Renal & Urinary

Membranous nephropathy: workup and treatment

Clinical Overview and When to Suspect Membranous Nephropathy

— Most common cause of primary nephrotic syndrome in non-diabetic White adults, peak age 40–60

— Male predominance ~2:1

— Accounts for ~20–30% of adult nephrotic syndrome

— Primary (~80%): autoimmune; anti-PLA2R antibodies in ~70–80%, anti-THSD7A in ~3–5%

— Secondary (~20%): SLE (class V lupus nephritis), hepatitis B/C, solid tumors (lung, colon, prostate, breast — especially in patients >65), NSAIDs, penicillamine, gold, syphilis

— Adult with insidious-onset edema, foamy urine, weight gain, and nephrotic-range proteinuria (>3.5 g/day) without hematuria or HTN early on

— Normal or near-normal creatinine at presentation

— Hypoalbuminemia, hyperlipidemia, and bland urine sediment (oval fat bodies, fatty casts, but no RBC casts)

— Unprovoked DVT/PE or renal vein thrombosis in a nephrotic adult — MN has the highest VTE risk of any glomerular disease

— ~1/3 spontaneous remission

— ~1/3 persistent proteinuria with stable function

— ~1/3 progression to ESRD over 5–10 years

Board pearl: In any adult >65 with new nephrotic syndrome and biopsy-proven MN, age-appropriate cancer screening is mandatory — MN can precede the diagnosis of malignancy by 12–18 months. Order colonoscopy, low-dose chest CT (if smoker), mammography, PSA, and a careful skin exam before labeling the disease "idiopathic."

Step 3 management: Recognition hinges on the triad — adult + nephrotic-range proteinuria + bland sediment — which should prompt PLA2R serology and renal biopsy rather than empiric steroids.

Definition: Membranous nephropathy (MN) is a podocyte injury syndrome characterized by subepithelial immune complex deposition along the glomerular basement membrane (GBM), producing the classic "spike and dome" pattern on EM and silver stain.

Epidemiology:

Primary vs secondary:

When to suspect MN in a Step 3 vignette:

Natural history (rule of thirds):

Presentation Patterns and Key History

— Gradual lower-extremity edema progressing over weeks; periorbital puffiness on waking

— Foamy/frothy urine (proteinuria), weight gain of 5–15 lb from fluid retention

— Fatigue, dyspnea on exertion from anasarca or pleural effusion

— Less commonly: scrotal/vulvar edema, ascites

— Acute flank pain + gross hematuria + AKI → think renal vein thrombosis (MN has highest association of any glomerulonephropathy)

— Pulmonary embolism as the index event in a previously well middle-aged man

— Cellulitis or spontaneous bacterial peritonitis from urinary loss of immunoglobulins and complement factor B

— Medications: NSAIDs (chronic use), penicillamine, gold salts, captopril, anti-TNF agents

— Infections: hepatitis B (cccDNA reactivation risk), hepatitis C, secondary syphilis, schistosomiasis travel exposure

— Autoimmune symptoms: photosensitive rash, arthralgias, oral ulcers, Raynaud → lupus membranous (class V)

— Cancer red flags: weight loss, hemoptysis, change in bowel habits, hematochezia, hematuria, breast lump

— Family history: less relevant (MN is rarely heritable, unlike Alport or FSGS)

— Onset over weeks to months distinguishes MN from minimal change disease (often abrupt, days) and rapidly progressive GN (days–weeks with hematuria and AKI)

Key distinction: Minimal change disease in adults presents acutely with massive edema and is typically NSAID- or Hodgkin-associated, while MN is more insidious and tumor-associated with solid organ malignancies — both can have nephrotic-range proteinuria but the tempo and demographic differ.

Board pearl: A 58-year-old man with new edema, proteinuria 8 g/day, and an unprovoked segmental PE is the prototypical MN stem — order PLA2R antibody, hepatitis serologies, and ANA before biopsy.

