How should renal involvement in antiphospholipid antibody syndrome be diagnosed and managed?

Diagnosis and Management of Renal Involvement in Antiphospholipid Antibody Syndrome

Long-term warfarin anticoagulation (target INR 2.0–3.0) is the cornerstone of treatment for APS nephropathy, achieving approximately 59% complete response rates compared to 31% with immunosuppression alone, and direct oral anticoagulants are contraindicated. 1

Diagnostic Approach

Laboratory Testing

• Perform all three antiphospholipid antibody assays (lupus anticoagulant, anticardiolipin IgG/IgM, and anti-β₂-glycoprotein-I IgG/IgM) in every patient with unexplained proteinuria, declining renal function, or hypertension. 1
• Repeat testing must occur ≥12 weeks apart to confirm persistent positivity before making treatment decisions. 1, 2
• Triple positivity (all three antibodies positive) confers the highest thrombotic risk and should prompt aggressive management. 2

Indications for Kidney Biopsy

• Biopsy is mandatory when proteinuria ≥0.5 g/24 hours (or urine protein-to-creatinine ratio ≥500 mg/g) persists, especially with positive antiphospholipid antibodies. 1
• Unexplained decline in glomerular filtration rate warrants biopsy even without significant proteinuria. 1
• Clinical and laboratory data cannot replace histology; biopsy is the only way to distinguish APS nephropathy from lupus nephritis or other causes of thrombotic microangiopathy. 1

Histopathologic Features to Identify

The pathologist must specifically evaluate for:

• Acute thrombotic microangiopathy lesions (glomerular capillary thrombi). 3
• Chronic vascular lesions: fibrous intimal hyperplasia, organizing thrombi with recanalization, fibrous arterial occlusions, and focal cortical atrophy. 3, 4
• Any thrombotic microangiopathy finding should trigger repeat antiphospholipid antibody testing if not previously performed. 1

Clinical Presentation

Look for these specific features:

• Systemic hypertension (ranging from mild to malignant). 5, 3
• Proteinuria (mild to nephrotic range). 3
• Microscopic hematuria. 6
• Progressive renal insufficiency (slowly to rapidly progressive). 5
• Thrombocytopenia or hemolytic anemia should raise suspicion for concurrent thrombotic microangiopathy. 4

Management Strategy

Primary Treatment: Anticoagulation

Warfarin is the only acceptable anticoagulant for APS nephropathy:

• Target INR 2.0–3.0 for renal vascular thrombosis (venous or small-vessel disease). 1, 2
• For concurrent arterial thrombotic events, either target INR 3.0–4.0 or use moderate-intensity warfarin (INR 2.0–3.0) plus low-dose aspirin 81 mg daily. 1, 2
• Monthly INR monitoring is required, with more frequent checks if unstable. 1

Direct oral anticoagulants (DOACs) are absolutely contraindicated:

• DOACs increase recurrent thrombotic events compared to warfarin in APS patients. 1, 7
• Rivaroxaban specifically increases arterial thrombosis risk in triple-positive patients. 2
• If a patient is already on a DOAC, transition immediately to warfarin. 2

Adjunctive Therapies

Hydroxychloroquine 200–400 mg daily:

• Use in all patients with concurrent systemic lupus erythematosus to reduce renal flares and provide additional thrombotic protection. 6, 2
• Continue throughout pregnancy in SLE patients. 2

Renin-angiotensin-aldosterone system blockade:

• ACE inhibitors or angiotensin receptor blockers are indicated for proteinuria >50 mg/mmol (approximately 500 mg/g) or hypertension. 6
• Optimize for at least 3 months before escalating immunosuppression in patients with proteinuria >1 g/24 hours. 1

Low-dose aspirin:

• Consider acetyl-salicylic acid in patients with antiphospholipid antibodies to reduce cardiovascular and thrombotic complications. 6

Prophylactic anticoagulation for nephrotic syndrome:

• Consider anticoagulation when serum albumin <20 g/L, especially if persistent or in the presence of antiphospholipid antibodies. 6

Role of Immunosuppression

Immunosuppression is adjunctive, not primary therapy:

