What is the recommended management for a patient with systemic lupus erythematosus who develops lupus nephritis?

Management of Lupus Nephritis

For induction therapy in lupus nephritis, use glucocorticoids combined with either mycophenolate mofetil (2-3 g/day) or cyclophosphamide, with MMF preferred for most patients due to comparable efficacy and superior safety profile; for maintenance therapy, use MMF or azathioprine over cyclophosphamide to minimize long-term toxicity while preventing relapses. 1, 2

Initial Diagnostic Workup

Essential Screening and Monitoring

• Perform routine screening at every visit with urinalysis with microscopy, urine protein-to-creatinine ratio (UPCR), serum creatinine, and blood pressure in all SLE patients 2
• Red blood cell casts on urinalysis are highly specific for glomerulonephritis and warrant immediate further evaluation 2
• Quantify proteinuria using spot UPCR (preferred for convenience) or 24-hour urine collection 2
• Measure serum albumin to identify nephrotic syndrome and provide prognostic information 2

Immunologic Assessment

• Check anti-dsDNA antibodies and complement levels (C3, C4), as low complement correlates with active disease and predicts lupus nephritis 1, 2
• Note that changes in anti-dsDNA and C3 have only limited ability to predict treatment response and should be used as supplemental information 1
• Measure antiphospholipid antibodies to assess thrombosis risk 2

Kidney Biopsy Indications

• Perform kidney biopsy in any SLE patient with proteinuria ≥0.5 g/24h (or ≥500 mg/g UPCR) with or without hematuria, cellular casts, or unexplained decline in kidney function 2
• Biopsy provides critical information including ISN/RPS histologic class, activity and chronicity indices, and excludes alternative diagnoses 1, 2

Induction Therapy

Standard Glucocorticoid Protocol

• Initiate high-dose glucocorticoids as the foundation of induction therapy 1, 2
• Use weight-based oral prednisone dosing: <50 kg → 50 mg/day; 50-75 kg → 60 mg/day; >75 kg → 75 mg/day 3
• For severe presentations (e.g., concurrent diffuse alveolar hemorrhage), administer IV methylprednisolone 500-1000 mg/day for three consecutive days before transitioning to oral therapy 3

Immunosuppressive Agent Selection

First-Line Options:

• Mycophenolate mofetil 2-3 g/day (or equivalent mycophenolic acid) is recommended as first-line therapy for Class III/IV lupus nephritis 1, 2
• MMF demonstrates at least similar efficacy to cyclophosphamide with a more favorable toxicity profile, particularly regarding gonadal toxicity 1
• Tacrolimus is an alternative option, though evidence is primarily from Asian populations 1

Cyclophosphamide Indications:

• Reserve cyclophosphamide for severe presentations: crescentic glomerulonephritis with rapidly deteriorating renal function, significant renal impairment at presentation (creatinine >3.4 mg/dL), or refractory disease 3, 4, 5
• Use low-dose IV cyclophosphamide (500 mg every 2 weeks for 6 doses, Euro-Lupus regimen) to minimize gonadal toxicity 1, 6
• Alternative dosing: 15 mg/kg IV at weeks 0,2,4,7,10,13, with dose reduction of 2.5 mg/kg for age >60 years or eGFR <30 mL/min/1.73 m² 3
• High-dose intermittent cyclophosphamide (pulse therapy) demonstrates a more favorable efficacy-to-toxicity ratio than oral cyclophosphamide 1

Critical Caveat: Although MMF is increasingly used as first-line therapy, long-term data show cyclophosphamide may result in better preservation of kidney function and fewer relapses in severe lupus nephritis, despite higher short-term toxicity 5, 7

Treatment Response Assessment

• Failure to achieve significant response by 6 months (defined as improvement in serum creatinine and reduction of proteinuria to <1 g/day) should prompt discussions for intensification of therapy 1
• Expect ≥25% proteinuria reduction by 3 months, ≥50% reduction by 6 months, and target <0.5-0.7 g/24h by 12 months 2, 8
• Complete response: proteinuria <0.5 g/g with stable/improved kidney function within 6-12 months 2
• Partial response: ≥50% proteinuria reduction to <3 g/g with stable kidney function within 6-12 months 2

