Membranous Nephropathy

• Antigen-Antibody Complex Formation and Podocyte Injury: In primary MN, circulating or in situ formed immune complexes (predominantly IgG, occasionally IgA or IgM) deposit along the subepithelial aspect of the GBM. The primary antigenic targets in idiopathic MN include phospholipase A2 receptor (PLA2R) (~70% of cases) and thrombospondin type-1 domain-containing 7A (THSD7A) (~2-5% of cases), though other podocyte antigens continue to be identified. IgG antibodies bind these podocyte-associated antigens, forming immune complexes that activate complement and trigger podocyte cytotoxicity, leading to extensive foot process effacement. This antigen-antibody interaction occurs in the context of altered glomerular permselectivity and may involve cross-reactivity with exogenous antigens (drugs, infections, malignancy-associated antigens) in secondary forms.

• Complement Activation and Membrane Attack Complex Formation: Subepithelial immune complex deposition activates the classical complement pathway (C1q binding), leading to sequential activation of C4, C2, and C3, ultimately generating the membrane attack complex (C5b-9). This is the predominant complement activation pattern in MN, distinguishing it from proliferative glomerulonephritis where C3 predominates. C5b-9 insertion into the glomerular basement membrane and podocyte plasma membrane triggers cell lysis, release of proteolytic enzymes, reactive oxygen species generation, and massive proteinuria. Interestingly, complete complement system activation does not necessarily lead to glomerular necrosis; instead, sublytic C5b-9 complexes (insufficient to create pores) activate signal transduction pathways that perpetuate inflammation through production of chemokines, adhesion molecules, and pro-inflammatory cytokines.

• Progressive Glomerular Basement Membrane Remodeling: Chronic immune complex deposition and complement activation trigger GBM remodeling characterized by electron-dense subepithelial humps or deposits with intervening GBM projections (creating the pathognomonic "spike and dome" appearance on electron microscopy). Matrix metalloproteinases degraded by activated podocytes and infiltrating immune cells remodel the GBM architecture. The GBM deposits are eventually incorporated into the GBM matrix over months to years, a process termed resorption, which may correlate with disease stabilization or spontaneous remission. Meanwhile, the proteinuria itself perpetuates injury through several mechanisms: (1) proteinuria activates proximal tubule epithelial cells to produce chemokines and cytokines; (2) filtered proteins (albumin, transferrin, immunoglobulins) are reabsorbed via endocytosis in proximal tubules, overwhelming cellular capacity and triggering apoptosis; (3) urinary proteins aggregate in tubular lumens causing obstruction; (4) toxic proteins directly injure tubular epithelium.

• Podocyte Dysfunction and Foot Process Effacement: Beyond immune injury, MN involves intrinsic podocyte dysfunction. IgG deposition on podocyte surface antigens (PLA2R, THSD7A) and C5b-9 membrane attack complex formation trigger podocyte cytoskeletal reorganization, with actin filaments collapsing and focal adhesion complexes disrupting. This results in widespread foot process effacement visible on electron microscopy, representing loss of the slit diaphragm architecture (composed of nephrin, podocin, and zonula occludens proteins). Podocytes undergo apoptosis and detach from the GBM basement, leading to progressive nephron loss. The degree of foot process effacement correlates with proteinuria severity but not necessarily with disease progression.

• Secondary Membranous Nephropathy Pathophysiology: In secondary MN (associated with malignancy, infections like hepatitis B, medications like NSAIDs/ACE inhibitors, or autoimmune diseases), pathogenic mechanisms differ. For example, in malignancy-associated MN, tumor-derived antigens or tumor antigen-antibody complexes deposit in glomeruli; in hepatitis B, viral surface antigen (HBsAg) and corresponding antibodies form complexes. Infectious antigens may directly cross-react with or deposit alongside endogenous glomerular antigens. Drug-induced MN may result from hapten formation (drug binding to native antigen) or immune complex formation with drug metabolites.

