Adult nephrotic syndrome from subepithelial immune deposits; primary form mediated by anti-PLA2R antibodies.
Also known as: membranous nephropathy, MN, membranous glomerulonephritis, MGN, PLA2R nephropathy
Overview
An immune-mediated glomerular disease characterized by subepithelial immune complex deposition along the glomerular basement membrane, producing diffuse GBM thickening. Clinically presents as adult nephrotic syndrome.
Epidemiology
The most common primary cause of nephrotic syndrome in non-diabetic White adults. Peak incidence between ages 40-60; male predominance (~2:1). Approximately 70-80% of cases are primary (autoimmune) and the remainder are secondary to systemic disease, infection, drugs, or malignancy.
Try two board-style Membranous Nephropathy questions
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Question 1RenalMedium
A 34-year-old man with nephrotic syndrome due to membranous nephropathy presents to the ED with acute left flank pain and gross hematuria. Vitals: BP 138/86 mm Hg, HR 102/min, T 37.2°C. Exam shows pitting edema and left costovertebral angle tenderness. Labs: Cr 1.9 mg/dL (baseline 1.0), urine protein:creatinine 8.2, LDH elevated. Urinalysis shows RBCs and 4+ protein. Which of the following is the most appropriate imaging test to confirm the suspected diagnosis?
ANoncontrast CT of abdomen and pelvis
BRenal ultrasound with grayscale imaging
CTechnetium-99m MAG3 renal scintigraphy
DPlain abdominal radiograph
ECT angiography of the renal vessels
Reveal answer & full explanation
Correct answer: E — CT angiography of the renal vessels
ANoncontrast CT of abdomen and pelvis
BRenal ultrasound with grayscale imaging
CTechnetium-99m MAG3 renal scintigraphy
DPlain abdominal radiograph
ECT angiography of the renal vessels✓
Why CT angiography of the renal vessels is correct
This patient has nephrotic syndrome complicated by acute flank pain, hematuria, AKI, and elevated LDH — the textbook presentation of renal vein thrombosis (RVT)
CT angiography (or CT venography) of the renal vessels is the diagnostic test of choice, showing a filling defect in the renal vein with high sensitivity and specificity
MR venography is an alternative when contrast is contraindicated
Treatment is anticoagulation
Why the others are wrong
Technetium-99m MAG3 renal scintigraphy — assesses renal perfusion, split function, and drainage; it may show reduced uptake in the affected kidney but cannot visualize the renal vein or demonstrate a thrombus, so it cannot confirm renal vein thrombosis
Plain abdominal radiograph — cannot evaluate vascular structures or detect a thrombus; buzzword-matching on flank pain toward a stone series misses that the picture is a hypercoagulable venous event
Renal ultrasound with grayscale imaging — grayscale ultrasound has poor sensitivity for renal vein thrombosis and cannot confirm it; this is the anchoring trap of reaching for first-line renal imaging instead of the cross-sectional study that actually visualizes a venous filling defect
Noncontrast CT of abdomen and pelvis — flank pain with hematuria triggers the kidney-stone reflex, and noncontrast CT is the right study for a suspected stone; but without IV contrast the renal vein is not opacified, so a venous filling defect cannot be demonstrated and renal vein thrombosis cannot be confirmed
Additional high-yield points
Membranous nephropathy carries the highest RVT risk among nephrotic syndromes due to urinary loss of antithrombin III and other anticoagulant factors, creating a hypercoagulable state
Question 2RenalMedium
A 54-year-old man presents with 2 months of foamy urine, progressive lower-extremity swelling, and a 4 kg weight gain. He takes no medications and has no history of diabetes. On exam he has periorbital puffiness and 2+ pitting edema to the knees; blood pressure is 142/88 mm Hg. Labs show urine protein-to-creatinine ratio 6.2 g/g, serum albumin 2.4 g/dL, and elevated LDL. Serum C3 and C4 are normal, ANA is negative, and serum anti-phospholipase A2 receptor (anti-PLA2R) antibody is positive. Which of the following is the most likely diagnosis?
APrimary membranous nephropathy
BIdiopathic minimal change disease
CFocal segmental glomerulosclerosis
DImmune-complex membranoproliferative GN
ERenal light-chain amyloidosis
Reveal answer & full explanation
Correct answer: A — Primary membranous nephropathy
APrimary membranous nephropathy✓
BIdiopathic minimal change disease
CFocal segmental glomerulosclerosis
DImmune-complex membranoproliferative GN
ERenal light-chain amyloidosis
Why Primary membranous nephropathy is correct
Adult-onset nephrotic syndrome (UPCR >3.5 g/g, hypoalbuminemia, hyperlipidemia, edema) with an insidious course over weeks to months is the classic primary membranous nephropathy presentation, and it is the most common primary cause of nephrotic syndrome in non-diabetic White adults (peak age 40-60, male predominance).
