Management of Lupus Nephritis

Initial Diagnostic Approach

All patients with clinical evidence of active lupus nephritis require kidney biopsy for histological confirmation using the ISN/RPS 2003 classification system, as this directly determines treatment intensity. 1

Biopsy is indicated for reproducible proteinuria ≥0.5 g/24 hours, especially with glomerular hematuria and/or cellular casts 1
Assessment must include activity and chronicity indices, plus evaluation for vascular lesions associated with antiphospholipid syndrome 1
Test for antiphospholipid antibodies, anti-dsDNA, anti-C1q autoantibodies, and complement levels (C3, C4) 2
Patients require comanagement by both nephrologists and rheumatologists with lupus expertise from the point of clinical suspicion 3

Treatment Goals and Response Definitions

The target is complete clinical response—proteinuria <0.5-0.7 g/24 hours with normal or near-normal GFR—by 12 months, though this can be extended for patients with baseline nephrotic-range proteinuria. 1

Response Criteria:

Complete response: Proteinuria <0.5 g/g (50 mg/mmol) with stable/improved kidney function (±10-15% of baseline) within 6-12 months 1
Partial response: ≥50% reduction in proteinuria to <3 g/g (300 mg/mmol) with stable/improved kidney function within 6-12 months 1
Early indicators: Expect ≥25% proteinuria reduction by 3 months and ≥50% by 6 months 3, 2

Induction Therapy for Class III/IV Proliferative Lupus Nephritis

For active Class III or IV lupus nephritis (with or without membranous component), initiate treatment with glucocorticoids PLUS one of four equally recommended first-line options. 1

First-Line Induction Options (all graded 1B):

Option 1: Mycophenolic Acid Analogs (MPAA)

Mycophenolate mofetil (MMF) 1.0-1.5 g twice daily (total 2-3 g/day) OR mycophenolic acid 0.72-1.08 g twice daily 1
MMF may increase complete disease remission compared to IV cyclophosphamide (RR 1.17), with decreased alopecia and acceptable infection profile 4

Option 2: Low-Dose Intravenous Cyclophosphamide

500 mg IV every 2 weeks for 6 doses (Euro-Lupus protocol, cumulative 3 grams) 1, 5
This low-dose regimen has comparable efficacy to high-dose with fewer adverse effects, particularly reduced infertility risk 5
High-dose cyclophosphamide (0.5-0.75 g/m² monthly for 6 months) reserved only for patients with adverse prognostic factors and nephrotic-range proteinuria 1, 5

Option 3: Belimumab + MPAA or Cyclophosphamide

Belimumab 10 mg/kg IV every 2 weeks for 3 doses, then every 4 weeks, combined with either MPAA or low-dose IV cyclophosphamide 1
Continue belimumab for up to 2.5 years 1

Option 4: MPAA + Calcineurin Inhibitor (CNI)

Voclosporin 23.7 mg twice daily + MPAA in patients with eGFR >45 ml/min per 1.73 m² 1
Consider tacrolimus when voclosporin unavailable; use cyclosporine as third-line CNI 1
Caution: CNIs carry nephrotoxicity risk, particularly with significantly impaired kidney function 1
MMF/tacrolimus combination may increase complete disease remission (RR 2.38) compared to IV cyclophosphamide 4

Glucocorticoid Regimen (Combined with All Options):

Methylprednisolone IV 0.25-0.50 g/day for 1-3 days based on disease severity 1, 5
Followed by oral prednisone 0.3-0.5 mg/kg/day (maximum 80 mg/day) 1
Taper over several months to ≤7.5 mg/day by 3-6 months 1, 5
Lower steroid dosing (reduced-dose regimen from voclosporin trials) is acceptable when using CNI-based therapy 1

Maintenance Therapy

After achieving response with induction therapy, transition to long-term maintenance with MPAA or azathioprine for ≥36 months total duration (induction + maintenance). 1

Maintenance Regimens:

MMF 750-1000 mg twice daily OR mycophenolic acid 540-720 mg twice daily 1
Azathioprine 2 mg/kg/day is an alternative, particularly for patients planning pregnancy or without access to MPAA 1
Choice depends on induction regimen used and pregnancy plans—if MMF used for induction, continue MMF for maintenance 1
Azathioprine increases disease relapse compared to MMF (RR 1.75,114 more relapses per 1000 people) 4

Glucocorticoid Tapering in Maintenance:

Taper to lowest possible dose, ideally <7.5 mg/day or discontinue after ≥12 months of complete clinical response 1
Continue low-dose prednisone (2.5-5 mg/day) only when needed for extrarenal lupus activity 3

Triple Immunosuppression Maintenance:

Patients treated with belimumab or CNI plus standard therapy during induction can continue triple immunosuppression as maintenance 1
CNI duration up to 3 years 1

