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.
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Question 1RenalMedium
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?
AIdiopathic minimal change disease
BPrimary membranous nephropathy
CClass V membranous lupus nephritis
DFocal segmental glomerulosclerosis
Reveal answer & full explanation
Correct answer: B — Primary membranous nephropathy
AIdiopathic minimal change disease
BPrimary membranous nephropathy✓
CClass V membranous lupus nephritis
DFocal segmental glomerulosclerosis
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.
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.
Class V membranous lupus nephritis — can mimic primary membranous nephropathy histologically, but it features a positive ANA/anti-dsDNA, low C3/C4, extrarenal lupus, and full-house immunofluorescence; the negative ANA, normal complements, and positive anti-PLA2R here point to primary disease.
Question 2RenalMedium
A 54-year-old man presents with 6 weeks of foamy urine, progressive lower-extremity edema, and a 4 kg weight gain. He takes no medications and has no history of diabetes. Blood pressure is 142/88 mm Hg. Urinalysis shows 4+ protein without cellular casts, and a spot urine protein-to-creatinine ratio is 6.2 g/g. Serum albumin is 2.4 g/dL and the lipid panel shows elevated LDL. Serum creatinine and eGFR are normal. Which of the following findings best supports the diagnosis of primary membranous nephropathy?
AElevated serum free light chain ratio
BReduced serum C3 and C4 complement
CPositive serum anti-dsDNA antibody
DPositive serum anti-PLA2R antibody
Reveal answer & full explanation
Correct answer: D — Positive serum anti-PLA2R antibody
AElevated serum free light chain ratio
BReduced serum C3 and C4 complement
CPositive serum anti-dsDNA antibody
DPositive serum anti-PLA2R antibody✓
Why Positive serum anti-PLA2R antibody is correct
Roughly 70% of primary (autoimmune) membranous nephropathy is driven by circulating IgG4 autoantibodies against the M-type phospholipase A2 receptor (PLA2R) on podocytes.
In a patient with adult nephrotic syndrome, normal complements, and no systemic disease, a positive serum anti-PLA2R is highly specific for primary MN; per KDIGO 2021 it may obviate kidney biopsy in selected cases, and titers track disease activity.
Why the others are wrong
Reduced serum C3 and C4 complement — complements are characteristically normal in primary MN; hypocomplementemia points instead to lupus nephritis or membranoproliferative glomerulonephritis.
Positive serum anti-dsDNA antibody — indicates SLE and would suggest lupus nephritis (class V membranous), a secondary cause to be excluded, not primary MN.
Elevated serum free light chain ratio — suggests a monoclonal gammopathy with amyloidosis or light-chain deposition disease, a different cause of nephrotic syndrome rather than primary MN.
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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, occasional gross hematuria
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
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
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
Strict BP control (<125/75 if proteinuric)
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; staining of tissue for tumor-associated antigens (NELL-1, exostosin 1/2) can help.
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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