Membranous Nephropathy: What Causes It, How the PLA2R Blood Test Works, and Your Treatment Options

Research-informed explainer — last updated April 12, 2026

Membranous nephropathy is a leading cause of nephrotic syndrome in adults, and a blood test developed from a 2009 discovery can now confirm the diagnosis and guide treatment without waiting for a kidney biopsy to show treatment response. For patients with high anti-PLA2R antibody levels, rituximab has emerged as a first-line therapy that is more durable than older immunosuppressants.

This article draws on research from four nephrologists whose work defines how this disease is understood and treated. Laurence Beck, M.D., Ph.D., the David J. Salant Professor of Nephrology at Boston University Chobanian and Avedisian School of Medicine, is the lead author on the landmark 2009 paper identifying PLA2R as the target antigen in idiopathic membranous nephropathy — the discovery that made the blood test possible. He also co-authored the 2014 paper identifying THSD7A as a second major antigen and has shown that PLA2R antibody levels predict response to rituximab. Richard Lafayette, M.D., Founder and Director of the Stanford Glomerular Disease Center, was an investigator on the MENTOR trial comparing rituximab to cyclosporine, the study that established rituximab's superiority for long-term remission. Steven Coca, D.O., M.S., at The Mount Sinai Hospital in New York, has documented the unique cardiovascular risk that kidney disease patients carry, including why membranous nephropathy patients need management beyond immunosuppression alone. David Goldfarb, M.D., Clinical Director of Nephrology at NYU Langone, has contributed to research on mTOR signaling and tubular biology relevant to how glomerular protein loss damages the kidney over time.

What is membranous nephropathy?

Membranous nephropathy (MN) is a glomerular disease — a disease of the kidney's filtering units. In MN, immune complexes deposit on the outer surface of the glomerular capillary wall, triggering complement activation and progressive damage to the podocytes, specialized cells that form the kidney's filtration barrier. The result is heavy protein loss into the urine (proteinuria), which causes the characteristic features of nephrotic syndrome: protein in the urine often exceeding 3.5 grams per day, low blood albumin, leg swelling, and elevated cholesterol and triglycerides.

MN is described as "primary" (also called idiopathic) when it arises from autoimmune attack on the podocyte itself, and "secondary" when it results from an underlying cause such as cancer, lupus, hepatitis B, or certain medications (including NSAIDs and gold salts). Secondary causes must always be excluded — particularly malignancy in older adults — before treating as primary MN.

How the PLA2R blood test changed everything

Before 2009, diagnosing and monitoring MN required repeated kidney biopsies and waiting months or years to see whether proteinuria improved. The field changed fundamentally when Beck and colleagues published their discovery in the New England Journal of Medicine: the M-type phospholipase A2 receptor (PLA2R), expressed on the surface of podocytes, is the target antigen in approximately 70–80% of primary MN cases. Patients produce IgG4 autoantibodies against PLA2R, which can be detected in a simple blood draw.

The clinical implications are significant:

• A positive anti-PLA2R antibody strongly supports a diagnosis of primary MN — in the right clinical context, it can reduce the need for kidney biopsy in some patients.
• Antibody levels correlate with disease activity. High levels at diagnosis predict a more aggressive course. Falling levels often precede reduction in proteinuria by weeks to months.
• A 2011 study by Beck and colleagues in the Journal of the American Society of Nephrology showed that rituximab-treated patients who achieved depletion of anti-PLA2R antibodies were much more likely to achieve proteinuria remission than those who did not — making the blood test a real-time treatment monitoring tool.

A second antigen, THSD7A (thrombospondin type-1 domain-containing 7A), was identified in a 2014 NEJM paper co-authored by Beck. THSD7A accounts for about 3–5% of primary MN cases, and a proportion of these patients have an associated malignancy, making tumor screening particularly important when this antibody is found.

The remaining 15–25% of primary MN cases are seronegative for both antigens; newer antigens including NELL-1 and Sema3B are being actively characterized in research settings.