A positive serum anti-PLA2R antibody with normal complements and a negative ANA is essentially diagnostic of primary membranous nephropathy; per KDIGO 2021 it can obviate biopsy in selected patients with nephrotic syndrome and no systemic disease.
The pathology is subepithelial IgG4/PLA2R immune-complex deposition activating complement (C5b-9) on podocytes, producing GBM thickening with a spike-and-dome appearance.
Why the others are wrong
Idiopathic minimal change disease — causes nephrotic syndrome but classically has abrupt onset, is the leading cause in children, shows normal light microscopy with no immune deposits, and is anti-PLA2R negative.
Renal light-chain amyloidosis — also causes nephrotic-range proteinuria in middle-aged and older adults, but it results from deposition of monoclonal light chains (Congo red-positive with apple-green birefringence under polarized light), is detected with serum and urine immunofixation and a serum free light chain assay, and is not associated with anti-PLA2R antibodies; the positive anti-PLA2R here points to primary membranous nephropathy.
Focal segmental glomerulosclerosis — a common cause of nephrotic syndrome (notably in Black patients with APOL1 risk variants) but shows focal segmental sclerosis on biopsy and is not associated with anti-PLA2R antibodies.
Immune-complex membranoproliferative GN — its name is easily confused with membranous nephropathy and it can cause nephrotic-range proteinuria in adults, but it usually produces a mixed nephritic-nephrotic picture with hematuria and often low complement levels, is typically driven by chronic infection (especially hepatitis C), autoimmune disease, or a monoclonal gammopathy, and is not associated with anti-PLA2R antibodies.
Additional high-yield points
Class V (membranous) lupus nephritis is the main secondary mimic; it is almost always ANA-positive and shows full-house immunofluorescence on biopsy, so the negative ANA and normal C3 and C4 here support primary disease.
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Stem cell or solid organ transplantation (graft-versus-host or de novo)
Pathophysiology
In primary membranous nephropathy, circulating IgG4 autoantibodies (most commonly against the M-type phospholipase A2 receptor, PLA2R; less commonly against thrombospondin type-1 domain-containing 7A, THSD7A) bind antigens expressed on podocyte surfaces. The in situ immune complexes activate complement (C5b-9 membrane attack complex), causing podocyte injury, foot-process effacement, and proteinuria. The GBM thickens around the deposits, creating the classic 'spike-and-dome' appearance on silver stain.
Clinical presentation
Symptoms
Insidious onset of foamy urine, dependent edema, weight gain over weeks to months
Fatigue; microscopic hematuria in up to half of patients (not by itself an indication for immunosuppression), whereas gross hematuria is uncommon and should prompt evaluation for renal vein thrombosis
Often discovered on routine labs or with thromboembolic complication
Signs / physical exam
Periorbital and lower-extremity edema
Hypertension in 30-50% at presentation
Hyperlipidemia stigmata (xanthelasma) in chronic disease
Classic findings
Adult-onset nephrotic syndrome with normal complements and the highest rate of thromboembolic complications among glomerular diseases — particularly renal vein thrombosis.
Lupus nephritis (class V) — Positive ANA/anti-dsDNA, low C3/C4, extrarenal lupus; full-house IF on biopsy
Amyloidosis — Monoclonal gammopathy or chronic inflammation; Congo red apple-green birefringence
Hepatitis-associated MN/MPGN — Positive HBsAg or anti-HCV; treat the virus. HCV more classically causes MPGN (hematuria with an active sediment, low complement, cryoglobulins), whereas a positive anti-PLA2R with a bland sediment and normal complement favors primary membranous nephropathy
Diagnostic workup
Diagnostic criteria
Kidney biopsy shows diffuse GBM thickening on LM, granular IgG and C3 along capillary loops on IF, and subepithelial electron-dense deposits with GBM spikes on EM (Ehrenreich-Churg stages I-IV). A positive serum anti-PLA2R antibody in a patient with nephrotic syndrome and normal complements/no systemic disease may obviate biopsy in selected cases per KDIGO 2021.
