What is the treatment approach for a patient with anti-PLA (Phospholipase A2 Receptor) receptor antibodies?

Anti-PLA2R Antibody in Membranous Nephropathy

Diagnostic Utility

A positive anti-PLA2R antibody test is sufficient to diagnose primary membranous nephropathy without kidney biopsy in patients with nephrotic syndrome, provided the test is confirmed and secondary causes are excluded. 1

• Anti-PLA2R antibodies are detected in approximately 70-85% of patients with primary membranous nephropathy and have high specificity for distinguishing primary from secondary disease 1, 2
• The test should be confirmed with two additional assays if weakly positive, or consider the more sensitive immunofluorescence test over ELISA alone 1
• A positive anti-PLA2R test does not completely rule out secondary causes; patients still require evaluation for malignancy, autoimmune diseases, infections, and medications 1

When Kidney Biopsy Is Still Needed Despite Positive Anti-PLA2R

• Rapidly progressive eGFR decline out of proportion to expected disease course 1
• Strong clinical suspicion for secondary membranous nephropathy persists 1
• Patient fails to respond to treatment as expected based on seropositivity 1
• Need to assess degree of chronic interstitial fibrosis and tubular atrophy for prognostic information 1

Prognostic Value

Higher anti-PLA2R antibody levels at diagnosis predict worse outcomes, including lower rates of spontaneous remission, more severe proteinuria, and higher risk of progressive kidney disease. 3, 4

• Anti-PLA2R antibody levels correlate positively with proteinuria severity (r = 0.813) and negatively with eGFR at follow-up 3
• Patients with positive anti-PLA2R antibodies have significantly lower probability of spontaneous remission compared to seronegative patients 4
• Anti-PLA2R-positive patients have higher incidence of chronic kidney disease stage ≥3 4
• Low antibody levels at diagnosis predict complete remission following immunosuppressive treatment 3

Treatment Monitoring

Serial anti-PLA2R antibody measurements at 6-month intervals are essential for guiding immunosuppressive therapy duration, as immunologic remission (antibody disappearance) precedes clinical remission (proteinuria resolution) by several months. 1, 5

Defining Immunologic Remission

• Negative immunofluorescence test OR ELISA titer <2 RU/mL (some laboratories use <4 RU/mL) 1, 5
• Immunologic remission predicts subsequent clinical remission and should prompt discontinuation of immunosuppression 5

Treatment Response Patterns

• Declining antibody titers by 6 months indicate adequate treatment response; continue current therapy 1
• Persistent or rising antibody titers at 6 months indicate treatment failure; switch to alternative immunosuppressive agent 1
• After antibody disappearance, proteinuria typically persists for 12-24 months—this is expected and does NOT constitute treatment failure 1, 5
• The probability of halving proteinuria increases 6.5-fold after anti-PLA2R antibodies disappear 6

Monitoring Algorithm

• Measure anti-PLA2R antibodies at baseline, 6 months after treatment initiation, and whenever clinical status changes 1, 6
• If antibodies become negative: discontinue immunosuppression and monitor for clinical remission with supportive care only 5
• If antibodies remain positive at 6 months: continue or escalate immunosuppressive therapy 1
• If antibodies reappear during follow-up: indicates disease recurrence requiring treatment reassessment 5

Risk Stratification for Treatment Decisions

Immunosuppressive therapy should be restricted to patients with anti-PLA2R antibody levels >50 RU/mL combined with nephrotic syndrome, or those with serious complications regardless of antibody level. 1

Patients Who Do NOT Require Immunosuppression

• Proteinuria <3.5 g/day, serum albumin >30 g/L, and eGFR >60 mL/min/1.73m² 1
• Single anti-PLA2R measurement >50 RU/mL without longitudinal trend data 1
• Nephrotic syndrome with normal eGFR and no risk factors for progression (unless serious complications like AKI, infections, or thromboembolism occur) 1

Patients Who Require Immunosuppression

• Anti-PLA2R levels >50 RU/mL with rising trend over time combined with nephrotic syndrome 1
• Serious complications: acute kidney injury, severe infections, or thromboembolic events 1
• Progressive eGFR decline 1

Treatment Selection Based on Anti-PLA2R Status

For anti-PLA2R-positive primary membranous nephropathy requiring immunosuppression, rituximab is first-line therapy for patients with stable eGFR, while cyclophosphamide with glucocorticoids is preferred when eGFR is declining. 7

First-Line Options

• Rituximab: 1 gram on days 1 and 15, OR 375 mg/m² weekly for 4 weeks—both regimens equally effective 7
• Cyclophosphamide with glucocorticoids: preferred when kidney function is declining; cumulative dose must not exceed 36 grams 7
• Calcineurin inhibitors: alternative option but less effective at reducing autoantibodies; high relapse rates after discontinuation 1

Second-Line Treatment for Resistant Disease

• If calcineurin inhibitors fail with stable eGFR: switch to rituximab 7
• If rituximab fails with stable eGFR: switch to calcineurin inhibitors 1
• If any therapy fails with declining eGFR: use cyclophosphamide with glucocorticoids 1

Transplant Considerations

Patients with circulating anti-PLA2R antibodies at time of kidney transplantation will develop recurrent membranous nephropathy in the allograft; antibody levels should be measured pre-transplant and monitored post-transplant. 1

• Very high antibody levels at transplant or persistent/rising levels post-transplant predict clinically significant recurrence requiring additional immunosuppression with rituximab 1
• If antibodies are negative pre-transplant, risk of recurrence is significantly reduced 5
• No established threshold titer exists for safe transplantation; each case requires individual assessment 1

Critical Pitfalls to Avoid

• Do not continue immunosuppression after antibodies disappear—this exposes patients to unnecessary toxicity without benefit 5
• Do not interpret persistent proteinuria as treatment failure if antibodies are negative—proteinuria lags behind immunologic remission by 12-24 months 1, 5
• Do not make treatment decisions based on single antibody measurement—longitudinal trends are essential 1
• Do not assume positive anti-PLA2R excludes secondary causes—still evaluate for malignancy, autoimmune disease, and infections 1
• Do not use THSD7A or NELL1 antibodies alone for diagnosis without biopsy—these lack the same diagnostic accuracy as anti-PLA2R 1