Classic presentation:

Atypical/alarming first presentations (high yield):

Targeted history questions:

Symptom timeline clue:

Physical Exam Findings and Volume Assessment

— Puffy facies, periorbital edema worst in the morning

— Pallor uncommon early (creatinine often normal); look for xanthelasma from hyperlipidemia

— Pitting edema — grade 1+ (trace, 2 mm) through 4+ (>8 mm, persistent)

— Bilateral lower-extremity edema extending to thighs/sacrum suggests severe hypoalbuminemia (<2.5 g/dL)

— Ascites: shifting dullness, fluid wave — risk of SBP even without cirrhosis

— Pleural effusion: dullness to percussion, decreased breath sounds at bases

— Scrotal/labial edema in severe cases

— Patients are often intravascularly depleted despite total-body fluid overload ("underfill" physiology) — JVP may be low or normal, orthostatic vitals positive

— In contrast, "overfill" physiology shows elevated JVP and HTN — more common with advanced CKD or steroid effect

— Distinguishing the two guides diuretic vs albumin strategy

— S3 uncommon unless concomitant heart failure

— Tachypnea and hypoxia → consider PE (MN-associated) before attributing to volume overload

— Muehrcke lines (paired white transverse nail bands) from hypoalbuminemia

— Look for calf tenderness/asymmetric swelling → DVT

— Lymphadenopathy, hepatosplenomegaly → secondary causes (lymphoma, hepatitis)

— Malar rash, oral ulcers → lupus MN

— Breast/prostate/testicular exam, dermatologic survey for occult malignancy in older patients

Step 3 management: Before initiating loop diuretics in a nephrotic patient with anasarca, assess volume status carefully — orthostatics, JVP, and skin turgor. In underfilled patients, albumin infusion followed by IV furosemide is more effective and avoids precipitating AKI.

Board pearl: New asymmetric leg swelling in MN is DVT until proven otherwise — get a duplex ultrasound, not just more diuretic.

General appearance:

Volume exam (critical for management):

Hemodynamic assessment:

Cardiopulmonary:

Skin/extremities:

Other systems:

Diagnostic Workup — Initial Labs and Studies

— Urinalysis: 3–4+ protein, bland sediment (no RBC casts), oval fat bodies, "Maltese cross" lipid bodies under polarized light

— Spot urine protein-to-creatinine ratio (UPCR): >3.5 g/g = nephrotic range; preferred for initial quantification

— 24-hour urine protein: gold standard for baseline and serial monitoring; >3.5 g/day defines nephrotic-range

— Microscopic hematuria in ~30–40% but dysmorphic RBCs and RBC casts are absent — their presence shifts diagnosis toward proliferative GN

— Hypoalbuminemia (<3.5 g/dL, often <2.5)

— Hyperlipidemia (LDL, total cholesterol elevated; hepatic compensatory synthesis)

— Creatinine often normal at presentation — significant elevation suggests advanced disease, RVT, AKI, or alternate diagnosis

— Sodium may be mildly low (dilutional)

— Mild anemia possible; antithrombin III loss in urine contributes to hypercoagulability

— Check fibrinogen (often elevated)

— Anti-PLA2R antibody (ELISA or IFA) — positive in ~70–80% of primary MN, highly specific

— Anti-THSD7A — order if PLA2R negative

— ANA, anti-dsDNA, C3, C4 — lupus (low complements suggest class V + proliferative component)

— Hepatitis B surface antigen, HBV DNA, anti-HCV, HCV RNA

— HIV, RPR

— SPEP/UPEP, free light chains if >age 50 (rule out amyloid, MGRS)

— TSH (nephrotic patients can have functional hypothyroidism from TBG loss)

— Renal ultrasound — normal-sized or slightly enlarged kidneys; rules out obstruction; assess for RVT (Doppler)

— CXR for effusions

Board pearl: A positive anti-PLA2R titer with nephrotic-range proteinuria in a patient without diabetes can clinch primary MN without biopsy in selected cases — but most US nephrologists still biopsy for staging and to exclude superimposed disease.

