What is the recommended initial workup and treatment for a newly diagnosed patient with lupus nephritis?

Lupus Nephritis: Initial Workup and Treatment

Immediate Diagnostic Workup

Obtain a renal biopsy within the first month after disease onset to confirm diagnosis and guide treatment, as clinical findings alone do not reliably predict histological class. 1, 2

Essential Pre-Biopsy Laboratory Assessment

• Urinalysis with microscopy to detect proteinuria, hematuria (especially dysmorphic red blood cells), white blood cells, and cellular casts 1
• Quantify proteinuria using urine protein-to-creatinine ratio (UPCR) 2
• Serum creatinine and estimated GFR using Cockcroft-Gault or MDRD equations (Schwartz formula in children) 1
• Complement levels (C3, C4) and anti-dsDNA antibodies 3
• Complete blood count and serum albumin 3

Renal Biopsy Requirements

• Perform biopsy before initiating immunosuppression unless contraindicated, though high-dose glucocorticoids should not be delayed if biopsy cannot be readily performed 1
• **For GFR <30 ml/min**, only proceed with biopsy if kidney size is normal (>9 cm in adults) and/or there is evidence of active disease (proteinuria, active urinary sediment) 1
• Adequate tissue sample requires ≥8 glomeruli examined with light microscopy, immunofluorescence for IgG, C3, IgA, IgM, C1q, κ and λ light chains, and electron microscopy if possible 1
• Use ISN/RPS 2003 classification system to assess active and chronic glomerular/tubulointerstitial changes 1, 2

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Initial Treatment by Histological Class

Class III or IV (Proliferative Lupus Nephritis)

Initiate mycophenolic acid (MPA) combined with glucocorticoids as first-line therapy for most patients with Class III or IV lupus nephritis, as it offers comparable efficacy to cyclophosphamide with superior gonadal safety. 1, 2, 4

First-Line Immunosuppression Options (Choose One):

• Mycophenolate mofetil (MMF) 2-3 g/day for 6 months (or enteric-coated mycophenolic acid sodium 720 mg ≈ MMF 1 g) 1, 2, 4
• Low-dose intravenous cyclophosphamide (total 3 g over 3 months) for Caucasians or patients at high infertility risk 1, 2, 4
• High-dose intravenous cyclophosphamide (0.5-0.75 g/m² monthly for 6 months) reserved for patients at high risk for kidney failure (reduced GFR, crescents, fibrinoid necrosis, severe interstitial inflammation) 4
• MPA (1-2 g/day) plus calcineurin inhibitor (tacrolimus) particularly effective for nephrotic-range proteinuria 2, 4
• Belimumab plus either MPA or low-dose cyclophosphamide as an alternative first-line option 2

Glucocorticoid Regimen:

• Three consecutive intravenous methylprednisolone pulses (500-750 mg each) 2, 4
• Followed by oral prednisone 0.3-0.5 mg/kg/day for up to 4 weeks 2, 4
• Taper to ≤7.5 mg/day by 3-6 months and target ≤5 mg/day by 6 months 2, 4

Class V (Membranous Lupus Nephritis)

For pure Class V with nephrotic-range proteinuria, initiate MMF 3 g/day for 6 months combined with oral prednisone 0.5 mg/kg/day, as this provides the best efficacy-to-toxicity balance. 3

Treatment Indications:

• Start immunosuppression when proteinuria exceeds 1 g/24h despite optimal RAAS blockade 3
• Nephrotic-range proteinuria requires prompt treatment due to high risk of thromboembolism, infections, and progressive CKD 3

Alternative Options for Class V:

• Tacrolimus or cyclosporine plus glucocorticoids (note: 40% relapse rate within one year after CNI discontinuation) 3
• Low-dose intravenous cyclophosphamide (total 3 g over 3 months) for longer remission durability 3
• Triple therapy: glucocorticoids + tacrolimus + low-dose MMF (1-2 g/day) achieved 33.1% complete remission in Chinese cohorts 3

