Lupus Associated Nephrotic Syndrome

Lupus associated nephrotic syndrome is nephrotic range proteinuria in a patient with systemic lupus erythematosus. It occurs in about 30 to 50% of those with lupus nephritis. Nephrotic syndrome adds thrombosis and infection risk, so it needs both immunosuppression and supportive care.

It occurs with three patterns:

• Membranous lupus nephritis (class V, pure or mixed with class III or IV).
• Diffuse proliferative nephritis (class IV, the most common).
• Lupus podocytopathy (minimal change or focal segmental pattern with effaced foot processes and no or minimal immune deposits).

Lupus affects about 1 in 1000 to 1 in 2000 people, more often women of reproductive age and people of African, Asian and Hispanic ancestry. About 40 to 60% develop clinical lupus nephritis within 10 years.

Pathophysiology. Autoantibodies against nuclear antigens form immune complexes that deposit in the mesangium, subendothelial space and subepithelial space, activating complement and recruiting inflammatory cells. Subepithelial deposits drive nephrotic range proteinuria; podocytopathy results from cytokine mediated podocyte injury. Antiphospholipid antibodies may cause thrombotic microangiopathy and vascular lesions.

• Oedema, frothy urine, hypertension, dyslipidaemia, thrombotic complications.
• Class IV or III: active urine sediment (red cell casts), falling eGFR, hypertension, low C3 and C4, raised anti-dsDNA.
• Class V: bland sediment, nephrotic syndrome, normal or only mildly reduced complement, slowly progressive.
• Systemic lupus: rash (malar, photosensitive), arthritis, oral ulcers, serositis, cytopenias, neuropsychiatric disease, fever.
• Thrombosis (renal vein, deep vein, pulmonary, arterial) from nephrotic syndrome and antiphospholipid antibodies.

Red flags

• Creatinine rising over days to weeks or oliguria (crescents or thrombotic microangiopathy).
• Platelets under 100 x 10⁹/L with haemolysis (thrombotic microangiopathy, antiphospholipid syndrome).
• Hypertensive emergency, seizures, psychosis, cardiac tamponade.
• Pregnancy, especially with active nephritis.
• Fever on immunosuppression (opportunistic infection).

• Urine protein:creatinine ratio (and 24-hour collection), albumin, lipids, creatinine, eGFR, urine microscopy, full blood count and film, haemolysis markers.
• Antinuclear antibodies, anti-dsDNA, anti-Smith, anti-Ro, anti-La, C3, C4, antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, anti-beta-2 glycoprotein I), direct antiglobulin test.
• Hepatitis B and C, HIV, tuberculosis screen, thiopurine methyltransferase activity if azathioprine is planned, pregnancy test, bone health baseline.
• Kidney biopsy is indicated for proteinuria above 0.5 g daily with active sediment, any nephrotic syndrome, or unexplained fall in eGFR. Classify by activity and chronicity.
  • Class V: subepithelial deposits and spikes.
  • Class IV: endocapillary proliferation, wire loops, full house immunofluorescence, tubuloreticular inclusions.
  • Podocytopathy: foot process effacement without deposits.
• Repeat biopsy if there is no response after 6 months, or at relapse with new features.

Differential diagnosis

• Primary membranous nephropathy (anti-phospholipase A2 receptor positive), IgA nephropathy, antiphospholipid nephropathy, drug induced lupus, ANCA vasculitis, infection related glomerulonephritis, thrombotic microangiopathy from other causes, hepatitis B and C glomerulonephritis.

For all patients

• Hydroxychloroquine 200 to 400 mg daily (maximum 5 mg/kg actual body weight daily; reduce when eGFR is under 30). Eye screening after 5 years (or earlier with kidney disease).
• Blood pressure below 130/80 mmHg: ramipril 2.5 mg daily increased to 10 mg daily. Check creatinine and potassium at 1 to 2 weeks. Accept a rise up to 30%; stop if potassium exceeds 6.0 mmol/L.
• For persistent proteinuria once disease is controlled: dapagliflozin 10 mg daily (eGFR at least 25) or empagliflozin 10 mg daily (eGFR at least 20).
• Sodium under 2 g daily; furosemide 40 to 80 mg once or twice daily for oedema; atorvastatin 20 mg daily (up to 80 mg).
• Anticoagulation: enoxaparin 40 mg daily (20 mg if eGFR is under 30) for albumin under 20 g/L with additional risk factors.
• Antiphospholipid syndrome with thrombosis: warfarin to INR 2 to 3 (INR 3 to 4 for arterial events). Direct oral anticoagulants are not suitable.
• Antiphospholipid antibody positive patients without thrombosis: aspirin 75 mg daily.
• Vaccination (pneumococcal, influenza, hepatitis B, human papillomavirus). No live vaccines on high dose immunosuppression.
• Bone protection (calcium 1000 mg daily, cholecalciferol 800 to 2000 units daily); contraception planning.

