Lupus Nephritis
Renal involvement in systemic lupus erythematosus, affecting up to 50% of SLE patients. Classified by the ISN/RPS system (classes I-VI) based on renal biopsy. Class IV (diffuse proliferative) is the most common and severe form, requiring aggressive immunosuppression.
Key Facts
Lupus nephritis occurs in up to 50% of SLE patients and is a major determinant of morbidity and mortality ISN/RPS classification (classes I-VI): Class IV (diffuse proliferative) is the most common (40-60%) and most severe Characterised by low C3/C4, positive ANA and anti-dsDNA antibodies; anti-dsDNA titre correlates with disease activity Renal biopsy is essential for classification and guides treatment intensity Class III/IV: induction with mycophenolate mofetil 2-3g/day (ALMS trial) or IV cyclophosphamide (Euro-Lupus protocol: 500mg every 2 weeks × 6) + prednisolone Maintenance: mycophenolate mofetil 1-2g/day or azathioprine 2mg/kg/day for ≥3 years (MAINTAIN trial) Voclosporin (calcineurin inhibitor) added to MMF improves complete renal response (AURORA trial) 10-year renal survival: 80-90% for class III/IV with modern treatment
Overview
Key Facts
Lupus nephritis is one of the most serious manifestations of SLE and requires prompt diagnosis and treatment to prevent irreversible renal damage. Renal biopsy is critical for classification.
Epidemiology
- Affects 30-50% of SLE patients; higher in Afro-Caribbean, Hispanic, and Asian populations
- F:M ratio 9:1 (reflecting SLE demographics)
- Peak onset: 20-40 years
- Afro-Caribbean patients have more severe disease and worse outcomes
Aetiology
- Autoimmune disease with loss of tolerance to nuclear antigens
- Anti-dsDNA antibodies form immune complexes that deposit in glomeruli
- Genetic factors: complement deficiency (C1q, C2, C4), Fcγ receptor polymorphisms
- Environmental triggers: UV light, infections, drugs
Pathophysiology
- Circulating anti-dsDNA immune complexes deposit in glomerular subendothelial, subepithelial, and mesangial locations
- In situ immune complex formation also occurs
- Complement activation (classical pathway) → low C3 and C4
- Inflammatory cell infiltration → proliferative GN
- Full house immunofluorescence: IgG, IgA, IgM, C3, C1q deposition
Clinical Presentation
Presentation
- Proteinuria (ranges from mild to nephrotic)
- Haematuria (microscopic, with red cell casts in proliferative classes)
- Hypertension
- Oedema: nephrotic syndrome (particularly class V)
- Declining renal function: especially class III/IV
SLE Systemic Features
- Malar rash, discoid lupus, photosensitivity
- Arthralgia/arthritis, serositis, oral ulcers
- Cytopenias, lymphadenopathy
Red Flags
- Rapidly declining eGFR → urgent biopsy (may be class IV with crescents)
- Nephrotic-range proteinuria → class V or IV+V
- Rising anti-dsDNA and falling complement → flare
- Thrombocytopenia + renal failure → consider TTP-like syndrome (antiphospholipid)
Differential Diagnosis
| Diagnosis | Key Features | Investigation |
|---|---|---|
| IgA nephropathy | Normal complement, mesangial IgA only | Renal biopsy |
| MPGN | Low C3, hepatitis C, cryoglobulins | HCV, cryoglobulins |
| ANCA vasculitis | ANCA positive, normal complement | ANCA, biopsy |
| Anti-GBM disease | Linear IgG on IF, normal complement | Anti-GBM antibodies |
| Thrombotic microangiopathy | MAHA, thrombocytopenia | Blood film, ADAMTS13 |
| Drug-induced lupus | Drug history, anti-histone positive, no renal involvement | Anti-histone antibodies |
Diagnosis / Investigation
Bloods