Class I/II (Minimal Mesangial or Mesangial Proliferative)

Do not initiate immunosuppression for Class I/II unless nephrotic syndrome is present or extrarenal lupus manifestations require treatment. 1

• For nephrotic syndrome with Class I/II, treat as lupus podocytopathy similar to minimal change disease 1
• Monitor closely for disease transformation as class progression may occur within 1-5 years 1

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Mandatory Adjunctive Therapies (All Patients)

Every patient with lupus nephritis must receive hydroxychloroquine, ACE inhibitors or ARBs, and statins regardless of histological class. 2, 3

• Hydroxychloroquine (dose ≤5 mg/kg/day, adjusted for GFR) to reduce renal flares and limit organ damage 2, 3, 4
• ACE inhibitors or ARBs for any UPCR >50 mg/mmol (>500 mg/g) or hypertension 2, 3, 4
• Statins targeting LDL-cholesterol <2.58 mmol/L (<100 mg/dL) 2, 3
• Anticoagulation when serum albumin <20 g/L in nephrotic syndrome, especially if antiphospholipid antibodies present 3

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Treatment Goals and Monitoring Timeline

Target at least 25% reduction in proteinuria by 3 months, 50% reduction by 6 months, and complete clinical response (UPCR <50 mg/mmol with normal/near-normal renal function) by 12 months. 2, 3, 4

Monitoring Schedule:

• Every 2-4 weeks during first 2-4 months, then at least every 3-6 months lifelong 3
• At each visit assess: weight, blood pressure, serum creatinine/eGFR, serum albumin, proteinuria, urinary sediment, complement C3/C4, anti-dsDNA, complete blood count 3

Response Definitions:

• Complete renal response: UPCR <50 mg/mmol with normal or near-normal renal function (within 10% of baseline if previously abnormal) 2, 3
• Partial renal response: ≥50% reduction in proteinuria to subnephrotic levels with normal/near-normal renal function 3

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Maintenance Therapy (After Initial Response)

Transition to maintenance immunosuppression for at least 3 years after completing initial therapy. 2, 4

• Continue MMF at lower dose (1-2 g/day) for patients who responded to MMF 2, 3, 4
• Switch to azathioprine 2 mg/kg/day if pregnancy is contemplated (azathioprine should never be used for induction) 2, 3, 4
• Maintain low-dose prednisone (2.5-7.5 mg/day) as needed to control disease activity 2, 3, 4
• For Class V, calcineurin inhibitors may be used for maintenance 3

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Management of Treatment Failure

Treatment failure is defined as failure to achieve at least partial renal response by 12 months. 3, 4

Algorithmic Approach to Refractory Disease:

1. Switch from MPA to cyclophosphamide or vice versa 2, 4
2. Add rituximab for refractory cases 2, 3, 4
3. Assess medication adherence and consider therapeutic drug monitoring 2, 4
4. Consider repeat renal biopsy to evaluate for transformation to chronic disease or class transformation 2, 4

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Critical Pitfalls to Avoid

• Never delay renal biopsy as clinical-histological dissociation is common and treatment depends on accurate classification 2, 5, 6
• Never use azathioprine for induction therapy due to higher flare risk; reserve only for maintenance or when MMF/cyclophosphamide contraindicated 2, 3, 4
• Avoid excessive glucocorticoid exposure by adhering to reduced-dose schemes and rapid taper protocols 2, 4
• Do not abruptly discontinue calcineurin inhibitors as this leads to 40% relapse rate within one year 3
• Never postpone immunosuppression in nephrotic-range proteinuria as 10-30% of Class V patients progress to kidney failure 3
• Adjust all medications for pregnancy planning (stop MMF, cyclophosphamide, leflunomide; switch to azathioprine) 2, 3
• Manage patients in experienced centers whenever possible due to complexity of disease 1