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PubMed This is a summary of 18 peer-reviewed journal articles Updated
Nephrology · Membranous Nephropathy

Subtypes and Diagnosis: Finding the Cause

At a Glance

Membranous nephropathy is either primary, caused by an autoimmune attack on kidney filters, or secondary to lupus, cancer, infection, or medicines. Anti-PLA2R testing can support primary disease in selected patients, while biopsy confirms the pattern and helps identify other causes.

Membranous nephropathy (MN) is not a single disease, but a pattern of kidney injury that can be caused by several different underlying issues. Understanding which “subtype” you have is the first step in creating an effective treatment plan.

Primary vs. Secondary: The “Why” Behind the Disease

Doctors divide MN into two main categories based on what triggered the immune system’s attack:

  • Primary MN (70–80% of cases): This is an isolated autoimmune disease. The immune system mistakenly attacks the kidney’s filters (podocytes) directly, with no other underlying illness causing it [1][2].
  • Secondary MN (20–30% of cases): The kidney damage is a “side effect” of another condition. Common triggers include systemic lupus, certain cancers (solid tumors), chronic infections like Hepatitis B or C, or reactions to specific medications (such as NSAIDs) [2][3].

The Target Antigens: The “What” of the Attack

In recent years, scientists have discovered the specific proteins (antigens) that the immune system attacks. Identifying these antigens helps your doctor predict how the disease might behave and what secondary issues to look for.

Antigen Frequency Common Associations
PLA2R ~70–80% Mostly primary MN; the most common type [4].
THSD7A 1–5% Small association with malignancy (cancer); screening is usually recommended [5][6].
NELL-1 Varied Linked to cancer in older adults and sometimes exposure to mercury (in traditional medicines or skin creams) [7][8].
EXT1/EXT2 Varied Strongly linked to systemic lupus erythematosus (lupus) and other autoimmune diseases [9][10].
SEMA3B Rare Primarily seen in children and very young children [11].

How You Are Diagnosed: Blood vs. Biopsy

There are now two main ways to confirm you have MN. Your doctor will choose based on your specific health markers.

1. The Anti-PLA2R Blood Test

If you have nephrotic syndrome (heavy protein loss and swelling), a simple blood test for anti-PLA2R antibodies strongly supports a diagnosis of primary MN. Current guidelines (KDIGO 2021) state that a biopsy may not be necessary if [12][13]:

  • Your anti-PLA2R blood test is clearly positive.
  • Your kidney function is stable and “preserved” (often an eGFR of 60 or higher).
  • You do not have diabetes or signs of a secondary cause like lupus or cancer.
    However, a positive test does not completely rule out a secondary cause, so your doctor will still evaluate your full history.

2. The Kidney Biopsy

A biopsy—where a tiny piece of kidney tissue is removed and examined—remains the “gold standard.” It is often considered necessary if your blood test is negative, if your kidney function is declining rapidly (eGFR below 60), or if your doctor suspects a secondary cause [14][13].

Reading Your Pathology Report

If you have a biopsy, the pathologist uses three different views to confirm MN. You can look for these specific terms on your report:

  • Light Microscopy: This shows Glomerular Basement Membrane (GBM) thickening. In later stages, you may see “spikes” or “pinholes” as the membrane grows around the immune clumps [15][16]. These describe a microscopic pattern and do not by themselves tell you your clinical severity.
  • Immunofluorescence (IF): The pathologist adds a glowing dye to see where antibodies are sticking. In MN, they see a “granular” pattern of IgG (and sometimes a protein called C3) along the filter walls [15][17].
  • Electron Microscopy (EM): This is a high-power view that shows subepithelial electron-dense deposits. These are the physical “clumps” of antibodies sitting just under the outer layer of the kidney’s filters [15][18].

Completeness Checklist

A comprehensive pathology report for suspected MN should ideally include:

  • [ ] Presence of subepithelial deposits on electron microscopy.
  • [ ] Granular IgG staining on immunofluorescence.
  • [ ] Results of PLA2R staining in the tissue itself (helpful if blood tests are negative).
  • [ ] Assessment of interstitial fibrosis (scarring), which helps predict long-term kidney health.
  • [ ] Review for “organized deposits” which could point to other rare diseases.

Common questions in this guide

What is the difference between primary and secondary membranous nephropathy?
Primary membranous nephropathy is an autoimmune condition in which the immune system attacks the kidney filters without another identified underlying illness. Secondary membranous nephropathy results from another condition or exposure, such as lupus, cancer, hepatitis B or C, or certain medicines.
Can an anti-PLA2R blood test diagnose membranous nephropathy without a biopsy?
In a person with nephrotic syndrome, a clearly positive anti-PLA2R blood test can strongly support primary membranous nephropathy. A biopsy may not be necessary when kidney function is preserved, often with an eGFR of 60 or higher, and there are no signs of diabetes or another secondary cause. Doctors still review the full medical history because a positive result does not completely exclude a secondary cause.
When is a kidney biopsy needed for membranous nephropathy?
A kidney biopsy is often considered when the anti-PLA2R blood test is negative, kidney function is declining quickly or the eGFR is below 60, or another cause is suspected. The biopsy examines kidney tissue and remains the most definitive way to confirm the characteristic pattern and look for related conditions.
What findings might appear on a membranous nephropathy pathology report?
Light microscopy may show thickening of the glomerular basement membrane, sometimes with patterns called spikes or pinholes. Immunofluorescence typically shows granular IgG along the filter walls, while electron microscopy shows immune deposits beneath the outer layer of the filtration barrier. The report may also include tissue PLA2R staining, scarring, and whether deposits have an organized appearance.
What do PLA2R, THSD7A, NELL-1, and EXT1/EXT2 mean in membranous nephropathy?
These are proteins, or markers related to proteins, that can identify different forms of the disease. PLA2R is most often associated with primary membranous nephropathy, while THSD7A and NELL-1 can prompt evaluation for associated cancer or other exposures, especially when appropriate for a person's age and history. EXT1 and EXT2 are strongly associated with lupus and other autoimmune diseases.
If membranous nephropathy is linked to THSD7A or NELL-1, should I have cancer screening?
THSD7A and NELL-1 findings can be associated with cancer, but they do not prove that cancer is present. Your doctor can decide which screening is appropriate based on the marker, your age, symptoms, medical history, and routine screening recommendations.

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Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.Was my anti-PLA2R level measured with an ELISA test, and what was the exact numerical result?
  2. 2.Based on my eGFR and protein levels, do I meet the criteria to skip a kidney biopsy, or do you recommend one to look for other issues?
  3. 3.If my biopsy showed NELL-1 or THSD7A, what specific cancer screenings should I have given my age and history?
  4. 4.Did my pathology report mention 'spikes' or 'pinholes,' and what stage of the disease does that suggest?
  5. 5.If EXT1/EXT2 was found, should we run more detailed tests for lupus or other autoimmune conditions?

References

References (18)
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    Specific antigens in malignancy-associated membranous nephropathy.

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    Frontiers in medicine 2024; (11()):1368457 doi:10.3389/fmed.2024.1368457.

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    Anti-PLA2R and anti-THSD7A as Diagnostic Serological Markers of Idiopathic Membranous Nephropathy: A Single Centre Study.

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    In Patients with Membranous Lupus Nephritis, Exostosin-Positivity and Exostosin-Negativity Represent Two Different Phenotypes.

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This page explains membranous nephropathy subtypes, diagnostic tests, and biopsy findings for informational purposes only and does not constitute medical advice. Your nephrologist and pathologist should interpret your results and recommend care for your situation.