Renal Involvement in Antiphospholipid Syndrome: Diagnosis and Management
Diagnosis of APS Nephropathy
All patients with suspected kidney involvement should undergo antiphospholipid antibody testing for lupus anticoagulant, anticardiolipin antibodies (IgG/IgM), and anti-β2 glycoprotein-I antibodies (IgG/IgM), with confirmation on two separate occasions at least 12 weeks apart. 1
Clinical Presentation
The hallmark clinical features that should prompt evaluation include:
- Systemic hypertension (often severe and refractory) 2, 3, 4
- Proteinuria ranging from mild (<0.5 g/24h) to nephrotic range (>3.5 g/24h) 2, 5, 3
- Hematuria (microscopic or gross) 2, 5, 3
- Acute or chronic renal insufficiency with unexplained decline in GFR 2, 5
Kidney Biopsy Indications
Kidney biopsy should be performed when there is persistent proteinuria ≥0.5 g/24 hours (or UPCR ≥500 mg/g) and/or unexplained decrease in GFR, especially when antiphospholipid antibodies are positive. 1
The biopsy remains indispensable because clinical and laboratory variables cannot substitute for histological diagnosis. 1
Histopathological Features
Pathological assessment must specifically evaluate for thrombotic and vascular lesions associated with antiphospholipid syndrome, as TMA lesions should raise suspicion of APS nephropathy and prompt aPL (re-)testing. 1
APS nephropathy is characterized by two categories of lesions:
Acute lesions:
- Thrombotic microangiopathy (TMA) affecting glomeruli and/or arterioles 2, 5, 3
- Present in 100% of catastrophic APS, 35-37.5% of primary and SLE-related APS 3
Chronic vascular lesions:
- Fibrous intimal hyperplasia of interlobular arteries and arterioles 2, 5, 4
- Organized thrombi with or without recanalization 2, 5, 4
- Fibrous arterial and arteriolar occlusions 2, 5
- Focal cortical atrophy (distinctive lesion representing renal analogue to cerebral infarcts) 2, 4
Macrovascular Complications
Evaluate for:
- Renal artery stenosis or thrombosis (most common kidney complication, occurring in ~3% of APS patients) 6
- Renal vein thrombosis 2, 5
- Renal infarction 2, 5
Management of APS Nephropathy
Anticoagulation: The Cornerstone of Treatment
Long-term anticoagulation with warfarin is the primary treatment for APS nephropathy, achieving significantly higher complete response rates (59.5% vs 30.8%) compared to immunosuppression alone. 1
Specific warfarin dosing:
- Target INR 2.0-3.0 for venous thrombotic manifestations 1, 7
- Target INR 3.0-4.0 OR moderate-intensity warfarin (INR 2.0-3.0) combined with low-dose aspirin 81 mg daily for arterial thrombotic manifestations 7, 8
Direct oral anticoagulants (DOACs) are contraindicated in APS nephropathy, as they are inferior to warfarin in preventing thromboembolic events. 1, 7
Immunosuppression
Immunosuppressive therapy may be added to anticoagulation, particularly when APS nephropathy occurs in the context of SLE or when there is evidence of active inflammatory disease. 1
In a retrospective study of 97 patients with kidney TMA, complete and partial response rates were 38.1% and 22.6% respectively after 12 months of immunosuppressive treatment, but anticoagulated patients showed superior outcomes. 1
Adjunctive Therapy
Hydroxychloroquine 200-400 mg daily should be added in patients with concurrent SLE, as it provides additional thrombotic protection and should be continued throughout pregnancy. 1, 7, 8
Blood Pressure Management
Aggressive blood pressure control is essential, as systemic hypertension is the clinical hallmark of APS nephropathy. 2, 3, 4
Renin-angiotensin-aldosterone system blockers should be optimized for at least 3 months before escalating immunosuppression in cases with proteinuria >1 g/24 hours. 1
Management of Catastrophic APS with Renal Involvement
Catastrophic APS requires immediate aggressive treatment with the "triple therapy" approach:
Therapeutic anticoagulation with unfractionated heparin or LMWH, transitioning to warfarin (INR 2.0-3.0) once stabilized 1, 9
High-dose glucocorticoids: methylprednisolone 500-1000 mg IV daily for 3-5 days, followed by oral prednisone 1 mg/kg/day 1, 9
Plasma exchange initiated early, as it has been associated with improved patient survival in retrospective studies 1, 9
Additional therapies for refractory cases:
- Rituximab for patients failing initial therapy or with recurrent thrombotic events 1, 9
- Eculizumab (complement C5 inhibitor) for refractory catastrophic APS, as complement activation contributes to aPL-mediated tissue injury 1, 7, 9
- IVIG at 1 g/kg daily for 2 days or 0.4 g/kg daily for 5 days 9
If catastrophic APS occurs in the setting of SLE flare, add intravenous cyclophosphamide 500-1000 mg/m² monthly to address the underlying autoimmune trigger. 7
Monitoring Strategy
Monthly INR monitoring is required for patients on warfarin, with more frequent testing if results are unstable. 7
Regular assessment should include:
- Blood pressure at every visit 7
- Urinalysis with protein-to-creatinine ratio at least once per trimester in pregnant patients 7
- Serum creatinine and complement levels (C3/C4) at least once per trimester 7
- Surveillance for thrombotic symptoms: unexplained leg swelling/pain, chest pain/dyspnea, focal neurologic deficits 8
Common Pitfalls to Avoid
- Do not use DOACs in APS nephropathy—they increase recurrent thrombotic events compared to warfarin 1, 7
- Do not delay kidney biopsy in patients receiving anticoagulation—the benefits of histological evaluation outweigh bleeding risk in most cases 1
- Do not assume TMA is solely due to lupus nephritis—TMA lesions should always prompt aPL (re-)testing even in SLE patients 1
- Do not withhold anticoagulation during sepsis unless there is active bleeding or critically low platelet count—sepsis itself is prothrombotic and increases risk in APS patients 7
- Do not rely on immunosuppression alone—anticoagulation is the cornerstone of APS nephropathy treatment 1