• PLA2R-Associated Disease (70-75% of Primary MN): Circulating anti-PLA2R IgG antibodies develop against phospholipase A2 receptor, a 180-kDa podocyte-resident enzyme. The genetic basis involves HLA associations (HLA-DQA1) and polymorphisms in the PLA2R gene itself, suggesting inherited susceptibility. PLA2R-positive patients tend to have higher initial proteinuria and greater likelihood of nephrotic presentation. Serum anti-PLA2R antibody titers correlate with disease activity and may predict response to immunosuppressive therapy; serial monitoring can guide treatment decisions and identify disease relapse.

• THSD7A-Associated Disease (2-5% of Primary MN): Antibodies against thrombospondin type-1 domain-containing protein 7A define a subset of PLA2R-negative primary MN. THSD7A-positive patients tend to be older at presentation (median age 60 years) and may have higher baseline creatinine at diagnosis. The clinical course and response to therapy appear similar to PLA2R-positive disease, but longer-term outcome data are limited.

• Other Podocyte Antigens (5-25% of Primary MN): Emerging evidence identifies additional target antigens including NELL1 (neural EGFL-like protein 1), alpha-enolase, and IgG4-related antigens. These represent areas of active research, and commercial testing for these antigens is not yet routine but may be available through specialized centers.

• Malignancy-Associated MN (10-15% of Secondary Cases): Solid tumors (especially lung, gastric, colon, breast, ovarian, and renal cell carcinoma) and hematologic malignancies (lymphomas, chronic lymphocytic leukemia) are associated with MN, occasionally preceding cancer diagnosis. Tumor antigens or tumor-antigen-antibody complexes deposit in glomeruli. The presence of MN in an adult >50 years warrants malignancy screening (beyond standard cancer screening appropriate for age), including computed tomography of chest/abdomen/pelvis and age-appropriate cancer screening. MN may improve with cancer treatment, providing diagnostic confirmation.

• Hepatitis B Virus (HBV)-Associated MN: Particularly prevalent in endemic regions (Asia, Africa), HBV surface antigen (HBsAg) and corresponding antibodies form immune complexes that deposit subepithelially. This represents the most common cause of nephrotic syndrome in children and young adults in endemic regions. Unlike typical adult primary MN, HBV-related MN often presents with mixed nephritic-nephrotic features and may progress more rapidly. Treatment addresses both glomerulonephritis and viral hepatitis.

• Autoimmune Disease-Associated MN: Systemic lupus erythematosus (SLE) classically presents with proliferative patterns, but membranous lupus nephritis (Class V) occurs in 10-20% and may coexist with proliferative disease. Other connective tissue diseases (rheumatoid arthritis, Sjögren syndrome, scleroderma) occasionally associate with MN. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) frequently manifest with MN.

• Drug-Induced MN: NSAIDs (including both traditional and COX-2 selective inhibitors) cause MN through several proposed mechanisms including hapten formation, immune complex deposition, or direct podocyte toxicity. ACE inhibitors and angiotensin II receptor blockers paradoxically may cause MN, though they are also therapeutic agents for proteinuria. Mercury (elemental and organic forms) exposure causes MN, historically recognized in hat makers ("mad hatter" syndrome). Other implicated drugs include penicillamine, gold salts, and proton pump inhibitors.

• Infectious Disease-Associated MN: Beyond HBV, hepatitis C virus (HCV) associates with MN, particularly with mixed cryoglobulinemia. Syphilis (secondary and tertiary stages), malaria, schistosomiasis, and leprosy are important causes in endemic regions. Endocarditis and HIV infection may present with MN, though HIV more commonly causes focal segmental glomerulosclerosis (FSGS) or collapsing glomerulopathy.

• Systemic Disease-Associated MN: Diabetes mellitus rarely causes pure MN but may present as combined diabetic changes with concurrent MN. Thyroiditis, myasthenia gravis, and other organ-specific autoimmune conditions occasionally associate with MN.

