What are the ISN/RPS classes of lupus nephritis and the recommended treatment for each class?

Lupus Nephritis: ISN/RPS Classification and Treatment

ISN/RPS Classification System

Lupus nephritis is classified into six distinct classes (I-VI) based on renal biopsy findings, with the 2018 ISN/RPS revision providing clarified definitions that guide treatment intensity. 1

Class I: Minimal Mesangial Lupus Nephritis

• Mesangial immune deposits visible on immunofluorescence or electron microscopy without mesangial hypercellularity on light microscopy 2
• No immunosuppressive therapy required—observation and hydroxychloroquine suffice 3

Class II: Mesangial Proliferative Lupus Nephritis

• Mesangial immune deposits with mesangial hypercellularity (≥4 nuclei fully surrounded by matrix in the mesangial area) 3, 2
• Does not require immunosuppressive treatment in most cases; hydroxychloroquine and supportive care are appropriate 3
• Rare cases may present with nephrotic syndrome, requiring individualized assessment 4

Class III: Focal Lupus Nephritis

• Active or inactive focal, segmental, or global endocapillary or extracapillary glomerulonephritis involving <50% of total glomeruli 2
• The 2018 revision eliminated segmental/global subdivisions due to poor interobserver agreement and uncertain clinical significance 1
• Subdivisions now focus on active versus sclerotic lesions rather than the previous A/C designations 3

Class IV: Diffuse Lupus Nephritis

• Active or inactive diffuse, segmental, or global endocapillary or extracapillary glomerulonephritis involving ≥50% of total glomeruli 2
• The term "endocapillary proliferation" has been replaced with "endocapillary hypercellularity" because most hypercellularity results from inflammatory cell influx rather than actual cell proliferation 1, 3
• The 2018 revision eliminated the IV-S (segmental) versus IV-G (global) distinction from routine classification due to reproducibility issues, though research suggests IV-G lesions correlate with immune complex burden and complement consumption while IV-S lesions show more fibrinoid necrosis 1, 5

Class V: Membranous Lupus Nephritis

• Global or segmental subepithelial immune deposits by immunofluorescence or electron microscopy, with or without mesangial alterations 2
• When combined with Class III or IV, treat as proliferative disease (III or IV); pure Class V with nephrotic-range proteinuria warrants immunosuppression 3, 6
• The 2018 revision recommends evidence-based determination of whether to distinguish Class V with versus without mesangial hypercellularity 1

Class VI: Advanced Sclerosing Lupus Nephritis

• ≥90% of glomeruli globally sclerosed without residual activity 2
• Prepare for renal replacement therapy rather than immunosuppression, as this represents end-stage pathology 3
• The ISN/RPS acknowledges this class is rarely seen in biopsy specimens and may require re-evaluation or elimination 1

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Treatment Algorithms by Class

Classes I and II: Conservative Management

• Hydroxychloroquine ≤5 mg/kg/day (adjusted for renal function) indefinitely 7, 6
• ACE inhibitors or ARBs if proteinuria >500 mg/g or hypertension present 7, 6
• No immunosuppressive therapy required 3

Classes III and IV: Aggressive Induction Therapy

Four equally effective first-line induction regimens (all combined with reduced-dose glucocorticoids): 7, 6

1. Mycophenolic acid analogs (MPAA) 2-3 g/day (preferred by many centers) 7, 6
2. Low-dose intravenous cyclophosphamide 7, 6
3. Belimumab added to either MPAA or low-dose IV cyclophosphamide 7, 6
4. MPAA plus calcineurin inhibitor (only if eGFR ≥45 ml/min/1.73 m²) 7, 6

Glucocorticoid Protocol

• Short-course intravenous methylprednisolone pulses followed by oral prednisone at moderate doses 7, 6
• Taper as renal and extrarenal disease improve 7

Essential Adjunctive Measures

• ACE inhibitors or ARBs for all patients with UPCR >500 mg/g or hypertension 7, 6
• SGLT2 inhibitors in stable patients without acute kidney injury 7, 6
• Pneumocystis jirovecii prophylaxis during intensive immunosuppression 7, 6
• Screen for hepatitis B, C, HIV, and tuberculosis before starting therapy 7, 6
• Calcium and vitamin D supplementation with bone-density monitoring 7

Maintenance Therapy

• Continue ≥3-5 years after achieving clinical response 7, 6
• MPAA 1-2 g/day or azathioprine 2 mg/kg/day 7, 6
• Hydroxychloroquine indefinitely 7, 6
• Low-dose prednisone as needed 6

Treatment Goals and Monitoring

• ≥25% proteinuria reduction by 3 months 6
• ≥50% proteinuria reduction by 6 months 6
• UPCR <500-700 mg/g by 12 months (complete clinical response) 6
• Monitor every 2-4 weeks during first 2-4 months: body weight, blood pressure, complement levels (C3, C4), anti-dsDNA antibodies 7

Refractory Disease

• Switch to an alternative first-line regimen if treatment goals not met 6
• Consider rituximab for active non-responding/refractory disease 6

Class V: Membranous Lupus Nephritis

When Combined with Class III or IV

• Treat as proliferative disease using the Class III/IV algorithm above 3, 6

Pure Class V with Nephrotic-Range Proteinuria

• Use one of the four first-line induction regimens listed for Class III/IV 3
• Same adjunctive measures and maintenance strategy 7, 6

Class VI: End-Stage Management

• Focus on renal replacement therapy preparation 3
• Immunosuppression generally not indicated 3

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Critical Diagnostic Requirements

Renal biopsy is mandatory for all patients with clinical evidence of active lupus nephritis unless strongly contraindicated, because clinical, serologic, and laboratory parameters cannot reliably predict histologic class or severity 3, 7

Biopsy Adequacy Standards

• Minimum 10 glomeruli required for evaluation 1, 3, 7
• Process for light microscopy (H&E, PAS, Masson's trichrome, silver stains), immunofluorescence (IgG, C3, IgA, IgM, C1q, κ/λ light chains), and electron microscopy 3, 7

Biopsy Indications

• Proteinuria ≥0.5 g/24 hours with glomerular hematuria 3
• Unexplained decrease in GFR 3
• Even with eGFR <30 ml/min if kidney size normal and evidence of active disease 3, 7

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Special Populations and Considerations

Fertility Preservation (Before Cyclophosphamide)

• Gonadotropin-releasing hormone agonists (e.g., leuprolide) 7, 6
• Sperm or oocyte cryopreservation 7, 6
• Limit cumulative cyclophosphamide to <36 g to reduce long-term cancer risk 7, 6

Pregnancy Planning

• Pursue pregnancy only when disease inactive ≥6 months, proteinuria <500 mg/g**, and eGFR **>50 ml/min/1.73 m² 7
• Continue hydroxychloroquine, prednisone, azathioprine, and calcineurin inhibitors during pregnancy 7
• Low-dose aspirin during pregnancy to mitigate cardiovascular risk 7

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Common Pitfalls to Avoid

• Do not delay biopsy based on advanced GFR decline alone if kidneys are normal size and active disease is suspected 3, 7
• Do not rely on clinical parameters alone to determine treatment—biopsy classification is essential 3, 7
• Do not undertreat Class III assuming it is "less severe" than Class IV—both require aggressive immunosuppression 7, 6
• Do not continue cyclophosphamide beyond 36 g cumulative dose due to malignancy risk 7, 6
• Do not omit hydroxychloroquine—it reduces flares, slows progression, and lowers cardiovascular/thrombotic events 7, 6
• Do not forget SGLT2 inhibitors in stable patients—they provide renoprotection 7, 6