How the kidney biopsy fits in

Despite the utility of the blood test, kidney biopsy remains the definitive diagnostic procedure for MN. It is required when:

• The antibody test is negative (seronegative MN)
• Secondary causes need to be confirmed or excluded
• The clinical picture is atypical
• There is uncertainty about the degree of scarring (fibrosis) that may influence treatment decisions

The biopsy shows characteristic subepithelial immune deposits on light microscopy and electron microscopy — often described as "spike and dome" pattern — along with IgG4 and complement deposits on immunofluorescence staining.

Treatment: watchful waiting, rituximab, or calcineurin inhibitors?

Not all patients with MN require immediate immunosuppression. Primary MN has a natural history that includes spontaneous remission in roughly 30% of patients, particularly those with lower antibody levels and less severe proteinuria. Most guidelines recommend a period of conservative management — optimizing blood pressure with ACE inhibitors or ARBs, managing edema and lipids, and monitoring closely — before initiating immunotherapy.

Patients who do not remit spontaneously, or who have high proteinuria (greater than 8 grams per day), high anti-PLA2R levels, declining kidney function, or significant complications of nephrotic syndrome (including clotting risk and progressive CKD), are candidates for immunosuppressive therapy.

The MENTOR trial, published in the NEJM in 2019 and led by Lafayette and colleagues, directly compared rituximab (an anti-CD20 monoclonal antibody that depletes B cells) to cyclosporine (a calcineurin inhibitor) in 130 patients. Rituximab was non-inferior to cyclosporine at 12 months in achieving complete or partial remission of proteinuria. More importantly, at 24 months, rituximab was significantly superior: 60% of rituximab patients maintained remission compared to only 20% of cyclosporine patients (P < 0.001). Relapses occurred much more frequently after stopping cyclosporine than after rituximab.

This durability advantage has made rituximab the preferred first-line immunotherapy for primary MN at most major centers, with calcineurin inhibitors (cyclosporine or tacrolimus) generally reserved for patients who cannot receive rituximab or who have urgent need for rapid proteinuria reduction.

The cardiovascular and clotting risks of nephrotic syndrome

Heavy protein loss in MN creates systemic consequences beyond the kidneys. Research by Coca and colleagues has highlighted that kidney disease patients are systematically underrepresented in cardiovascular trials, meaning many treatment decisions rely on extrapolation rather than direct evidence. This matters because patients with nephrotic syndrome face:

• Elevated clotting risk (hypercoagulability) due to loss of anticoagulant proteins like antithrombin III and protein S in the urine, combined with elevated clotting factors — venous thromboembolism is a known complication, and in severe nephrotic syndrome, anticoagulation is often warranted
• Elevated LDL cholesterol and triglycerides requiring statin therapy, though evidence for specific LDL targets in nephrotic syndrome patients is limited

The mTOR pathway, studied by Goldfarb and others in the context of polycystic kidney disease, is also relevant to understanding how persistent tubular protein overload damages the kidney downstream from glomerular injury — a reminder that uncontrolled proteinuria is itself damaging to the nephron over time.

Questions to ask your doctor

• Should I have the anti-PLA2R antibody blood test, and what does my level mean for my prognosis?
• Given my protein levels and kidney function, am I a candidate for watchful waiting or immediate treatment?
• Is rituximab available at this center, and what monitoring will I need before and after treatment?
• Do I need anticoagulation given my albumin level and clotting risk?
• How will you monitor my response to treatment — through antibody levels, urine protein, or both?
• Should I be screened for an underlying malignancy given my diagnosis?

The bottom line

The discovery of PLA2R as the primary antigen in membranous nephropathy has transformed both diagnosis and treatment monitoring. The MENTOR trial established rituximab as the most durable immunotherapy option — superior to cyclosporine at 24 months — and anti-PLA2R antibody levels now allow real-time monitoring of treatment response. Patients with primary MN should be evaluated at a glomerular disease center with experience in antibody testing and biologic therapy.