• Asymptomatic Proteinuria (Most Common Initial Presentation): Approximately 30-40% of patients are discovered to have MN incidentally on routine urinalysis or screening studies performed for unrelated reasons. These patients may report no symptoms and have normal serum creatinine. Proteinuria is often substantial (>2-3 g/day) despite absence of clinical manifestations, as the kidneys maintain adequate clearance function. This asymptomatic phase may persist for years, allowing for non-immunosuppressive observation if risk factors for progression are absent.

• Nephrotic Syndrome (Present in 50-60% at Diagnosis): The classic nephrotic presentation includes heavy proteinuria (typically >3.5 g/day, often 5-10 g/day or greater), hypoalbuminemia (<2.5 g/dL due to urinary albumin losses exceeding hepatic synthesis), hyperlipidemia (elevated total cholesterol, LDL cholesterol, triglycerides from upregulated hepatic lipoprotein synthesis; HDL typically reduced), and edema. Patients complain of progressive lower extremity swelling (pitting edema of ankles and legs, worst at day's end), abdominal bloating, facial puffiness upon awakening, and weight gain (often 5-15 lbs over weeks). Dyspnea may occur from pulmonary edema or pleural effusions in severe cases. The edema results from both hypoalbuminemia (oncotic pressure loss) and secondary activation of sodium-retentive mechanisms (activation of renin-angiotensin-aldosterone system, sympathetic nervous system, and antidiuretic hormone).

• Nephritic Features (Less Common but Important): While MN is predominantly nephrotic, some patients present with concurrent nephritic features including hematuria (microscopic in most, gross hematuria in ~5%), cylindruria (RBC casts, hyaline casts), and mild hypertension. These features are more common in secondary MN (especially HBV-related and lupus-associated) than primary MN and may portend worse prognosis. Active urinary sediment suggests concurrent glomerular inflammation beyond the typical membranous pattern.

• Progressive Renal Dysfunction: Approximately 20-30% of patients present with reduced renal function (elevated serum creatinine, reduced glomerular filtration rate) at diagnosis. Proteinuria drives tubular injury and progressive nephron loss; patients with baseline creatinine >1.4 mg/dL have higher risk of progression to ESRD. Some patients present with acute kidney injury superimposed on chronic kidney disease, occasionally termed "acute nephrotic crisis," characterized by sudden severe proteinuria, rapid rise in creatinine, and sometimes acute tubular necrosis pattern on biopsy (rare).

• Thromboembolic Manifestations: Approximately 5-10% of MN patients present with thromboembolic complications (deep vein thrombosis, pulmonary embolism, renal vein thrombosis, stroke) as the initial clinical presentation. These occur due to loss of anticoagulant proteins (protein C, protein S, antithrombin III) in urine, hypercoagulability from loss of fibrinolytic proteins, increased blood viscosity from severe hypoalbuminemia, and increased platelet aggregation. Renal vein thrombosis specifically occurs in 10-50% of MN patients (varies by study, more common in severely nephrotic patients); many cases are clinically silent but detectable on imaging. Patients may present with acute flank pain, hematuria, or deterioration of renal function attributed to renal infarction.

• Complications of Nephrotic Syndrome: Acute peritonitis (from transperitoneal spread of ascitic fluid bacteria) occurs in approximately 1-3% of nephrotic patients and presents with acute abdominal pain, fever, and peritoneal signs. Lipid-laden foam cells in urine (oval fat bodies) reflect cellular response to lipiduria. Protein malnutrition develops insidiously from combined losses (albumin, binding proteins, immunoglobulins) and may manifest as muscle wasting, delayed wound healing, and increased susceptibility to infections (especially encapsulated organisms due to loss of IgG). Hair loss, nail changes, and fatigue may reflect severe nutritional depletion.