Step 3 management: Document quantitative proteinuria (24-hr or UPCR), eGFR, and PLA2R status before initiating immunosuppression — these are your monitoring anchors.

Urine studies (the cornerstone):

Serum chemistry:

CBC and coagulation:

Serologic workup for secondary causes (always send before calling it "primary"):

Imaging:

Diagnostic Workup — Renal Biopsy and Confirmatory Studies

— All adults with new nephrotic syndrome of unclear cause

— Atypical features: AKI, active sediment, low complements, suspected overlap

— Exception: consider deferring biopsy in patients with high-titer anti-PLA2R, preserved GFR, no secondary cause — KDIGO 2021 permits empiric treatment in select cases

— Light microscopy: diffuse thickening of GBM without proliferation; silver stain shows "spikes" projecting from GBM (subepithelial deposits between spikes)

— Immunofluorescence: granular IgG and C3 along capillary loops; IgG4 dominant in primary MN; IgG1/IgG2/IgG3 + "full house" (IgA, IgM, C1q) suggests lupus or secondary

— Electron microscopy: subepithelial electron-dense deposits; effaced podocyte foot processes

— Stage I: small subepithelial deposits

— Stage II: deposits with intervening GBM spikes

— Stage III: deposits incorporated into thickened GBM

— Stage IV: electron-lucent zones (resolving)

— Glomerular PLA2R antigen positivity confirms primary MN even when serum antibodies are negative

— Age-appropriate: colonoscopy, low-dose chest CT (smokers), mammography, Pap, PSA discussion, skin exam

— Anti-THSD7A positivity carries higher malignancy association — pursue aggressive workup

— If HBsAg+ → HBV DNA, HBeAg, liver elastography before immunosuppression

— If HCV Ab+ → HCV RNA, genotype

Key distinction: Lupus membranous (class V LN) shows "full-house" IF (IgG, IgA, IgM, C1q, C3), mesangial deposits, and tubuloreticular inclusions on EM — these are absent in primary MN.

Board pearl: Subepithelial deposits = MN; subendothelial deposits = lupus (proliferative) or MPGN; mesangial deposits = IgA nephropathy. Memorize the deposit location map.

Indications for renal biopsy:

Biopsy findings (the classic triad of microscopy):

Ehrenreich-Churg staging (EM-based, prognostic):

Tissue PLA2R staining:

Cancer screening (≥65 or risk factors):

Hepatitis B/C confirmation:

Risk Stratification and Initial Management Logic

— Low risk: normal eGFR, proteinuria <3.5 g/day OR >50% reduction in 6 months, serum albumin >3.0

— Moderate risk: normal eGFR, proteinuria 3.5–8 g/day not responding to 6 months of conservative therapy

— High risk: eGFR <60 OR proteinuria >8 g/day for >6 months OR high anti-PLA2R titer (>150 RU/mL)

— Very high risk: life-threatening nephrotic syndrome, rapid decline in eGFR not explained by complication

— ACE inhibitor or ARB titrated to maximum tolerated dose — reduces proteinuria 30–40%

— Sodium restriction (<2 g/day) and modest fluid restriction

— Loop diuretic (furosemide, often with thiazide adjunct) for edema; monitor for AKI

— Statin for nephrotic hyperlipidemia

— Anticoagulation prophylaxis if albumin <2.0–2.5 g/dL or other risk factors (see chunk 11)

— Vaccinations: pneumococcal (PCV20 or PCV15→PPSV23), influenza, COVID-19, HBV — before immunosuppression

— Low-risk patients: 6 months of conservative therapy with serial PLA2R, UPCR, eGFR — many remit spontaneously

— Moderate–high risk: shorter observation if PLA2R rising or proteinuria worsening

— Persistent nephrotic-range proteinuria >6 months despite RAAS blockade

— Decline in eGFR

— Disabling/refractory edema, thromboembolic complications, severe hypoalbuminemia

Step 3 management: A newly diagnosed MN patient with preserved GFR, proteinuria 4 g/day, and albumin 3.1 should get maximum ACEi/ARB + statin + diuretic + anticoagulation assessment for 6 months before initiating cytotoxic therapy — don't reach for cyclophosphamide on the first visit.