Labs
Spot UPCR or 24-hour urine — nephrotic-range proteinuria (>3.5 g/day)
Serum albumin (low), lipid panel (elevated LDL and triglycerides), BMP/Cr/eGFR
Serum anti-PLA2R antibody (ELISA or IFA) — positive in ~70% of primary MN; quantitative titers track disease activity
Anti-THSD7A antibody (less commonly available; positive in ~3-5% of remaining primary cases)
Hepatitis B and C serologies, HIV, RPR (syphilis)
ANA, complements C3/C4 (typically normal in primary MN), SPEP/UPEP/free light chains
Renal ultrasound — normal or enlarged kidneys; Doppler if renal vein thrombosis suspected
Consider CT abdomen/pelvis or PET to exclude occult malignancy in patients >65 or anti-PLA2R negative
Diagnostic algorithm
Risk category (KDIGO)
Definition
Management
Low
Normal eGFR, UPCR <3.5 g/g, albumin >3.0
Supportive care, RAAS blockade, observe 6 months
Moderate
Normal eGFR, UPCR 3.5-8 g/g, albumin <3.0
Supportive 6 months, then consider immunosuppression if no remission
High
eGFR <60 and/or proteinuria >8 g/day for >6 months, or proteinuria >3.5 g/day not falling >50% after 6 months of ACEi/ARB plus albumin <2.5 g/dL or anti-PLA2R >50 RU/mL
Initiate immunosuppression (rituximab or modified Ponticelli)
KDIGO 2021 risk stratification for primary membranous nephropathy — guides timing and intensity of immunosuppression.
Treatment
First-line
Supportive care for all patients — RAAS blockade with ACE inhibitor (lisinopril, enalapril) or ARB (losartan, valsartan, irbesartan) titrated to maximum tolerated dose
Blood pressure target systolic <120 mmHg by standardized office measurement when tolerated (KDIGO 2021)
Dietary sodium restriction (<2 g/day), moderate protein intake
Statin therapy (atorvastatin, rosuvastatin)
Loop diuretic (furosemide, torsemide, bumetanide) for edema
Risk-stratify (low/medium/high/very high) per KDIGO using proteinuria, eGFR, albumin, and anti-PLA2R titer; observe low-risk patients for 6 months before initiating immunosuppression
Primary MN, moderate-to-high risk (persistent nephrotic-range proteinuria after 6 months, declining GFR, or very high anti-PLA2R titer)
Rituximab — increasingly preferred first-line per KDIGO 2021 (MENTOR trial)
Modified Ponticelli regimen — alternating monthly cyclophosphamide and corticosteroids for 6 months
Calcineurin inhibitor (cyclosporine, tacrolimus) — alternative; high relapse rate after withdrawal
Secondary MN
Treat the underlying cause: antiviral therapy for HBV/HCV, oncologic treatment for malignancy, withdraw causative drug, immunosuppression for SLE
Avoid empiric immunosuppression without identifying the cause
Second-line / adjunct
Anticoagulation — prophylactic if serum albumin <2.5-2.8 g/dL with additional risk factors; therapeutic for confirmed thromboembolism (warfarin or DOAC depending on severity)
Obinutuzumab or ofatumumab in rituximab-refractory disease
Stem-cell-based therapies and CAR-T in investigational protocols
Complications
Renal vein thrombosis (highest incidence among glomerular diseases — up to 30%); also DVT and PE
Progression to CKD/ESKD in untreated disease (rule of thirds: 1/3 spontaneous remission, 1/3 persistent proteinuria, 1/3 progressive)
Infection from urinary loss of immunoglobulins; pneumococcal and influenza vaccination
Cardiovascular disease from chronic dyslipidemia and hypertension
Steroid and cyclophosphamide toxicity in patients on Ponticelli regimen
PANCE pearls
Membranous nephropathy carries the highest rate of renal vein thrombosis among glomerular diseases — sudden flank pain, gross hematuria, or worsening proteinuria should prompt evaluation with Doppler or CT venography.
Anti-PLA2R titers correlate with disease activity and predict response to therapy; a falling titer often precedes clinical remission.
Malignancy-associated MN typically presents in patients >65; kidney tissue staining for NELL-1 raises concern for an occult cancer, whereas exostosin 1/2 (EXT1/EXT2) points to autoimmune disease such as lupus class V.
Rule of thirds for spontaneous course remains a useful counseling framework.
Hepatitis B is the leading global cause of secondary MN, especially in pediatric populations.
References
KDIGO 2021 — KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases (Kidney Int 2021;100:S1-S276)
MENTOR Trial — Fervenza FC et al. Rituximab or cyclosporine in the treatment of membranous nephropathy (NEJM 2019;381:36-46)
PLA2R — Beck LH et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy (NEJM 2009;361:11-21)
STARMEN — Fernandez-Juarez G et al. Tacrolimus-rituximab vs cyclophosphamide-steroids in membranous nephropathy (Kidney Int 2021;99:986-998)
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