What is the recommended treatment regimen for a patient with systemic lupus erythematosus who develops rapidly progressive glomerulonephritis due to lupus nephritis?

Treatment of Lupus Nephritis with Rapidly Progressive Glomerulonephritis

For lupus nephritis presenting as rapidly progressive glomerulonephritis (RPGN), initiate immediate aggressive immunosuppression with high-dose corticosteroids combined with either low-dose intravenous cyclophosphamide (Euro-Lupus regimen: 500 mg IV every 2 weeks for 6 doses) or mycophenolate mofetil (2-3 g/day), plus consider adding plasmapheresis if the patient is dialysis-dependent or has rapidly rising serum creatinine. 1

Initial Assessment and Diagnosis

Confirm RPGN Features

• Document rapidly declining kidney function (rising serum creatinine over days to weeks) 2
• Verify presence of >25% glomeruli with crescents or necrosis on kidney biopsy 1
• Check for dialysis dependence or imminent need for dialysis 3
• Assess for pulmonary hemorrhage, which may coexist 4

Rule Out Thrombotic Microangiopathy

• Test ADAMTS13 activity and antibodies 2
• Check antiphospholipid antibodies 2
• If TMA is confirmed, manage according to underlying etiology (plasma exchange for TTP, anticoagulation for antiphospholipid syndrome) 2

Induction Therapy Regimen

Glucocorticoid Protocol (Mandatory)

Initiate with intravenous methylprednisolone 500-1000 mg daily for 3 consecutive days, followed immediately by oral prednisone 0.5-1.0 mg/kg/day (maximum 80 mg), tapering to <5 mg/day by week 25. 1, 2

The pulse methylprednisolone dosing should be tailored to disease severity—use 1000 mg daily for dialysis-dependent patients or those with >50% crescents. 1

Immunosuppressive Agent Selection

First-Line Option: Low-Dose IV Cyclophosphamide (Preferred for RPGN)

Administer 500 mg IV every 2 weeks for 6 doses (Euro-Lupus regimen, total ≈3 g over 3 months). 1, 2

This regimen is specifically preferred for RPGN because:

• IV administration ensures compliance in critically ill patients 1
• Provides rapid immunosuppression for severe nephritic features 1
• Ten-year follow-up demonstrates efficacy equivalent to high-dose protocols with markedly reduced toxicity 1
• Particularly appropriate when >25% of glomeruli show crescents/necrosis 1

Critical safety measures during cyclophosphamide:

• Co-administer mesna with each infusion to prevent hemorrhagic cystitis 1
• Provide Pneumocystis jirovecii prophylaxis 1
• For women of childbearing age, administer gonadotropin-releasing hormone agonist (leuprolide) for fertility preservation 1
• Monitor neutrophil counts monthly 1

Alternative First-Line: Mycophenolate Mofetil

Dose 2-3 g/day divided twice daily if cyclophosphamide is contraindicated or fertility preservation is paramount. 1, 2

However, cyclophosphamide is generally preferred for true RPGN with crescentic disease because evidence for MMF efficacy comes primarily from trials of less severe proliferative nephritis. 5

Plasmapheresis Consideration

Add plasmapheresis for patients requiring dialysis or with rapidly increasing serum creatinine despite initial immunosuppression. 2

The evidence supporting plasmapheresis in lupus RPGN:

• One study of 10 dialysis-dependent RPGN patients (3 with SLE) showed 9/10 regained renal function after immunoadsorption plus cyclophosphamide and prednisolone 3
• Mean time to dialysis independence was 4.6 days (range 3-7 days) 3
• KDIGO guidelines suggest plasmapheresis addition for patients requiring dialysis or with rapidly increasing creatinine 2

Plasmapheresis protocol: Perform daily or every-other-day sessions while continuing immunosuppression, typically 5-7 exchanges over 10-14 days. 3

Mandatory Adjunctive Therapy

• Hydroxychloroquine ≤5 mg/kg/day (typically 200-400 mg daily) for all patients unless contraindicated 2, 1
• ACE inhibitor or ARB for proteinuria control and blood pressure management 1, 2

Early Response Assessment

8-Week Milestone

A ≥25% reduction in proteinuria and/or normalization of complement C3/C4 predicts favorable response. 1

3-Month Decision Point

If serum creatinine increases ≥50% or proteinuria worsens within the first 3 months, immediately switch to alternative therapy or perform repeat kidney biopsy. 2, 1

The repeat biopsy distinguishes:

• Active inflammatory disease requiring different immunosuppression 2
• Chronic scarring where further immunosuppression is futile 2
• Transformation to different histologic class 2

6-Month Continuation Rule

Continue induction therapy for the full 6 months unless clear clinical deterioration occurs, because 65-80% of responders emerge by 12-24 months. 1

Approximately 50% achieve definite improvement by 6 months, but premature switching is a common pitfall. 1

Transition to Maintenance Therapy

After Completing Induction (6 Months)

Switch to mycophenolate mofetil 1.5-2 g/day divided twice daily as preferred maintenance agent. 2, 1

MMF is superior to azathioprine for maintenance because:

• Fewer renal relapses in the ALMS extension phase 2
• Better outcomes when steroids are tapered and stopped 2

Alternative maintenance: Azathioprine 1-2 mg/kg/day if MMF is intolerable or unavailable. 2, 1

Maintenance Duration

Continue maintenance therapy for minimum 36 months total (induction + maintenance), and at least 12 months after achieving complete remission before considering taper. 2, 1

The high relapse risk in lupus nephritis typically occurs within 5-6 years, justifying prolonged maintenance. 1

Glucocorticoid Management During Maintenance

Taper prednisone to ≤5-7.5 mg/day, aiming for complete withdrawal when disease control permits. 2, 1

Avoid rapid steroid taper, especially before 6 months, as this increases relapse risk. 2

Management of Refractory Disease

If No Response After 6 Months of Standard Therapy

First verify medication adherence—non-adherence is the most common cause of apparent treatment failure, especially in young women experiencing steroid side effects. 2, 1

Then perform repeat kidney biopsy to distinguish active disease from chronic scarring. 2

For Confirmed Refractory Active Disease

Add rituximab for patients failing both cyclophosphamide and mycophenolate. 2, 1

Rituximab is reserved for salvage therapy because:

• The LUNAR trial showed no benefit when added to MMF as initial therapy 2
• Open-label studies report ~50% response rates in refractory patients 1
• It is not validated as primary second-line therapy 1

Alternative salvage options include:

• Extended course of IV cyclophosphamide 2
• Calcineurin inhibitors (tacrolimus) if eGFR >45 mL/min/1.73 m² 1
• Enrollment in clinical trials of novel biologics 2

Common Pitfalls and How to Avoid Them

Premature Treatment Switching

Do not change therapy before 6 months unless clear worsening occurs, because most responders emerge between 6-24 months. 1

Persistence of microscopic hematuria or low-grade proteinuria alone does not indicate treatment failure. 2

Inadequate Glucocorticoid Taper

Failure to reduce prednisone below 7.5 mg/day by 3-6 months contributes to organ-damage accumulation. 1

However, overly rapid taper (aiming for steroid-free by 6 months) increases relapse risk. 2

Assuming Treatment Failure Without Checking Adherence

Always explore adherence issues before altering immunosuppressive regimens, particularly in young women with steroid side effects. 2, 1

Using High-Dose Cyclophosphamide Unnecessarily

The Euro-Lupus low-dose regimen (≈3 g total) provides equivalent efficacy with superior safety compared to the NIH high-dose protocol (cumulative 6-12 g). 1

The low-dose regimen markedly reduces:

• Serious infections and leukopenia 1
• Gonadotoxicity (4.5% vs 12-62% amenorrhea risk) 1
• Lifetime cumulative exposure (stays well below 36 g threshold) 1

Omitting Hydroxychloroquine

Hydroxychloroquine is foundational therapy that reduces flares, prevents organ damage, and improves survival in SLE. 2, 1

It should be continued indefinitely unless contraindicated (retinal toxicity). 2

Delaying Plasmapheresis in Dialysis-Dependent Patients

For patients requiring dialysis at presentation, add plasmapheresis immediately rather than waiting to see if immunosuppression alone will work. 2, 3

The window for renal recovery narrows rapidly in crescentic disease. 3, 6

Definition of Treatment Success

Complete Response (Target Outcome)

• Proteinuria <0.5 g/g (50 mg/mmol) by urine protein-to-creatinine ratio 2, 1
• Stabilization or improvement in kidney function (±10-15% of baseline eGFR) 2, 1
• Achieved within 6-12 months, though may take >12 months 2

Partial Response (Acceptable Outcome)

• ≥50% reduction in proteinuria to <3 g/g (300 mg/mmol) 2
• Stabilization or improvement in kidney function 2

Patients achieving only partial remission have excellent long-term outcomes and should not be overtreated. 2