Board pearl: Spontaneous remission occurs in ~30% of primary MN — the rationale behind the watchful conservative phase in low-risk disease.

KDIGO 2021 risk categories (drive treatment intensity):

Universal conservative/supportive therapy (start day 1 for all):

Observation period:

Treatment thresholds for immunosuppression:

Pharmacotherapy — Immunosuppressive Regimens

— Rituximab — increasingly preferred first-line: 1 g IV on days 0 and 14 (or 375 mg/m² weekly × 4); repeat at 6 months based on CD19 and PLA2R response

— Cyclophosphamide + glucocorticoids (modified Ponticelli regimen) — preferred for very high-risk or rapidly declining eGFR; alternates monthly cyclophosphamide and steroids over 6 months

— Calcineurin inhibitors (CNIs): cyclosporine or tacrolimus ± low-dose prednisone — alternative for moderate risk, but high relapse rate on withdrawal

— Rituximab non-inferior to cyclosporine at 12 months and superior at 24 months for maintaining remission

— Drives the shift toward rituximab as first-line in many centers

— Months 1, 3, 5: IV methylprednisolone 1 g × 3 days, then oral prednisone 0.5 mg/kg/day × 27 days

— Months 2, 4, 6: oral cyclophosphamide 2 mg/kg/day

— Monitor CBC weekly (cyclophosphamide nadir at days 10–14), urinalysis (hemorrhagic cystitis)

— Tacrolimus 0.05–0.075 mg/kg/day divided BID, trough 5–7 ng/mL

— Cyclosporine 3.5 mg/kg/day divided BID, trough 125–175 ng/mL

— Taper slowly over 12+ months to reduce relapse

— PJP prophylaxis (TMP-SMX) with cyclophosphamide or prolonged high-dose steroids

— HBV reactivation prophylaxis (entecavir/tenofovir) if HBsAg+ or anti-HBc+ before rituximab

— Bone health: calcium, vitamin D, bisphosphonate for steroids

— Anti-PLA2R falls before proteinuria — immunologic remission precedes clinical remission by 6–12 months

— Complete remission: proteinuria <0.3 g/day; partial: <3.5 g/day with >50% reduction

Board pearl: A falling anti-PLA2R titer at 3–6 months predicts treatment success even when proteinuria still appears high — don't switch therapy prematurely.

Step 3 management: Before rituximab, screen and treat latent TB, HBV, and update vaccines — these are the highest-yield safety steps.

First-line immunosuppression for moderate-to-high risk MN (KDIGO 2021):

MENTOR trial (landmark):

Modified Ponticelli (high-yield specifics):

Calcineurin inhibitor dosing:

Adjunctive considerations:

Monitoring response:

Expanded Pharmacology and Refractory Disease

— Confirm adherence, exclude renal vein thrombosis, re-biopsy if eGFR declining

— Re-check PLA2R — persistently high titer = ongoing immunologic activity

— Switch agents: rituximab if started on Ponticelli, or vice versa

— Combination rituximab + cyclophosphamide + steroid (off-label, severe cases)

— Obinutuzumab (anti-CD20) — emerging option for rituximab-resistant disease

— Adrenocorticotropic hormone (ACTH) gel — limited evidence; rarely used

— RAAS blockade: lisinopril 10–40 mg daily or losartan 50–100 mg daily; titrate to BP <130/80 and maximum tolerated dose. Monitor K+ and creatinine 1–2 weeks after each increase. Hold if K+ >5.5 or Cr rises >30%.

