In an adult with nephrotic‑range proteinuria and a kidney biopsy consistent with membranous glomerulopathy, how should anti‑phospholipase A2 receptor (PLA2R) antibody testing be used to differentiate primary from secondary disease and guide first‑line therapy?

PLA2R Antibody Testing in Membranous Glomerulopathy

Diagnostic Approach

A positive anti-PLA2R antibody test in an adult with nephrotic-range proteinuria and biopsy-confirmed membranous nephropathy establishes the diagnosis of primary (idiopathic) disease and distinguishes it from secondary causes. 1, 2

Using PLA2R to Differentiate Primary from Secondary Disease

• Positive anti-PLA2R antibodies (present in 70-80% of primary MN cases) indicate immunologically active primary membranous nephropathy, confirming this is a renal-limited autoimmune disorder rather than secondary disease. 1, 2

• Patients who are anti-PLA2R seronegative fall into two categories: 1

  • Those with recent spontaneous remission may still have primary MN if PLA2R antigen is detected within immune deposits on biopsy 1
  • Those with neither circulating antibodies nor tissue PLA2R antigen likely have secondary MN and warrant investigation for lupus, hepatitis B/C, malignancy, or drug-induced disease (especially NSAIDs) 1

• Critical pitfall: A positive PLA2R test does NOT exclude secondary causes. Some patients with anti-PLA2R antibodies may have coexisting lupus, hepatitis B, hepatitis C, or malignancy. 1, 2 The relationship may be coincidental rather than causal, requiring clinical judgment to determine whether both conditions exist independently. 1

Evaluation for Secondary Causes Regardless of PLA2R Status

All patients with membranous nephropathy should be evaluated for associated conditions regardless of PLA2R antibody status. 1

• Primary secondary causes in the United States to exclude: 1

  • Systemic lupus erythematosus
  • Hepatitis B virus infection
  • Therapeutic agents, particularly NSAIDs
  • Malignancy (age-appropriate cancer screening recommended) 1

• For malignancy screening, limit workup to age-appropriate cancer screening (colonoscopy, mammography, PSA, chest imaging) unless specific risk factors or symptoms suggest additional testing. 1 The association between cancer and MN may be causative or coincidental, with higher frequency in older patients. 1

Prognostic Value and Treatment Guidance

Risk Stratification Using PLA2R Antibody Levels

Anti-PLA2R antibody titers at diagnosis provide critical prognostic information that guides treatment decisions. 1, 2, 3

• High antibody titers at diagnosis predict: 1, 2, 3

  • Lower rates of spontaneous remission
  • Longer duration of proteinuria
  • Higher likelihood of requiring immunosuppressive therapy

• Low antibody levels at diagnosis correlate with: 4, 5

  • Higher probability of spontaneous remission
  • Better response to immunosuppressive therapy when needed
  • Shorter time to achieve remission

• In patients with non-nephrotic proteinuria at diagnosis, positive PLA2R antibodies increase risk of progression to nephrotic-range proteinuria (HR 3.66,95% CI 1.39-9.64). 6 These patients require closer monitoring and earlier consideration of immunosuppression. 6

First-Line Therapy Algorithm

Immunosuppressive therapy should be initiated only in patients meeting specific high-risk criteria, not based solely on PLA2R positivity. 1

Do NOT treat with immunosuppression if: 1, 3

• Proteinuria <3.5 g/day AND
• Serum albumin >30 g/L (by bromocresol purple or immunometric assay) AND
• eGFR >60 mL/min/1.73 m²

Consider immunosuppressive therapy when at least one of the following is present: 1

1. Persistent nephrotic syndrome: Urinary protein excretion persistently exceeds 4 g/day AND remains at ≥50% of baseline AND shows no progressive decline during 6 months of optimal antihypertensive and antiproteinuric therapy 1

2. Severe complications: Life-threatening or disabling symptoms related to nephrotic syndrome (AKI, infections, thromboembolic events) 1

3. Declining kidney function: Serum creatinine risen by ≥30% within 6-12 months from diagnosis, with eGFR still >25-30 mL/min/1.73 m², not explained by superimposed complications 1

Do NOT use immunosuppressive therapy if: 1

• Serum creatinine persistently ≥3.5 mg/dL (eGFR ≤30 mL/min/1.73 m²) AND
• Reduced kidney size on ultrasound (e.g., <8 cm in length)

First-Line Immunosuppressive Options

When treatment is indicated, choose between: 1

• Rituximab (preferred in many centers) 1
• Cyclophosphamide with alternating monthly glucocorticoids for 6 months 1
• Tacrolimus-based therapy for ≥6 months 1

The choice depends on individual risk assessment, with rituximab increasingly favored due to its safety profile. 1

Monitoring Treatment Response

Serial PLA2R Antibody Measurements

Longitudinal monitoring of anti-PLA2R antibody levels is essential for evaluating treatment response and should guide therapy adjustments. 1, 3

• Changes in antibody titers precede changes in proteinuria by 6 or more months, providing an early indicator of treatment success or failure. 1, 3, 7

• Immunologic remission (disappearance of antibodies) predicts subsequent clinical remission (reduction in proteinuria). 1, 7, 5 The probability of halving proteinuria increases 6.5-fold after antibody disappearance. 7

• Measure antibody levels every 3 months during treatment: 1, 3

  • Decreasing titers indicate successful immunosuppression
  • Stable or rising titers suggest treatment failure and need for therapy modification
  • Disappearance by 6 months indicates successful immunologic remission and should prompt limiting further immunosuppression 3

• Rising antibody levels during follow-up predict relapse before proteinuria increases, allowing preemptive treatment adjustments. 4, 7

Defining Remission

Future definitions of remission should incorporate both clinical (proteinuria) and immunological (anti-PLA2R antibody) parameters, as this combination more accurately reflects disease activity than proteinuria alone. 1

Key Clinical Pitfalls to Avoid

• Never assume PLA2R positivity excludes secondary causes—always evaluate for malignancy, lupus, hepatitis, and medications. 1, 2, 3

• Do not rely on single antibody measurements for treatment decisions—serial measurements showing trajectory are far more informative. 2, 3

• Do not delay kidney biopsy when eGFR is rapidly declining—this suggests alternative or additional pathology requiring histologic evaluation. 2, 3

• Do not use THSD7A or NELL1 antibodies alone without biopsy—these lack the diagnostic accuracy of PLA2R testing. 2, 3

• Do not interpret weakly positive results without confirmation—false positives exist and require validation with additional assays or biopsy. 2