What is the management approach for a patient with anti-phospholipid (anti-PLA2) antibodies, considering their risk of thrombotic events and potential complications?

Management of Anti-PLA2R Antibodies

Anti-PLA2R antibodies are specific markers for primary membranous nephropathy (MN) and should be used to guide immunosuppressive therapy decisions and monitor treatment response, with declining or disappearing antibody levels predicting clinical remission and guiding therapy duration. 1

Diagnostic and Monitoring Role

Anti-PLA2R (phospholipase A2 receptor) antibodies are found in approximately 70% of patients with primary membranous nephropathy and serve as both diagnostic and prognostic biomarkers. 1

Key Testing Principles

• Serial monitoring of anti-PLA2R antibody levels is essential for evaluating treatment response, as changes in antibody titers precede changes in proteinuria by several months 1
• Immunologic remission is defined as either a negative immunofluorescence test or an ELISA titer <2 RU/mL (some laboratories use <4 RU/mL) 1
• Antibody levels should guide therapy adjustments: declining levels by 6 months indicate adequate immunosuppression, while persistent or rising levels warrant continuation or change of therapy 1

Treatment Decision Algorithm

For Patients with Subnephrotic Proteinuria

• If serum albumin >3.0 g/dL and proteinuria is subnephrotic, provide optimal supportive care with close monitoring rather than immunosuppression 1
• Monitor anti-PLA2R antibody titers over time: increasing titers or worsening proteinuria changes the risk estimate and may warrant treatment 1

For Patients with Nephrotic Syndrome

• Immunosuppressive therapy is indicated when at least one risk factor for disease progression is present OR serious complications (AKI, infections, thromboembolic events) have occurred 1
• First-line therapy options include rituximab (preferred based on MENTOR trial superiority) or alkylating agents 1
• Treatment response assessment should incorporate trends in eGFR, proteinuria, AND serum anti-PLA2R antibody levels—not eGFR alone 1

Defining Treatment Resistance

Treatment-resistant disease is characterized by:

• Persistence of high-level or unchanged anti-PLA2R antibody levels after one line of immunosuppression 1
• Important caveat: Persistence of proteinuria for 12-24 months AFTER disappearance of anti-PLA2R antibodies is expected and does NOT constitute resistant disease 1
• For patients without measurable autoantibodies, persistent or worsening nephrotic syndrome without substantial improvement in serum albumin may indicate resistance 1

Management of Resistant Disease

• Refer to glomerulonephritis centers for consideration of experimental therapies including more potent anti-CD20 agents (obinutuzumab), anti-CD38 therapy, or proteasome inhibitors 1
• Consider alkylating agents as second-line therapy in select situations even with stable eGFR 1

Thrombosis Risk Management

Patients with membranous nephropathy and nephrotic syndrome have elevated thrombotic risk, particularly when serum albumin falls below 2.9 g/dL. 1

Anticoagulation Considerations

• Prophylactic anticoagulation decisions should balance thrombotic event risk against bleeding complications 1
• The albumin threshold varies by assay: bromocresol green (BCG) overestimates serum albumin in nephrotic syndrome compared to bromocresol purple (BCP)—know your laboratory's assay 1
• Direct oral anticoagulants (DOACs) are NOT recommended for prophylactic treatment of VTE in nephrotic syndrome due to insufficient data 1
• When anticoagulation is used, the dose should be that recommended for known VTE, not lower prophylactic doses 1

Transplant Considerations

Screen all patients with kidney failure from MN or unknown etiology for anti-PLA2R antibodies before transplantation. 1

• Circulating anti-PLA2R antibodies at transplant will rapidly initiate recurrent MN in the allograft 1
• Very high antibody levels or persistent/increasing levels post-transplant will likely cause clinically apparent recurrent MN requiring additional immunosuppression with anti-CD20 agents 1
• No established threshold exists for acceptable antibody titers to proceed with transplant—each case requires individual evaluation 1
• Standard transplant immunosuppression alone may be sufficient to cause antibody decline if levels are not excessively elevated 1

Common Pitfalls

• Do not confuse anti-PLA2R antibodies with antiphospholipid antibodies—these are entirely different entities with different clinical implications
• Do not discontinue immunosuppression based solely on persistent proteinuria if anti-PLA2R antibodies have disappeared, as proteinuria may persist 12-24 months after immunologic remission 1
• Do not base treatment decisions on eGFR trends alone—incorporate antibody levels and proteinuria trends into the assessment 1