• Physical Examination Findings: Pitting edema of dependent areas (ankles, sacrum in bedridden patients), ascites (when nephrotic syndrome is severe), and occasionally periorbital edema are characteristic. Careful blood pressure assessment reveals hypertension in 50% of patients at presentation, though some remain normotensive. Fundoscopy may reveal hypertensive changes if severe hypertension coexists. Lymphadenopathy, hepatosplenomegaly, or other systemic findings suggest secondary causes (malignancy, sarcoidosis, infection).

• Clinical Variants and Special Presentations: Pregnant women with MN may experience worsening proteinuria during pregnancy and postpartum exacerbations, with increased risk of thromboembolism. Pediatric MN (rare in children) typically reflects secondary causes (HBV in endemic regions, medications). Elderly patients presenting with MN warrant particular vigilance for underlying malignancy. Rapid progression over weeks to months ("rapidly progressive MN") is uncommon but signals need for aggressive evaluation and consideration of crescentic lesions on biopsy or concurrent ANCA-associated disease.

• Serum Creatinine and Estimated Glomerular Filtration Rate (eGFR): Baseline renal function assessment establishes the degree of kidney disease severity. Normal creatinine does not exclude MN; many patients maintain normal or near-normal function despite heavy proteinuria. Creatinine >1.4 mg/dL (eGFR <60 mL/min) at presentation predicts higher risk of progression. The creatinine ratio (creatinine-to-proteinuria ratio) provides prognostic information: high creatinine relative to proteinuria suggests longer disease duration and more advanced injury.

• **24-Hour Urine

Immediate stabilisation

• Volume management: loop diuretics (e.g., furosemide) plus dietary sodium restriction for symptomatic edema; severe hypoalbuminemia blunts diuretic delivery, so higher or IV dosing is often needed. Anasarca with respiratory compromise or suspected pulmonary embolism requires urgent evaluation.
• Identify secondary MN first: KDIGO's 2021 Glomerular Diseases guideline stresses treating the underlying cause (malignancy, HBV, lupus, offending drug such as an NSAID or penicillamine) rather than immunosuppressing an unrecognised secondary form.

First-line conservative therapy (all patients)

• RAAS blockade: an ACE inhibitor (lisinopril) or ARB reduces intraglomerular pressure and proteinuria; KDIGO recommends this as baseline antiproteinuric/antihypertensive therapy. All ACE inhibitors and ARBs are contraindicated in pregnancy (fetal renal dysgenesis, oligohydramnios).
• Statin therapy for nephrotic hyperlipidemia, and prophylactic anticoagulation (traditionally warfarin; DOAC data are limited) in patients with markedly low serum albumin and additional thrombotic risk, per KDIGO.

Immunosuppression for moderate/high/very-high risk

• Anti-CD20 monoclonal antibody: rituximab depletes B cells and anti-PLA2R production; favoured first-line by KDIGO given efficacy and tolerability (supported by the MENTOR trial versus cyclosporine).
• Cyclophosphamide plus corticosteroid: the alternating modified Ponticelli regimen, preferred when risk of progression is very high.
• Calcineurin inhibitor: tacrolimus or cyclosporine (stabilises the podocyte actin cytoskeleton), often with rituximab; relapse after withdrawal is common.

Refractory or end-stage disease

• Serologic monitoring: falling anti-PLA2R titre (immunologic remission) precedes proteinuric remission and guides retreatment.
• Kidney replacement therapy/transplantation for ESRD; MN can recur in the allograft.

Avoid

• Corticosteroid monotherapy: ineffective in primary MN and not recommended.
• NSAIDs: worsen proteinuria, precipitate AKI, and can themselves cause MN.

