What is the recommended management for a patient with previously positive PLA2R (Phospholipase A2 Receptor) antibodies that are now negative?

Management of Patients with Previously Positive PLA2R Antibodies That Are Now Negative

For patients with previously positive PLA2R antibodies that are now negative, immunosuppressive therapy should be discontinued if already initiated, and the patient should be monitored for clinical remission which typically follows immunologic remission. 1

Understanding Immunologic vs. Clinical Remission

• Disappearance of PLA2R autoantibodies (immunologic remission) is defined by either a negative immunofluorescence test or an ELISA titer < 2 RU/mL (some laboratories report <4 RU/mL) 1
• Proteinuria can persist for 12-24 months after circulating anti-PLA2R antibodies are no longer detectable, which is expected and does not constitute resistant disease 1, 2
• Immunologic remission (disappearance of antibodies) precedes and predicts clinical remission (resolution of proteinuria) 1

Management Algorithm Based on Treatment Status

If Patient is Currently on Immunosuppressive Therapy:

1. For patients on cyclophosphamide and glucocorticoids:

   • Stop immunosuppressive therapy when PLA2R antibodies become negative 1
   • Continue supportive care with optimal antiproteinuric therapy (ACEi/ARB) 1

2. For patients on calcineurin inhibitors:

   • Begin tapering the calcineurin inhibitor 1
   • Monitor proteinuria and kidney function every 3 months 3

3. For patients on rituximab:

   • No additional rituximab doses are needed 1
   • Continue monitoring for B-cell recovery but additional treatment is not required 1

If Patient is Not on Immunosuppressive Therapy:

• Continue optimal supportive care with ACEi/ARB 1
• Monitor proteinuria, serum albumin, and kidney function every 3 months 3
• No immunosuppressive therapy is indicated unless proteinuria persists at nephrotic levels with normal or near-normal serum albumin, in which case consider kidney biopsy to evaluate for secondary FSGS 1

Monitoring After Immunologic Remission

• Continue monitoring proteinuria every 3 months until clinical remission is achieved 3
• Monitor kidney function (eGFR) at regular intervals 1
• Consider repeat PLA2R antibody testing if proteinuria worsens or nephrotic syndrome recurs 1
• The risk of relapse is lower in patients who achieve immunologic remission 4

Special Considerations

• In transplant recipients with previously positive PLA2R antibodies that are now negative, the risk of recurrent membranous nephropathy is significantly reduced 1, 5
• Patients with previously high antibody titers who achieve immunologic remission have better long-term outcomes than those with persistent antibodies 4, 2
• Low anti-PLA2R levels or negative antibodies are associated with higher spontaneous remission rates (79%) 4

Common Pitfalls to Avoid

• Do not continue immunosuppression unnecessarily: Disappearance of anti-PLA2R antibodies should lead to limiting further immunosuppression to avoid unnecessary toxicity 1
• Do not interpret persistent proteinuria as treatment failure: Proteinuria often persists for months after immunologic remission and does not indicate need for additional therapy 1
• Do not restart immunosuppression based on proteinuria alone: If proteinuria persists while serum albumin has increased and PLA2R antibodies are negative, consider secondary FSGS rather than active MN 1
• Do not ignore reappearance of antibodies: If PLA2R antibodies reappear during follow-up, this may indicate disease recurrence requiring reassessment of treatment strategy 1