Maintenance Therapy

Agent Selection

• Use MMF or azathioprine over cyclophosphamide for maintenance therapy to minimize long-term toxicity 1, 2
• This is a strong recommendation based on high certainty of fewer adverse events with MMF or azathioprine compared to cyclophosphamide, despite low certainty regarding superior efficacy 1
• MMF is preferred for patients unable to tolerate azathioprine or whose symptoms flare while on azathioprine 1
• Cost and availability issues may favor azathioprine in resource-limited settings 1

Duration and Monitoring

• Continue immunosuppressive maintenance for 18 months to 4 years to prevent relapse 3
• Combine with low-dose glucocorticoids (<7.5 mg/day) 2, 6
• Monitor urine sediment, UPCR, serum creatinine, and immunologic markers (anti-dsDNA, C3, C4) at each visit 1, 2

Adjunctive Therapies

Universal Recommendations

• Continue or initiate hydroxychloroquine (≤5 mg/kg real body weight) in all SLE patients unless contraindicated, as it reduces flares and improves survival 6
• Hydroxychloroquine efficacy and safety in lupus pregnancy have been evaluated in randomized trials 1
• Provide regular ophthalmologic monitoring for hydroxychloroquine toxicity 3

Renoprotective Measures

• Use angiotensin-converting enzyme inhibitors for blood pressure control and proteinuria reduction 4
• Implement vigorous blood pressure control 4
• Address hyperlipidemia and osteoporosis prevention 4

Emerging Therapies

• Avacopan 30 mg twice daily may replace glucocorticoids in patients at high risk for steroid toxicity, especially when eGFR <30 mL/min/1.73 m² 3
• Rituximab (375 mg/m² IV weekly for 4 weeks) can be considered for refractory disease, with small trials suggesting up to 50% of cyclophosphamide-refractory patients may respond 1, 3
• Belimumab and other B-cell modulation therapies are confined to refractory disease pending further controlled trials 4

Special Populations

Pregnancy Considerations

• Safe medications during pregnancy: prednisolone and other non-fluorinated glucocorticoids, azathioprine, hydroxychloroquine, and low-dose aspirin 1
• Contraindicated medications: mycophenolate mofetil, cyclophosphamide, and methotrexate must be avoided during pregnancy 1
• Patients with lupus nephritis and antiphospholipid antibodies are at higher risk of pre-eclampsia and require closer monitoring 1
• Combined unfractionated or low-molecular-weight heparin plus aspirin reduce pregnancy loss and thrombosis in pregnant patients with antiphospholipid syndrome 1

Childhood-Onset Lupus Nephritis

• Use high-dose glucocorticoids (prednisone 1-2 mg/kg/day, maximum 60 mg/day) plus MMF or cyclophosphamide for induction 1
• Use MMF or azathioprine over cyclophosphamide for maintenance, with cost and availability potentially favoring azathioprine 1
• Note that differential pharmacokinetic effects of MMF in childhood lupus nephritis may require dosing increases 1

Management of Refractory or Severe Disease

Escalation Strategy

• For patients not responding within 48-72 hours, escalate glucocorticoid dose 3
• Consider switching between rituximab and cyclophosphamide 3
• Re-evaluate diagnosis to exclude medication non-adherence, infection, malignancy, or drug-induced vasculitis 3
• Refer immediately to a center with expertise in vasculitis and lupus nephritis 3

Plasma Exchange Considerations

• Strongly consider therapeutic plasma exchange when lupus nephritis is accompanied by serum creatinine >3.4 mg/dL or need for dialysis 3
• Note that the PEXIVAS trial showed no definitive mortality benefit and increased infection risk, tempering this recommendation 3
• Plasma exchange remains reasonable rescue therapy in refractory cases 3

Common Pitfalls to Avoid

• Do not delay immunosuppressive therapy while awaiting diagnostic confirmation—start empiric treatment immediately when immune-mediated disease is suspected 3
• Do not use mycophenolate mofetil, cyclophosphamide, or methotrexate during pregnancy 1
• Do not rely solely on anti-dsDNA and complement levels to guide treatment decisions, as their predictive value for treatment response is limited 1
• Do not continue cyclophosphamide for maintenance therapy when MMF or azathioprine are available, due to cumulative toxicity 1, 2
• Do not use NSAIDs indiscriminately in lupus nephritis patients, as they pose additional nephrotoxic risk 1