Notes · Pathology · 30 September 2026

Lupus Nephritis

Definition

• Lupus nephritis (LN) is a renal manifestation of systemic lupus erythematosus (SLE) caused by immune‑complex deposition in the glomerulus, leading to inflammation and varying degrees of scarring.

Epidemiology

• Occurs in ~60–70 % of SLE patients during their disease course.
• Peak incidence in women of childbearing age (15–45 y), female:male ratio ≈ 9:1.
• Higher prevalence in African‑American, Hispanic, and Asian populations.
• Early onset (≤ 30 y) associated with more aggressive histology and poorer renal survival.

Aetiology

• Autoantibody‑mediated immune complex deposition:
  • Anti‑dsDNA, anti‑Smith, anti‑RNP, anti‑SSA/SSB, anti‑phospholipid antibodies.
• Complement consumption (low C3/C4) reflects ongoing immune activation.
• Genetic predisposition: HLA‑DR2/DR3, IRF5, STAT4, PTPN22.
• Environmental triggers: UV light, infections, certain drugs (e.g., procainamide, hydralazine).

Pathophysiology

• Immune complex formation → deposition in glomerular basement membrane (GBM) and mesangium.
• Complement activation (classical pathway) → C3a/C5a release → chemotaxis of neutrophils, monocytes.
• Inflammatory cascade: cytokines (IL‑1, IL‑6, TNF‑α), chemokines attract leukocytes → glomerular injury.
• Mesangial proliferation and matrix expansion → glomerular capillary wall thickening.
• Endocapillary proliferation → narrowing of capillary lumens.
• Fibrinoid necrosis (classical lesions) → crescents in Bowman’s space.
• Scarring (fibrosis, tubular atrophy) → irreversible loss of function.

Clinical Features

• Early (Class I–III): asymptomatic hematuria, proteinuria <1 g/day, mild edema.
• Advanced (Class IV–V): nephrotic syndrome (proteinuria >3.5 g/day, hypoalbuminemia, edema), hypertension, oliguria, renal insufficiency.
• Systemic signs: fever, arthralgia, rash, serositis may coexist.
• Pregnancy: increased risk of flare; careful monitoring of proteinuria and BP.

Investigations

Management (Current Guideline – 2023 ACR & KDIGO)

1. Initial assessment

   • Confirm SLE diagnosis, baseline renal function, complement, autoantibodies.
   • Classify LN by biopsy (ISN/RPS 2003/2021).

2. Induction therapy

   • Class I & II: Hydroxychloroquine (HCQ) 200–400 mg/day + low‑dose steroids (≤ 10 mg/day prednisone).
   • Class III & IV:
     • Steroids: Prednisone 1 mg/kg/day (max 60 mg) for 2–4 weeks → taper over 6–12 months.
     • Immunosuppressants:
       • Mycophenolate mofetil (MMF) 1 g BID (or 2 g/day) for 12–18 months.
       • Cyclophosphamide (IV pulse 0.5–1 g/m² monthly ×6–12 months) as alternative.
   • Class V (membranous):
     • MMF 1 g BID + steroids (prednisone 0.5 mg/kg/day) for 6–12 months.
     • Consider rituximab (375 mg/m² weekly ×4) if refractory.

3. Maintenance therapy

   • MMF 1 g BID or azathioprine 2–2.5 mg/kg/day for 2–3 years.
   • HCQ 200–400 mg/day lifelong.
   • Low‑dose steroids (≤ 5 mg/day) if needed.

4. Adjunctive measures

   • ACE inhibitors/ARBs for proteinuria ≥0.5 g/day or hypertension.
   • Statins for dyslipidemia.
   • Vaccinations (influenza, pneumococcal, HPV) before immunosuppression.
   • Prophylaxis for Pneumocystis jirovecii (TMP‑SMX) if high‑dose steroids or cyclophosphamide.

5. Monitoring

   • Urine protein, creatinine, eGFR, complement, anti‑dsDNA every 4–6 weeks during induction.
   • Blood pressure, weight, HCQ serum levels (if available).
   • Renal biopsy repeat if clinical relapse or plateau.

6. Pregnancy considerations

   • Avoid cyclophosphamide; use MMF only after pregnancy planning.
   • Close monitoring of proteinuria, BP, fetal growth.

Complications

• Renal: Chronic kidney disease, end‑stage renal disease (ESRD), hypertension, electrolyte disturbances.
• Systemic: Cardiovascular disease (accelerated atherosclerosis), infections (due to immunosuppression), thromboembolism (especially with antiphospholipid syndrome).
• Medication‑related: MMF hepatotoxicity, cyclophosphamide gonadal toxicity, steroid‑induced osteoporosis, cataracts.
• Pregnancy: Pre‑eclampsia, fetal growth restriction, preterm delivery.

High‑Yield Exam Points

• ISN/RPS 2003 classification: Class I (minimal mesangial) to Class VI (advanced sclerosing).
• Class IV (diffuse proliferative) is most common and carries worst prognosis.
• Low complement (C3/C4) + high anti‑dsDNA = active LN.
• MMF preferred induction agent over cyclophosphamide in most centers (2023 ACR).
• ACEi/ARB reduce proteinuria and slow progression; start even with mild proteinuria.
• HCQ reduces flares and improves survival; monitor for retinopathy (baseline & yearly).
• Pregnancy: MMF is teratogenic; switch to azathioprine or continue HCQ.
• Rituximab is second‑line for refractory Class III/IV or Class V with inadequate response.
• ESRD risk: 10–20 % of LN patients progress within 10 years if untreated.

Practice Questions

1. A 28‑year‑old woman with SLE presents with 4 g/day proteinuria, low C3, and a renal biopsy shows diffuse proliferative glomerulonephritis (Class IV). Which induction regimen is most appropriate according to the 2023 ACR guidelines?
   Answer: MMF 1 g BID plus prednisone 1 mg/kg/day (≤ 60 mg) – MMF is preferred over cyclophosphamide for induction.

2. Which of the following is the best long‑term strategy to reduce the risk of renal relapse in a patient with Class IV lupus nephritis who has completed 12 months of induction therapy?
   A) Discontinue steroids and start azathioprine.
   B) Continue low‑dose prednisone (≤ 5 mg/day) and start MMF 1 g BID.
   C) Switch to rituximab every 6 months.
   D) Stop all immunosuppression and monitor.
   Answer: B – Low‑dose steroids plus MMF for maintenance is recommended for 2–3 years.

3. A patient with SLE on hydroxychloroquine develops a sudden rise in serum creatinine and new-onset hematuria. Complement levels are low. Which diagnostic step is essential before initiating aggressive therapy?
   Answer: Perform a renal biopsy – it is the gold standard to classify LN and guide treatment.

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AI-assisted study material for exam revision. Always confirm with standard textbooks and current guidelines; not medical advice.