Lupus Nephritis

Symptoms

• Hematuria, proteinuria, peripheral edema
• Hypertension (often severe in class IV)
• Constitutional and extrarenal SLE features — fatigue, arthralgia, malar rash, photosensitivity, oral ulcers, alopecia, Raynaud, serositis
• Acute kidney injury or rapidly progressive course in severe class III/IV

Signs / physical exam

• Malar rash, discoid lesions, oral ulcers, alopecia
• Synovitis (nonerosive)
• Pericardial or pleural friction rub
• Peripheral edema, hypertension
• Livedo reticularis if antiphospholipid antibody syndrome coexists

Classic findings

Active urine sediment (dysmorphic RBCs, RBC casts) with low C3 and C4 and rising anti-dsDNA titer.

Diagnostic criteria

Kidney biopsy is essential for any SLE patient with proteinuria >0.5 g/day, active urine sediment, or unexplained creatinine rise. Biopsy provides ISN/RPS class, activity index (acute injury — reversible), and chronicity index (irreversible damage). The 2024 ACR/EULAR guidelines emphasize biopsy-driven therapy.

Labs

• CBC (cytopenias — anemia, leukopenia, thrombocytopenia), BMP, eGFR
• UA with microscopy (dysmorphic RBCs, RBC casts), spot UPCR or 24-hour urine protein
• ANA, anti-dsDNA, anti-Smith, anti-Ro/La, anti-RNP, complement C3 and C4, CH50
• Antiphospholipid antibody panel (lupus anticoagulant, anti-cardiolipin, anti-beta2 glycoprotein I)
• Direct Coombs, haptoglobin, LDH, reticulocyte count if hemolysis suspected
• Hepatitis B and C, HIV, TB screening (prior to immunosuppression)
• Pregnancy test in reproductive-age women

Imaging

• Renal ultrasound — normal-sized kidneys early; atrophy with chronic disease
• Echocardiogram if pericardial effusion or pulmonary hypertension suspected

First-line

• Hydroxychloroquine for all SLE patients (300-400 mg/day; check ophtho for retinal toxicity annually after 5 years)
• RAAS blockade — ACE inhibitor (lisinopril, enalapril) or ARB (losartan, valsartan) for proteinuria
• Blood pressure control (<125/75 if proteinuric)
• Pneumococcal, influenza, COVID, and HPV vaccination before immunosuppression
• Class I or II — supportive care; treat extrarenal lupus only

Class III / IV (proliferative) — induction

• Glucocorticoids — IV methylprednisolone pulse (250-1000 mg × 3 days) then prednisone 0.5-1 mg/kg/day tapered over 6 months
• Combine with one of: mycophenolate mofetil (target 2-3 g/day), low-dose IV cyclophosphamide (Euro-Lupus regimen — 500 mg q2 weeks × 6 doses), or high-dose IV cyclophosphamide (NIH regimen)
• Add belimumab (anti-BLyS monoclonal) or voclosporin (calcineurin inhibitor) as 'triple therapy' per 2024 ACR — improves response rates

Class III / IV — maintenance (after induction response)

• Mycophenolate mofetil 1-2 g/day or azathioprine 1.5-2 mg/kg/day
• Continue belimumab or voclosporin if used in induction
• Taper steroids to lowest effective dose (target <7.5 mg/day by 6 months)
• Duration ≥3 years from complete response

Class V (membranous)

• If nephrotic-range proteinuria or worsening renal function: corticosteroids + mycophenolate mofetil, calcineurin inhibitor (tacrolimus, cyclosporine), or cyclophosphamide
• If sub-nephrotic and stable: RAAS blockade + hydroxychloroquine

Mixed III+V or IV+V

• Treat as proliferative disease with induction + maintenance regimens

Class VI (advanced sclerosing)

• Supportive nephroprotective care; prepare for renal replacement therapy
• Immunosuppression only for extrarenal disease

Second-line / adjunct

• Rituximab — refractory disease or contraindication to cyclophosphamide/MMF
• Obinutuzumab in clinical trials
• Plasmapheresis for severe AKI with crescents or coexisting antiphospholipid syndrome / TMA
• Renal transplantation for ESKD — outcomes generally good; consider delaying until SLE is quiescent