What is the role of PLA2R (Phospholipase A2 Receptor) antibody testing in the diagnosis and treatment of nephrotic syndrome?

PLA2R Antibody Testing in Nephrotic Syndrome

In patients with nephrotic syndrome, anti-PLA2R antibody testing can eliminate the need for kidney biopsy when positive, allowing immediate diagnosis of primary membranous nephropathy and initiation of treatment without exposing patients to procedural risks. 1

Diagnostic Role of PLA2R Testing

When Biopsy Can Be Avoided

• A positive anti-PLA2R antibody test in a patient with nephrotic syndrome is sufficient to diagnose primary membranous nephropathy (MN) without requiring kidney biopsy, according to the 2023 KDOQI/KDIGO guidelines 1
• The high specificity of anti-PLA2R antibodies (94%) allows high-confidence diagnosis of primary MN while avoiding the risks, costs, and inconvenience of biopsy 1, 2
• Approximately 70-80% of patients with primary MN test positive for anti-PLA2R antibodies 1, 3

Confirming Weakly Positive Results

• Weakly positive anti-PLA2R results should be confirmed with immunofluorescence testing or consideration of kidney biopsy before making treatment decisions 1
• A positive test should ideally be confirmed in 2 additional assays when biopsy cannot be safely performed and treatment is being considered 1
• Testing methods vary by center (ELISA vs immunofluorescence), with immunofluorescence being more sensitive for weak positives 1

When Kidney Biopsy Is Still Necessary

Mandatory Biopsy Scenarios

Despite positive anti-PLA2R antibodies, kidney biopsy remains indicated in the following situations 1:

• Suspicion of secondary MN (lupus, hepatitis B/C, malignancy, NSAIDs) persists despite positive antibodies 1
• Rapidly progressive eGFR decline out of proportion to expected disease course 1
• Patients not responding to treatment as expected after initiating therapy based on seropositivity 1
• Need to assess disease chronicity (interstitial fibrosis and tubular atrophy) to guide aggressive versus conservative therapy 1

Seronegative Patients

• All anti-PLA2R negative patients with nephrotic syndrome require kidney biopsy to establish diagnosis 1
• Approximately 20% of primary MN cases are PLA2R-negative and may have other autoantibodies (THSD7A, NELL1) 1
• Other autoantibodies (THSD7A, NELL1) do not yet have sufficient accuracy to replace biopsy as sole diagnostic tests 1

Prognostic and Monitoring Role

Risk Stratification

Anti-PLA2R antibody titers provide critical prognostic information beyond diagnosis 1:

• High antibody titers at diagnosis predict lower rates of spontaneous remission and longer duration of proteinuria 1
• Low antibody levels at diagnosis correlate with higher spontaneous remission rates 1
• Changes in antibody levels precede changes in proteinuria by approximately 6 months, allowing early assessment of treatment response 1, 4

Serial Monitoring

• Decreasing antibody titers (immunologic remission) predict subsequent clinical remission (reduced proteinuria) 1, 4
• Patients achieving remission have significantly lower baseline PLA2R antibody levels compared to non-responders 4
• Serial measurements showing increasing levels indicate greater risk of prolonged disease than decreasing trajectories 1

Practical Implementation Algorithm

Step 1: Initial Workup

• Order anti-PLA2R antibody testing in all patients presenting with nephrotic syndrome 1
• Simultaneously evaluate for secondary causes regardless of antibody status 1

Step 2: Interpret Results Based on Titer

• High titer (>20 RU/ml): 91% positive predictive value for primary MN; can proceed without biopsy in appropriate clinical context 2
• Intermediate titer (2-20 RU/ml): Confirm with immunofluorescence or consider biopsy 1
• Negative (<2 RU/ml): Kidney biopsy mandatory 1

Step 3: Risk-Stratify for Biopsy Decision

Higher diagnostic accuracy without biopsy when 2:

• Age <60 years
• Preserved renal function (normal eGFR)
• Negative workup for secondary causes
• High antibody titer (>20 RU/ml)

Proceed to biopsy despite positive antibodies when 1:

• Concern for secondary MN persists
• Rapid eGFR decline present
• Need to assess chronicity for treatment intensity decisions
• Immunosuppression being strongly considered

Critical Pitfalls to Avoid

• Do not assume positive anti-PLA2R antibodies exclude secondary causes—evaluate for malignancy, lupus, hepatitis, and medications regardless of antibody status 1
• Do not use THSD7A or NELL1 antibodies alone without biopsy—these lack the diagnostic accuracy of PLA2R testing 1
• Do not ignore clinical context with weakly positive results—false positives exist and require confirmation 1
• Do not perform single antibody measurements for prognosis—serial measurements showing trajectory are more informative than isolated values 1
• Do not delay biopsy when kidney function is rapidly declining—this suggests alternative or additional pathology requiring histologic evaluation 1