— Loop diuretic: furosemide 40–80 mg PO BID, often combined with metolazone 2.5–5 mg for diuretic resistance; albumin 25% IV before furosemide in severely hypoalbuminemic, underfilled patients

— Statin: atorvastatin 40–80 mg or rosuvastatin 20–40 mg

— Anticoagulation: see chunk 11 — warfarin (target INR 2–3) traditionally; DOACs increasingly used but evidence in heavy proteinuria limited

— Cyclosporine + statins → rhabdomyolysis (avoid simvastatin; prefer pravastatin or low-dose rosuvastatin)

— Tacrolimus + azoles → CNI toxicity

— Rituximab + live vaccines → contraindicated for 6+ months

— Dapagliflozin or empagliflozin — increasingly added for proteinuric CKD (DAPA-CKD, EMPA-KIDNEY); reduces proteinuria and slows progression even in non-diabetics

— Initiate when eGFR ≥20, hold during acute illness/volume depletion

Step 3 management: For a refractory MN patient with persistent 6 g proteinuria after 12 months of CNI, rituximab is the next step — combined with continued RAAS blockade and SGLT2i.

Board pearl: Diuretic resistance in nephrotic syndrome often responds to IV furosemide + albumin combo or addition of a thiazide-type agent for sequential nephron blockade.

Refractory MN (no response after 6–12 months of first-line therapy):

Second-line/salvage options:

Supportive pharmacology (the "background bundle"):

Drug interactions to remember:

SGLT2 inhibitors:

Special Populations — Elderly and Renal/Hepatic Impairment

— Higher malignancy association — up to 20–25% have an underlying solid tumor

— Mandatory cancer screening: colonoscopy, low-dose chest CT (smokers/former smokers within 15 years), mammography, PSA discussion, derm exam, urine cytology if hematuria

— Anti-THSD7A positivity carries a particularly strong cancer link

— Treatment of MN may be deferred until malignancy is treated — paraneoplastic MN often remits with tumor resection/treatment

— Cyclophosphamide: reduce dose by 25–50% if age >65 or eGFR <50 to limit cytopenia and bladder toxicity

— Rituximab: no renal dose adjustment; preferred in elderly due to lower marrow toxicity

— Avoid CNIs in patients with marginal GFR — nephrotoxicity risk

— Confirm MN is the cause of CKD, not coincident — re-biopsy may be indicated

— Avoid cyclophosphamide if eGFR <30 (toxicity, poor response)

— Rituximab remains usable across CKD stages

— ACEi/ARB: continue unless K+ >5.5 or creatinine rises >30% acutely; do not stop reflexively for stable rise

— Adjust loop diuretic dose upward (furosemide 80–160 mg+ doses needed in advanced CKD)

— Hepatitis B/C-associated MN: treat the virus first (entecavir/tenofovir for HBV; DAAs for HCV) — often induces renal remission without immunosuppression

— Avoid rituximab in active untreated HBV → fulminant reactivation

— Statins: prefer pravastatin or rosuvastatin in mild hepatic dysfunction; avoid in decompensated cirrhosis

— Weigh expected lifespan, comorbidities, and treatment burden — older frail patients with slowly progressive proteinuria may be best served by conservative therapy alone

Key distinction: Hepatitis B-associated MN is treated primarily with antivirals (entecavir or tenofovir) — immunosuppression alone risks viral reactivation and fulminant hepatitis.

Board pearl: A 70-year-old smoker with new MN deserves a low-dose chest CT before any immunosuppression — paraneoplastic MN from lung cancer is a classic Step 3 trap.

