ml/min per 1.73 m² 1, 5

Glucocorticoid Regimen

Use a reduced-dose glucocorticoid protocol: start with short-course methylprednisolone IV pulses followed by oral prednisone at moderate doses, tapering as kidney and extrarenal manifestations improve. 1, 5

Essential Adjunctive Therapies

Implement the following risk-reduction measures for all patients: 1, 5

• ACE inhibitors or ARBs for all patients with proteinuria (UPCR >500 mg/g) or hypertension 1, 3, 5
• SGLT2 inhibitors in stable patients without acute kidney injury 1, 5
• Pneumocystis jirovecii prophylaxis during intensive immunosuppression 1, 5
• Screen for hepatitis B, C, HIV, and tuberculosis before starting therapy 1, 5
• Calcium and vitamin D supplementation with bone density monitoring 1
• Low-dose aspirin during pregnancy for cardiovascular risk reduction 1
• Broad-spectrum sunscreen and limit ultraviolet light exposure 1

Maintenance Therapy

Continue maintenance immunosuppression for at least 3-5 years after achieving clinical response: 3, 5

• Mycophenolic acid analogs (1-2 g/day) or azathioprine (2 mg/kg/day) 1, 3, 5
• Low-dose prednisone (2.5-5 mg/day) as needed to control disease activity 3, 5
• Hydroxychloroquine must be continued indefinitely 5

Treatment Goals and Monitoring

Target the following response milestones: 3, 5

• ≥25% reduction in proteinuria by 3 months
• ≥50% reduction by 6 months
• Complete clinical response (UPCR <500-700 mg/g with normal or near-normal GFR) by 12 months

Monitor every 2-4 weeks for the first 2-4 months, then according to response, checking: 3

• Body weight, blood pressure
• Serum creatinine, eGFR, serum albumin
• Proteinuria, urinary sediment
• Serum C3, C4, and anti-dsDNA antibodies

Management of Refractory Disease

If treatment goals are not met, switch to one of the alternative initial therapy regimens listed above; consider rituximab for active non-responding or refractory disease. 5

Fertility Preservation

Before initiating cyclophosphamide, discuss and implement: 1, 5

• Gonadotropin-releasing hormone agonists (e.g., leuprolide)
• Sperm or oocyte cryopreservation
• Minimize lifetime cyclophosphamide exposure to <36 g to reduce cancer risk 1, 5

Pregnancy Planning

Pregnancy may be planned when disease is stable with: 3

• Inactive lupus nephritis for preceding 6 months
• UPCR <500 mg/g
• GFR >50 ml/min
• Continue hydroxychloroquine, prednisone, azathioprine, and calcineurin inhibitors throughout pregnancy 3

Specialist Comanagement

All patients with lupus nephritis require comanagement by both nephrologists and rheumatologists with lupus expertise from the point of clinical suspicion—do not delay referral while awaiting biopsy results. 3

• Nephrologists guide kidney-specific management, biopsy decisions, and immunosuppressive dosing adjustments based on kidney function 3
• Rheumatologists manage systemic SLE activity, extrarenal manifestations, and ensure appropriate hydroxychloroquine use 3
• Kidney biopsies must be evaluated by a nephropathologist with lupus nephritis expertise 3
• Children require pediatric nephrology and pediatric rheumatology comanagement 3

Critical pitfall: Avoid single-specialty management even with stable disease—both specialties provide complementary expertise that improves long-term outcomes. 3