What is the role of PLA2R (Phospholipase A2 Receptor) and THSD7a (Thrombospondin Type 1 Domain Containing 7a) in diagnosing and managing adult patients with suspected membranous nephropathy?

Clinical Use of PLA2R and THSD7A in Membranous Nephropathy

Diagnostic Applications

A positive anti-PLA2R antibody test in a patient with nephrotic syndrome is sufficient to diagnose primary membranous nephropathy without requiring kidney biopsy. 1

When to Order These Tests

• Order anti-PLA2R antibody testing in all patients presenting with nephrotic syndrome as part of the initial workup 1
• Anti-PLA2R antibodies are positive in approximately 70-80% of primary MN cases, with 94% specificity 1
• THSD7A antibodies are positive in only 2.4-4.9% of primary MN cases and should be tested when PLA2R is negative 2, 3
• Dual positivity (PLA2R + THSD7A) occurs in approximately 10% of primary MN cases 4

Avoiding Kidney Biopsy

High titer anti-PLA2R (>20 RU/mL) has 91% positive predictive value for primary MN and allows proceeding without biopsy in appropriate clinical context. 1

• Confirm diagnosis with two additional assays if relying solely on serology to guide treatment decisions 5
• Intermediate titers (2-20 RU/mL) should be confirmed with immunofluorescence or consider proceeding to biopsy 1
• This approach is particularly valuable when biopsy cannot be safely performed or is not readily available 5

When Biopsy Remains Mandatory

Despite positive antibodies, proceed to kidney biopsy in these situations:

• All anti-PLA2R and anti-THSD7A negative patients with nephrotic syndrome require biopsy 1
• Rapidly progressive eGFR decline suggesting alternative or additional pathology 1, 6
• Strong clinical suspicion for secondary MN (lupus, hepatitis B/C, malignancy, NSAIDs) regardless of antibody status 5, 1
• Patients not responding to treatment as expected 1
• Need to assess disease chronicity (interstitial fibrosis, tubular atrophy) to guide treatment intensity 1

Prognostic Applications

Risk Stratification at Diagnosis

• High anti-PLA2R antibody titers at diagnosis predict lower rates of spontaneous remission and longer duration of proteinuria 5, 1
• Spontaneous remission rates are inversely related to antibody levels at diagnosis 5
• Single antibody measurements above 50 RU/mL in the presence of nephrotic syndrome do not automatically indicate need for immunosuppression 5
• The likelihood of spontaneous remission is consistently highest among patients with low anti-PLA2R antibody levels 5

Serial Monitoring for Treatment Decisions

Longitudinal monitoring of anti-PLA2R antibody levels at 6 months after starting therapy is critical for evaluating treatment response and guiding adjustments. 5

• Changes in antibody levels precede and predict changes in proteinuria by 6 or more months 5
• Immunologic remission (antibody disappearance) is defined as negative immunofluorescence or ELISA titer <2 RU/mL (some labs use <4 RU/mL) 5
• Disappearance of anti-PLA2R antibodies by 6 months indicates successful immunologic remission and should prompt limiting further immunosuppression 5
• Persistence of antibodies at 6 months should lead to continuing therapy or changing to another agent 5
• Declining titers of THSD7A antibodies are suspected to show treatment response, but insufficient data exists to confidently use them for monitoring like PLA2R 5

Treatment Algorithms Based on Antibody Status

When Immunosuppression Is NOT Required

• Proteinuria <3.5 g/day, serum albumin >30 g/L, and eGFR >60 mL/min/1.73m² 5
• Nephrotic syndrome with normal eGFR and no risk factors for progression (unless serious complications like AKI, infections, or thromboembolic events occur) 5
• Increasing proteinuria or rising anti-PLA2R antibody titers over time changes the risk estimate and may warrant treatment 5

Monitoring During Conservative Management

• Serial anti-PLA2R antibody measurements showing trajectory are more informative than isolated values 1
• Rising titers indicate greater risk of prolonged disease and may prompt initiation of immunosuppression 5

Critical Pitfalls to Avoid

Diagnostic Pitfalls

• Do not assume positive anti-PLA2R antibodies exclude secondary causes—evaluate for malignancy, lupus, hepatitis, and medications regardless of antibody status 5, 1
• Anti-PLA2R antibodies can occasionally occur with other diseases historically associated with secondary MN, making causality versus coincidence difficult to assess 5
• 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

Monitoring Pitfalls

• Do not interpret antibody levels at a single time point for treatment decisions 5, 1
• Do not perform single antibody measurements for prognosis—serial measurements are essential 1
• Do not delay biopsy when kidney function is rapidly declining—this suggests alternative pathology requiring histologic evaluation 1

Special Considerations

• THSD7A and NELL1 antibodies may be more often associated with malignancy compared to anti-PLA2R antibodies 5
• Patients with THSD7A-associated MN may have lower probability of achieving complete remission and longer time to remission, though no significant difference in clinical features compared to PLA2R-positive patients 7
• The field lacks sufficient data to confidently assess if THSD7A antibodies can be used for monitoring in the same manner as PLA2R 5