- ANA: positive (>95% sensitive for SLE)
- Anti-dsDNA: correlates with disease activity and renal involvement
- C3/C4: low (correlates with flare)
- Anti-C1q antibodies: correlate with lupus nephritis specifically
- U&Es: creatinine, eGFR
- Urine ACR/PCR: quantify proteinuria
- FBC: cytopenias (lymphopenia, thrombocytopenia)
- ESR: typically elevated; CRP may be normal (unless co-infection)
- Anti-Sm antibodies: specific for SLE
- Antiphospholipid antibodies: lupus anticoagulant, anticardiolipin, anti-β2GP1
Imaging
- Renal USS: normal or slightly enlarged kidneys
Special Tests
- Renal biopsy: essential for classification
- IF: "full house" pattern (IgG, IgA, IgM, C3, C1q)
- LM: varies by class (mesangial, proliferative, membranous)
- Activity and chronicity indices guide treatment decisions
Management
Class I/II (Mesangial)
- Supportive: ACEi/ARB for proteinuria, hydroxychloroquine 200-400mg/day (reduces flares by 50%)
- No specific immunosuppression required
Class III/IV (Proliferative) – Induction
- Mycophenolate mofetil 2-3g/day for 6 months (ALMS trial: non-inferior to cyclophosphamide, better side-effect profile) + prednisolone 0.5-1mg/kg/day tapering
- OR IV cyclophosphamide: Euro-Lupus protocol (500mg every 2 weeks × 6 doses) + prednisolone
- Hydroxychloroquine 200-400mg/day: continue in all patients (reduces flares and mortality)
- Voclosporin 23.7mg BD + MMF: improves complete renal response (AURORA trial)
- Belimumab (anti-BLyS): can be added to standard therapy (BLISS-LN trial)
Class III/IV – Maintenance
- MMF 1-2g/day or azathioprine 2mg/kg/day for ≥3-5 years
- Continue hydroxychloroquine
- Gradual steroid taper to ≤5mg/day
Class V (Membranous)
- If subnephrotic: ACEi/ARB + hydroxychloroquine
- If nephrotic: MMF ± calcineurin inhibitor or rituximab
Supportive
- ACEi/ARB for proteinuria
- Vitamin D and calcium supplementation
- Thromboprophylaxis if nephrotic
- Cardiovascular risk management
Referral Criteria
- All suspected lupus nephritis → nephrology + rheumatology
- Class III/IV → tertiary centre
- Treatment-resistant disease → consider belimumab, voclosporin, or rituximab
Prognosis
- Class I/II: excellent prognosis; rarely progresses to ESRD
- Class III/IV: 10-year renal survival 80-90% with modern treatment; 20-30% may relapse
- Class V: 10-year renal survival ~85%; chronic disease with risk of thromboembolic events
- Class VI: advanced sclerosis; not responsive to immunosuppression; plan RRT
- Afro-Caribbean patients: worse outcomes; higher relapse rates
- Flare rate: 30-50% over 5 years on maintenance therapy
- SLE patients on dialysis do relatively well; lupus tends to become quiescent once on RRT
Other Relevant Information
ISN/RPS Classification of Lupus Nephritis
| Class | Description | Frequency | Treatment |
|---|---|---|---|
| I | Minimal mesangial | 5% | Supportive |
| II | Mesangial proliferative | 15-20% | Supportive |
| III | Focal proliferative (<50% glomeruli) | 10-15% | Immunosuppression |
| IV | Diffuse proliferative (≥50% glomeruli) | 40-60% | Aggressive immunosuppression |
| V | Membranous | 10-15% | Varies |
| VI | Advanced sclerotic (>90% sclerosed) | 5% | Dialysis/transplant |
Landmark Trials
| Trial | Finding |
|---|---|
| ALMS (2009) | MMF non-inferior to CYC for induction |
| Euro-Lupus (2004) | Low-dose CYC effective for induction |
| MAINTAIN (2010) | MMF and AZA equivalent for maintenance |
| AURORA (2021) | Voclosporin + MMF improved complete renal response |
| BLISS-LN (2020) | Belimumab added to standard therapy improved renal response |