Elderly (>65 years):

Drug dosing in elderly:

Reduced eGFR (CKD stage 3b–5):

Hepatic impairment:

Frailty considerations:

Special Populations — Pregnancy and Pediatrics

— MN can present or relapse during pregnancy; proteinuria worsens physiologically due to increased GFR

— Differential against preeclampsia is critical: preeclampsia after 20 weeks with HTN, proteinuria, possibly HELLP; MN typically antedates pregnancy or presents earlier

— Maternal risks: VTE (compounded), preeclampsia, fetal growth restriction, preterm birth

— Fetal risks: prematurity, IUGR, stillbirth (higher if albumin <2.5 or creatinine elevated)

— Continue/initiate: labetalol or nifedipine for BP, low-dose aspirin (preeclampsia prophylaxis from 12 weeks), LMWH for thromboprophylaxis if indicated

— Stop ACEi/ARB before conception (teratogenic — renal dysgenesis, oligohydramnios) — switch to labetalol or nifedipine

— Allowed immunosuppressants: prednisone (low dose), azathioprine, tacrolimus, cyclosporine, hydroxychloroquine

— Contraindicated: cyclophosphamide (teratogenic, gonadotoxic), mycophenolate (cleft palate, embryopathy — stop ≥6 weeks before conception), rituximab (generally avoided, especially first trimester)

— Defer pregnancy until remission for ≥6 months and off contraindicated agents

— Co-manage with maternal-fetal medicine and nephrology

— MN is uncommon in children (<5% of pediatric nephrotic syndrome — minimal change disease dominates)

— When seen, consider secondary causes: hepatitis B (especially in endemic regions), lupus, congenital syphilis

— Anti-PLA2R is rare in pediatric MN

— Treatment mirrors adults but more often responds to addressing underlying cause; cyclophosphamide use weighed against gonadal toxicity

Step 3 management: A 28-year-old woman with PLA2R-positive MN planning pregnancy should achieve remission, transition off ACEi/ARB and mycophenolate, and switch to azathioprine ± tacrolimus as bridging therapy if needed.

Board pearl: In any nephrotic syndrome diagnosed during pregnancy, rule out preeclampsia first — timing, BP trajectory, uric acid, and LFTs guide the distinction; renal biopsy is rarely performed during pregnancy unless rapid decline.

Pregnancy:

Pregnancy-safe management:

Counseling:

Pediatrics:

Complications and Adverse Outcomes

— MN has the highest VTE rate of any glomerulopathy — up to 7–60% lifetime risk depending on severity

— Mechanisms: urinary loss of antithrombin III, protein S, plasminogen; increased fibrinogen and platelet activation

— Sites: renal vein thrombosis (classic; presents with flank pain, hematuria, AKI, or asymptomatic), DVT, PE, cerebral venous sinus thrombosis

— Risk highest when serum albumin <2.5 g/dL (some use <2.0–2.8 thresholds)

— Indicated when albumin <2.0–2.5 g/dL and additional risk factors (proteinuria >10 g, BMI >35, prior VTE, immobility, HF)

— Use the Lin/Cattran nomogram to weigh thrombosis vs bleeding risk

— Agents: warfarin (INR 2–3) is best studied; prophylactic-dose LMWH acceptable; DOAC evidence emerging but limited in heavy proteinuria

— Urinary loss of IgG and complement factor B → encapsulated organism risk (S. pneumoniae, H. influenzae)

— Spontaneous bacterial peritonitis in nephrotic ascites

— Cellulitis, sepsis — especially in children

— Vaccinate before immunosuppression

— Causes: aggressive diuresis, RVT, drug nephrotoxicity (NSAIDs, contrast, CNIs), bilateral renal vein thrombosis, superimposed crescentic GN (rare)

— Accelerated atherosclerosis from chronic hyperlipidemia

— HTN from sodium retention or treatment

— Vitamin D deficiency (loss of vitamin D binding protein)

— Functional hypothyroidism (TBG loss)

— Iron deficiency anemia (transferrin loss)

— Hypocalcemia (loss of albumin-bound calcium)

— ~1/3 over 5–10 years if untreated; doubling of creatinine over 6–12 months is a strong progression marker

Board pearl: Sudden flank pain + hematuria + AKI in a known MN patient → get renal vein Doppler or CT venography — RVT requires immediate anticoagulation.

Step 3 management: Prophylactic anticoagulation decision = serum albumin + risk calculator + bleeding history — document the discussion.

