What is lupus nephritis?

Lupus Nephritis: Definition and Clinical Implications

Lupus nephritis is an inflammatory kidney condition that occurs as a complication of systemic lupus erythematosus (SLE), characterized by immune complex deposition in the kidneys that can lead to various patterns of glomerular and tubulointerstitial damage, significantly increasing morbidity and mortality if left untreated. 1, 2

Pathophysiology and Classification

Lupus nephritis results from the deposition of immune complexes in the glomeruli, triggering inflammation and potentially irreversible kidney damage. The International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification system categorizes lupus nephritis into six classes based on histopathological findings:

• Class I: Minimal mesangial lupus nephritis
• Class II: Mesangial proliferative lupus nephritis
• Class III: Focal lupus nephritis (<50% of glomeruli affected)
• Class IV: Diffuse lupus nephritis (≥50% of glomeruli affected)
• Class V: Membranous lupus nephritis
• Class VI: Advanced sclerosing lupus nephritis 3

The ISN/RPS classification has undergone revisions to improve definitions and standardize terminology. For example, "endocapillary proliferation" has been replaced with "endocapillary hypercellularity" to better reflect that most glomerular capillary hypercellularity in lupus nephritis is caused by inflammatory cell infiltration rather than actual cell proliferation. 1

Clinical Manifestations

Lupus nephritis can present with various clinical manifestations:

• Proteinuria (often ≥0.5 g/24 hours)
• Hematuria
• Cellular casts in urine
• Elevated serum creatinine
• Decreased estimated glomerular filtration rate (eGFR)
• Hypertension
• Edema in severe cases 2, 4

Diagnostic Approach

Diagnosis requires a comprehensive approach:

1. Urinalysis: Look for proteinuria (dipstick ≥2+) and active urinary sediment (acanthocytes, RBC casts, WBC casts)
2. Quantification of proteinuria: Urine protein-to-creatinine ratio (UPCR) in morning first void urine and 24-hour urine protein collection
3. Kidney biopsy: Essential when there is evidence of kidney involvement, particularly persistent proteinuria ≥0.5 g/24 hours (or UPCR ≥500 mg/g) or unexplained decrease in GFR 3

Kidney biopsy provides critical information about:

• ISN/RPS classification
• Activity and chronicity indices
• Thrombotic and vascular lesions associated with antiphospholipid syndrome
• Tubulointerstitial lesions (fibrosis and tubular atrophy) 3

Treatment Approach

Treatment is guided by the ISN/RPS classification:

For Class III or IV LN (with or without Class V):

• Induction therapy:
  • Mycophenolate mofetil (MMF) 2-3 g/day + glucocorticoids OR
  • Low-dose IV cyclophosphamide (Euro-Lupus regimen: 500 mg × 6 biweekly doses) + glucocorticoids 3, 2
  • Initial treatment with IV methylprednisolone pulses, followed by oral prednisone 0.3-0.5 mg/kg/day, with aim to taper to low-dose (<7.5 mg/day) during maintenance phase

For pure Class V LN with nephrotic-range proteinuria:

• MMF plus glucocorticoids 3

For all patients with lupus nephritis:

• Hydroxychloroquine: Should be given to all patients unless contraindicated, with regular ophthalmological monitoring 3, 2
• Renin-angiotensin system blockade: For proteinuria and hypertension management 2, 5

Monitoring and Follow-up

Regular monitoring is essential:

• Urinalysis and UPCR at each visit
• Serum creatinine and eGFR
• Anti-dsDNA antibodies and complement levels
• Blood pressure control 3, 4

Complete response to treatment is defined as proteinuria <0.5-0.7 g/24h with normal or near-normal GFR by 12 months 3

Emerging Therapies

Recent advances in lupus nephritis treatment include:

• Belimumab: B-cell targeting therapy approved for lupus nephritis
• Voclosporin: Calcineurin inhibitor recently approved for lupus nephritis
• Rituximab: Can be considered for refractory disease 3, 6, 7

Risk Factors for CKD Progression

Managing non-immune risk factors is crucial to prevent chronic kidney disease (CKD) progression:

• Obesity
• Hypertension
• Sodium- or protein-rich diets
• Type 2 diabetes mellitus
• Nephrotoxic agents
• Smoking 5

Common Pitfalls to Avoid

1. Delaying kidney biopsy: Clinical findings do not always correlate with histological severity
2. Underestimating mild proteinuria: Severity can vary considerably in active nephritis
3. Inadequate monitoring: Regular monitoring is essential for early detection of silent kidney involvement
4. Overlooking antiphospholipid syndrome: Thrombotic microangiopathy carries prognostic implications
5. Discontinuing hydroxychloroquine: This medication reduces flare rates and improves outcomes 3

Early diagnosis and appropriate treatment are essential to prevent progression to end-stage kidney disease and improve long-term outcomes in patients with lupus nephritis.