Universal Adjunctive Therapies

Hydroxychloroquine should be prescribed for ALL lupus nephritis patients unless contraindicated, with dose not exceeding 5 mg/kg/day adjusted for GFR. 1, 3, 2

Requires regular ophthalmological monitoring 1
Renin-angiotensin system blockade (ACE inhibitors or ARBs) for all patients with proteinuria or hypertension 3, 2
Optimize blood pressure control and manage dyslipidemia 2

Management of Pure Class V Membranous Lupus Nephritis

For pure membranous LN with nephrotic-range proteinuria OR proteinuria >1 g/24 hours despite renin-angiotensin blockade, use MMF combined with glucocorticoids as preferred initial treatment. 1

MMF plus glucocorticoids more effective than glucocorticoids alone (60-84% response vs 27%) 1
Tacrolimus plus glucocorticoids is an alternative, particularly for nephrotic syndrome (median time to proteinuria <0.5 mg/mg was 3.6 months with voclosporin) 1
Triple immunosuppression (glucocorticoids + tacrolimus + low-dose MPAA) achieved higher complete remission (33.1% vs 7.8% with cyclophosphamide/azathioprine) 1

Monitoring Protocol

Schedule visits every 2-4 weeks for the first 2-4 months after diagnosis or flare, then adjust frequency based on response. 3

Parameters to Monitor:

Body weight, blood pressure, serum creatinine, eGFR 3
Serum albumin, 24-hour proteinuria or protein-creatinine ratio, urinary sediment 3
Serum C3 and C4, anti-dsDNA antibody levels 3
For patients on MPAA, measure plasma mycophenolic acid levels to ensure adequate dosing 1

Management of Unsatisfactory Response

If response is inadequate by 6-12 months, follow this algorithmic approach: 1

Verify treatment adherence—nonadherence prevalence exceeds 60% in SLE patients; consider switching to IV cyclophosphamide if nonadherence suspected 1
Ensure adequate immunosuppressive dosing by measuring plasma drug levels (mycophenolic acid) or checking infusion records (cyclophosphamide) 1
Repeat kidney biopsy if concerned about chronicity or alternative diagnosis (e.g., thrombotic microangiopathy) 1
Switch to alternative recommended induction regimen when persistent active disease confirmed 1
For refractory disease, consider:
- Addition of rituximab (46% complete response, 32% partial response in meta-analysis) 1
- Extended course of IV pulse cyclophosphamide 1
- Other biologics (obinutuzumab, anti-CD19 CAR-T cell therapy) 1
- Enrollment in clinical trials 1

Management of Disease Relapse

After achieving complete or partial remission, treat relapses with the same initial therapy that achieved the original response, or switch to an alternative recommended regimen. 1

Relapse rates range 10-50%, with higher risk in patients who achieved only partial remission 1
Failure to achieve complete remission increases relapse risk (HR 6.2) 1
Median time to relapse: 36 months after complete response vs 18 months after partial response 1

Special Populations and Complications

Pregnancy Planning:

Pregnancy may be planned when disease is stable with UPCR <500 mg/g for preceding 6 months and GFR >50 ml/min 3
Switch to pregnancy-compatible medications: hydroxychloroquine, prednisone, azathioprine, and calcineurin inhibitors can be continued 3
Discontinue MMF at least 6 weeks before conception; discontinue leflunomide at least 2 years before conception 1
Consider gonadotropin-releasing hormone agonists for women receiving cyclophosphamide 5

Lupus Nephritis with Thrombotic Microangiopathy:

Test for ADAMTS13 activity/antibodies and antiphospholipid antibodies 1
Start plasma exchange and glucocorticoids while awaiting results if PLASMIC score indicates moderate/high risk 1
Manage according to underlying TMA etiology (TTP vs antiphospholipid-associated vs complement-mediated) 1

Fertility Preservation:

Minimize lifetime cyclophosphamide exposure to <36 grams to reduce malignancy risk 5
Low-dose Euro-Lupus protocol (3 grams total) significantly reduces infertility risk compared to high-dose regimens 5

Common Pitfalls to Avoid

Do not delay biopsy—clinical parameters cannot accurately predict histological class, which determines treatment intensity 1
Do not manage with single specialty—both nephrology and rheumatology expertise are essential throughout disease course 3
Do not continue high-dose glucocorticoids beyond 3-6 months—prolonged use increases toxicity without additional benefit 1, 5
Do not use azathioprine for maintenance after MMF induction—this increases relapse risk 4
Do not prescribe CNIs when eGFR ≤45 ml/min per 1.73 m² without careful consideration of nephrotoxicity risk 1
Screen for tuberculosis, hepatitis B, hepatitis C, and HIV before initiating immunosuppression 5
Ensure adequate contraception with cyclophosphamide (teratogenic) and provide hydration/mesna to prevent hemorrhagic cystitis 5

What is the approach to and management of lupus nephritis?

Help us tailor your experience