Class III or IV (with or without class V): induction (start within days of biopsy)

• Methylprednisolone 500 mg intravenously daily for 3 days (or 250 mg for 3 days in milder disease), then prednisolone 0.5 mg/kg daily (maximum 40 mg), reduced to 5 mg daily or less by 6 months. Reduced dose steroid regimens are preferred to limit toxicity.
• Plus one of the following:
  • Mycophenolate mofetil 1 g twice daily, increasing to 1.5 g twice daily if tolerated, for at least 6 months (in patients of African ancestry, 1.5 g twice daily may be preferred).
  • Low dose intravenous cyclophosphamide 500 mg every 2 weeks for 6 doses (total 3 g), an alternative when adherence to oral therapy is a concern.
  • High dose cyclophosphamide 0.5 to 1 g/m² monthly for 6 months for severe crescentic disease or in patients of African ancestry.
• With specialist input, add one of the following in refractory or high risk disease:
  • Belimumab 10 mg/kg intravenously at weeks 0, 2 and 4, then every 4 weeks.
  • Voclosporin 23.7 mg twice daily (eGFR above 45; reduced dose or stop if eGFR falls by more than 20%).
  • Obinutuzumab.
• Rituximab 1 g on days 1 and 15 in refractory disease or relapse.
• Crescentic disease with rapid decline: methylprednisolone 500 mg to 1 g daily for 3 days, then prednisolone 1 mg/kg daily (maximum 60 mg) with cyclophosphamide.
• Plasma exchange (60 mL/kg, 5 to 7 sessions) for thrombotic microangiopathy or antiphospholipid catastrophe.

Maintenance (at least 3 years, often longer)

• Mycophenolate mofetil 1 g daily to 1 g twice daily, or azathioprine 2 mg/kg daily (maximum 150 mg daily). Check thiopurine methyltransferase activity; reduce the dose by 75% if allopurinol is co-prescribed.
• Give prednisolone 5 mg or less daily. Stop gradually after 3 or more years of sustained remission.
• Add belimumab or tacrolimus (0.05 mg/kg daily in divided doses, trough 5 to 8 ng/mL) when relapsing.

Pure class V with nephrotic syndrome

• Supportive measures with hydroxychloroquine and renoprotection.
• If proteinuria is above 3 g daily or persists after 6 months: prednisolone 0.5 mg/kg daily with mycophenolate mofetil 1 g twice daily.
• Alternatives to mycophenolate mofetil: tacrolimus 0.05 to 0.1 mg/kg daily in divided doses (trough 5 to 8 ng/mL), low dose cyclophosphamide, or rituximab 1 g on days 1 and 15.

Lupus podocytopathy. Prednisolone 1 mg/kg daily (maximum 60 mg) for 4 to 8 weeks, then taper. Add mycophenolate mofetil 1 g twice daily or azathioprine 2 mg/kg daily to prevent relapse. Early response is typical.

Response targets. Urine protein:creatinine ratio falls by at least 25% by 3 months, at least 50% by 6 months, and under 50 mg/mmol (0.5 g daily) by 12 months, with stable eGFR. Complement and anti-dsDNA improve within weeks. If no response, confirm adherence (mycophenolic acid levels), check for infection, repeat biopsy, and switch therapy.

Prophylaxis during immunosuppression.

• Co-trimoxazole 480 mg daily (or atovaquone 1500 mg daily if sulphonamide allergy) with cyclophosphamide, rituximab or prednisolone 20 mg or more.
• Proton pump inhibitor; bone protection.
• Hepatitis B screening and antiviral cover before rituximab.
• Ovarian protection with leuprorelin 3.75 mg monthly during cyclophosphamide where fertility is a priority.
• Mesna if high dose cyclophosphamide.

Kidney failure. Dialysis at eGFR 5 to 10 with symptoms. Transplantation after 6 to 12 months of quiescent disease. Recurrence of lupus nephritis in the graft is uncommon (under 5%).

Monitoring. Urine protein:creatinine ratio, creatinine, albumin, C3, C4, anti-dsDNA and full blood count every 2 to 4 weeks during induction, then every 3 months. Blood pressure every visit; bone density and eye checks.

Referral and escalation. Joint nephrology and rheumatology care; urgent for crescents, thrombotic microangiopathy, seizures, or infection on treatment; obstetric and nephrology planning for pregnancy.

Special groups

• Pregnancy: plan conception after 6 months of quiescence. Continue hydroxychloroquine 200 to 400 mg daily, azathioprine 2 mg/kg daily or tacrolimus 0.05 mg/kg daily. Stop mycophenolate (switch 6 weeks before conception), cyclophosphamide, ACE inhibitors and angiotensin receptor blockers. Aspirin 75 to 150 mg daily from 12 weeks.
• Children: more severe disease; avoid long term high dose steroids to protect growth; specialist dosing.
• Older adults: lower immunosuppression targets with infection prophylaxis.
• Sub-Saharan Africa: screen for tuberculosis, hepatitis B and HIV before and during treatment; infection is the leading cause of death.