• Add immunosuppressive agents only when APS nephropathy coexists with active systemic lupus erythematosus or when inflammatory disease is evident on biopsy. 1
• In a retrospective series of 97 patients with renal thrombotic microangiopathy, immunosuppression alone achieved only 38% complete response and 23% partial response at 12 months, inferior to anticoagulation. 1
• When lupus nephritis is present alongside APS nephropathy, follow standard lupus nephritis protocols (mycophenolate or cyclophosphamide induction, then maintenance immunosuppression) while continuing anticoagulation. 6

Management of Catastrophic APS with Renal Involvement

"Triple therapy" is mandatory:

1. Immediate therapeutic anticoagulation:

   • Start unfractionated heparin or low-molecular-weight heparin immediately. 1, 7
   • Transition to warfarin (target INR 2.0–3.0) once stable. 1, 7
   • Do not withhold anticoagulation during sepsis unless active bleeding or severe thrombocytopenia is present. 2

2. High-dose glucocorticoids:

   • Methylprednisolone 500–1000 mg IV daily for 3–5 days. 1, 7
   • Then oral prednisone ≈1 mg/kg/day. 1

3. Plasma exchange:

   • Early plasma exchange improves survival in retrospective analyses. 1, 7
   • Initiate promptly given multi-organ involvement. 7

Additional therapies for refractory cases:

• Intravenous immunoglobulin: 1 g/kg daily for 2 days or 0.4 g/kg daily for 5 days. 1, 7
• Rituximab for patients failing initial therapy. 1, 7
• Eculizumab (C5 complement inhibitor) for refractory catastrophic APS. 1, 7
• If catastrophic APS occurs during an SLE flare, add intravenous cyclophosphamide 500–1000 mg/m² monthly. 1, 7

Monitoring Protocol

Regular surveillance is essential:

• Monthly INR checks for patients on warfarin. 1
• Blood pressure at every clinical encounter. 1
• Serum creatinine, eGFR, serum albumin, and proteinuria at each visit. 6
• Urinary sediment with microscopic evaluation to detect active disease. 6
• Serum C3, C4, and anti-dsDNA antibodies (if concurrent SLE) at baseline and intermittently. 6
• Antiphospholipid antibodies and lipid profile at baseline and monitored intermittently. 6
• Screen regularly for thrombotic symptoms: unexplained limb swelling, chest pain, dyspnea, or focal neurologic deficits. 1

Visit frequency:

• Every 2–4 weeks for the first 2–4 months after diagnosis or flare. 6
• Then every 3–6 months lifelong for monitoring renal and extra-renal disease activity. 6

Special Considerations

End-Stage Renal Disease

• All renal replacement modalities can be used, but peritoneal dialysis carries increased infection risk if still on immunosuppression. 6
• Vascular access thrombosis risk is higher with antiphospholipid antibodies. 6
• Transplantation should be delayed until lupus activity is absent or low for 3–6 months. 6
• Antiphospholipid antibodies must be checked during transplant preparation because they increase vascular thrombosis risk in the allograft. 6

Pregnancy Management

• Urine protein-to-creatinine ratio at least once per trimester. 1
• Serum creatinine and complement (C3/C4) at least once per trimester. 1
• Therapeutic anticoagulation must continue for 6–12 weeks postpartum in patients with thrombotic APS. 2

Critical Pitfalls to Avoid

• Do not use DOACs in APS nephropathy; they are inferior to warfarin and increase thrombotic events. 1, 2
• Do not delay kidney biopsy in anticoagulated patients; the diagnostic benefit outweighs bleeding risk. 1
• Do not attribute thrombotic microangiopathy solely to lupus nephritis; any TMA lesion mandates repeat antiphospholipid antibody testing. 1
• Do not withhold anticoagulation during sepsis unless active bleeding or severe thrombocytopenia is present; sepsis is prothrombotic and synergizes with APS risk. 2
• Do not rely on immunosuppression alone; anticoagulation is the cornerstone and achieves superior outcomes. 1
• Do not assume normal complement levels exclude SLE flare; look for declining trends even within normal range. 2