Disease-related

• Venous thromboembolism: urinary loss of antithrombin III, protein C and protein S plus increased hepatic fibrinogen synthesis creates hypercoagulability; MN carries the highest thrombotic risk of the nephrotic glomerulopathies. Signalled by unilateral leg swelling, pleuritic chest pain, or hypoxemia. Pulmonary embolism is an emergency.
• Renal vein thrombosis: classically acute flank pain, gross hematuria, and an abrupt rise in creatinine with a sudden increase in proteinuria; confirm with CT or MR venography. Urgent anticoagulation is indicated.
• Infection: urinary loss of IgG and complement factor B impairs opsonisation of encapsulated organisms. Spontaneous bacterial peritonitis (classically pneumococcal) presenting with fever and abdominal pain in a patient with ascites is an emergency.
• Acute kidney injury: from intravascular depletion, aggressive diuresis, interstitial edema, or superimposed renal vein thrombosis; a rapid creatinine rise should prompt reconsideration of crescents or concurrent ANCA disease.
• Progression to ESRD: chronic proteinuric tubulointerstitial injury; heralded by rising creatinine and persistent nephrotic-range proteinuria.
• Metabolic sequelae: accelerated atherosclerosis from hyperlipidemia; loss of vitamin D–binding protein causing hypocalcemia; transferrin loss causing iron-refractory anemia; thyroxine-binding globulin loss altering thyroid indices.

Treatment-related

• Rituximab: infusion reactions, prolonged hypogammaglobulinemia with late infection, and hepatitis B reactivation — screen HBsAg and anti-HBc before dosing; rare progressive multifocal leukoencephalopathy.
• Cyclophosphamide: acrolein-mediated hemorrhagic cystitis (hematuria; mitigated with hydration and mesna), marrow suppression, infertility, and later bladder cancer and myelodysplasia.
• Calcineurin inhibitors: dose-dependent afferent arteriolar vasoconstriction causing nephrotoxicity and hypertension; tremor; gingival hyperplasia and hirsutism with cyclosporine; hyperglycemia with tacrolimus.
• Corticosteroids: hyperglycemia, osteoporosis, adrenal suppression, and opportunistic infection (consider Pneumocystis prophylaxis with intensive regimens).
• Anticoagulation: bleeding risk, magnified in patients with uremic platelet dysfunction.

• The buzzword pair: "spike and dome" on silver stain with subepithelial electron-dense deposits on EM, and diffuse granular IgG/C3 on immunofluorescence. Light microscopy shows uniformly thickened GBM without hypercellularity — a bland glomerulus with heavy proteinuria is the tell.
• The association examiners test: anti-PLA2R antibodies (IgG4 subclass) in roughly 70% of primary MN. A nephrotic adult with positive anti-PLA2R and preserved eGFR may be diagnosed without biopsy; titres track disease activity and predict relapse.
• Single best next step in an adult over ~50 with new MN: evaluate for secondary causes — age-appropriate malignancy screening (solid tumours: lung, GI, breast), hepatitis B and C serologies, ANA, and a drug review (NSAIDs, penicillamine, gold). MN can precede the cancer diagnosis.
• Single best next step for acute flank pain + hematuria + creatinine bump in known MN: imaging for renal vein thrombosis (CT/MR venography), then anticoagulation. MN is the nephrotic disease most linked to thromboembolism because of urinary antithrombin III loss.
• Treatment pearl: per KDIGO, steroid monotherapy does not work — a stem offering "start prednisone alone" is a distractor. Rituximab, cyclophosphamide plus steroid (modified Ponticelli), or a calcineurin inhibitor are the risk-stratified options; low-risk patients get RAAS blockade and observation because about one-third remit spontaneously.
• Lupus clue: membranous Class V lupus nephritis mimics primary MN but shows "full-house" immunofluorescence (IgG, IgA, IgM, C1q, C3), mesangial as well as subepithelial deposits, and tubuloreticular inclusions; anti-PLA2R is negative.
• Common distractors: minimal change disease (children, normal LM, effaced foot processes only), FSGS (HIV, obesity, sickle cell), diabetic nephropathy (Kimmelstiel–Wilson nodules), and MPGN (tram-track GBM with subendothelial deposits and low complement). Deposit location is the discriminator.