What is the best course of treatment for a young to middle-aged female patient with a history of Systemic Lupus Erythematosus (SLE) presenting with impaired renal function (elevated creatinine), hematuria, elevated erythrocyte sedimentation rate (ESR), and hyperferritinemia?

Management of Active Lupus Nephritis with Renal Dysfunction

This patient requires urgent kidney biopsy to classify lupus nephritis and immediate initiation of combination immunosuppressive therapy with corticosteroids plus either mycophenolate mofetil (MMF) or cyclophosphamide, along with hydroxychloroquine. 1, 2

Immediate Diagnostic Workup

Kidney biopsy is essential and should not be delayed when a patient with SLE presents with elevated creatinine, hematuria, and elevated ESR, as clinical findings do not reliably predict histologic class of lupus nephritis. 1, 3

• Quantify proteinuria using urine protein-to-creatinine ratio to determine if nephrotic-range proteinuria (>3.5 g/day or >0.5 g/g) is present 1, 2
• Perform urine sediment analysis specifically looking for red blood cell casts, white blood cell casts, or acanthocytes (≥5%), which indicate active glomerulonephritis 1
• Measure complement levels (C3, C4) and anti-dsDNA antibodies, as low complement and elevated anti-dsDNA are significantly associated with active renal disease and predict outcomes 1, 2
• Obtain kidney biopsy to classify according to ISN/RPS criteria (Classes I-VI), as this directly determines treatment intensity—similar clinical presentations can represent vastly different histologic classes requiring different therapies 1, 3

The combination of elevated creatinine, hematuria, elevated ESR, and hyperferritinemia strongly suggests active proliferative lupus nephritis (Class III or IV), though membranous (Class V) or mixed patterns are possible. 2, 4

Initial Immunosuppressive Treatment

For proliferative lupus nephritis (Class III or IV), initiate combination therapy immediately:

• Corticosteroids: High-dose prednisone or methylprednisolone pulses followed by oral prednisone taper 1
• Plus either:
  • Mycophenolate mofetil (MMF) 2-3 g/day in divided doses (preferred first-line agent) 1, 2, OR
  • Cyclophosphamide using low-dose Euro-Lupus protocol (500 mg IV every 2 weeks × 6 doses) or NIH protocol (0.5-1.0 g/m² monthly × 6 doses) 1

MMF is preferred over cyclophosphamide as first-line therapy based on comparable efficacy with better tolerability and lower toxicity, particularly for young women of childbearing age. 1

Essential Concurrent Therapy

• Hydroxychloroquine 200-400 mg daily should be initiated immediately unless contraindicated, as it reduces disease flares, progressive kidney damage, and improves long-term outcomes 1, 2
• Antiproteinuric therapy with ACE inhibitors or ARBs for blood pressure control and proteinuria reduction 1
• Aggressive blood pressure control targeting <130/80 mmHg 1

Special Considerations for Hyperferritinemia

Elevated ferritin in this context likely reflects:

• Disease activity marker rather than iron overload, as ferritin is an acute phase reactant that correlates with lupus activity 4
• Potential marker of treatment response: Serum ferritin may decline with effective immunosuppression (particularly MMF) as renal function improves 4
• Do not treat with iron chelation unless true iron overload is documented 4

Treatment for Class V (Membranous) Lupus Nephritis

If biopsy shows pure Class V with nephrotic-range proteinuria:

• Corticosteroids plus MMF is the preferred regimen (2D evidence grade) 1
• Alternative options include corticosteroids plus calcineurin inhibitors (CNIs) or cyclophosphamide 1
• If subnephrotic proteinuria with normal kidney function: Conservative management with antiproteinuric/antihypertensive therapy alone may be appropriate 1

Maintenance Therapy Strategy

After achieving remission (typically 3-6 months of induction):

• Continue maintenance immunosuppression for at least 1 year after achieving remission before considering taper 1
• Preferred maintenance agents: MMF or azathioprine with low-dose corticosteroids 1
• Taper oral steroids earlier (before 1 year) while maintaining other immunosuppression to minimize steroid toxicity 1

Critical Monitoring Parameters

During active treatment, monitor every 4-12 weeks: 1

• Urine protein-to-creatinine ratio and urine microscopy
• Serum creatinine and eGFR to detect worsening renal function
• Complete blood count for cytopenias from disease or treatment
• C3, C4, and anti-dsDNA as serologic markers of disease activity
• ESR (though less specific than complement/anti-dsDNA)
• Blood pressure at every visit

For patients with established lupus nephritis, increase monitoring frequency to every 3 months for the first 2-3 years given high relapse rates (up to 45% of patients). 1, 5

When to Consider Repeat Biopsy

Repeat kidney biopsy is indicated when: 1

• Disease relapse occurs and there is uncertainty whether the histologic class has evolved (e.g., Class III progressing to Class IV)
• Rising creatinine or worsening proteinuria without clear explanation, to distinguish active inflammation (requiring intensified immunosuppression) from chronic scarring (which will not respond to immunosuppression)
• Inadequate response to initial induction therapy after 3-6 months

Prognosis and Long-term Risks

Without aggressive treatment, this patient faces:

• 7.4-8.5% risk of doubling serum creatinine at 5 years 2, 5
• 14.3-18.2% risk at 10 years 5
• Relapse rates of 0.1-0.2 per patient-year even with treatment 5
• Earlier relapses (18 months) if only partial response achieved versus 36 months with complete response 5

Critical Pitfalls to Avoid

• Do not delay biopsy waiting for serologic confirmation—up to 9% of patients presenting with nephrotic syndrome have non-lupus nephropathy requiring different treatment 3
• Do not rely on clinical presentation alone to determine treatment intensity—49-55% of patients with subnephrotic or nephrotic proteinuria have proliferative disease requiring aggressive immunosuppression 3
• Do not undertreat based on "stable" creatinine—persistent proteinuria with elevated creatinine indicates ongoing kidney injury 1, 2
• Do not continue high-dose steroids long-term—taper to ≤7.5 mg/day by 6-12 months to minimize toxicity while maintaining other immunosuppression 1