Thromboembolic disease (the signature complication):

Anticoagulation prophylaxis (high-yield):

Infection:

Acute kidney injury:

Cardiovascular:

Metabolic:

Progression to ESRD:

When to Escalate Care — ICU, Consult, Hospitalization

— Coordinate biopsy interpretation, immunosuppression selection, monitoring

— Outpatient management for most stable patients

— Acute pulmonary embolism or extensive DVT requiring IV anticoagulation initiation

— Renal vein thrombosis with AKI

— AKI of unclear etiology in nephrotic patient — need urgent biopsy or workup

— Severe symptomatic edema (anasarca, pleural effusion, ascites) requiring IV diuretics ± albumin

— Sepsis, SBP, or severe cellulitis in immunosuppressed/nephrotic host

— Rapidly progressive renal failure — suspect crescentic transformation, RVT, or superimposed disease

— Massive PE with hemodynamic instability → thrombolysis evaluation

— Respiratory failure from bilateral effusions/pulmonary edema requiring NIV or intubation

— Severe hyponatremia from aggressive diuresis with seizures

— Hematology — complex anticoagulation, recurrent VTE on therapy, bleeding on warfarin

— Oncology — workup of paraneoplastic MN

— Hepatology — HBV/HCV-associated MN before immunosuppression

— Rheumatology — lupus membranous (class V)

— Interventional radiology — RVT requiring catheter-directed thrombolysis (rare)

— Outpatient nephrology follow-up within 1–2 weeks of hospital discharge

— Reconcile anticoagulation, immunosuppression, diuretics, vaccinations

— Document anti-PLA2R, UPCR, eGFR, albumin at discharge for outpatient trending

CCS pearl: For a CCS case of new MN with anasarca: admit, IV furosemide (with albumin if albumin <2), low-sodium diet, daily weights, strict I/Os, renal biopsy, anti-PLA2R, hepatitis serologies, ANA, UPCR, anticoagulation assessment, nephrology consult, and transition to outpatient follow-up in 1 week.

Board pearl: Don't miss the PE in the dyspneic MN patient — order CTPA early; tachypnea is not just edema.

Nephrology consult — required for all biopsy-proven MN:

Indications for hospitalization:

ICU triage:

Specialty consults:

Transitions of care:

Key Differentials — Other Causes of Nephrotic Syndrome

— Children >> adults; abrupt onset, often massive proteinuria

— Bland sediment, normal LM, foot process effacement on EM, no immune deposits

— Associations: NSAIDs, Hodgkin lymphoma, atopy

— Steroid-responsive in >90% — empiric prednisone often initiated before biopsy in children

— More common in African American adults; presents with nephrotic syndrome, HTN, hematuria, often AKI

— Causes: primary (APOL1 risk alleles), secondary (HIV, heroin, obesity, reflux, sickle cell)

— Biopsy: segmental sclerosis in some glomeruli; podocyte effacement

— Less steroid-responsive than MCD; immunosuppression in primary forms

— Most common cause of nephrotic syndrome overall in US

— Long-standing diabetes, retinopathy in 90% of type 1 with nephropathy, gradual proteinuria progression

— Biopsy (if performed): Kimmelstiel-Wilson nodules, mesangial expansion, GBM thickening

— Older adults; nephrotic proteinuria + enlarged kidneys, hepatomegaly, macroglossia, cardiomyopathy, neuropathy

— Congo red apple-green birefringence on biopsy

— Order SPEP/UPEP, free light chains, fat pad biopsy

— Nephritic-nephrotic overlap, low complements (especially C3)

— Biopsy: double-contour GBM ("tram-tracks"), subendothelial deposits

— Causes: hepatitis C with cryoglobulins, monoclonal gammopathy, complement dysregulation

Key distinction: Among nephrotic glomerulopathies, MN has subepithelial deposits, MPGN has subendothelial deposits, IgA has mesangial deposits, and MCD has no deposits — deposit location is the highest-yield distinguisher.

Board pearl: A diabetic patient with sudden-onset nephrotic syndrome and no retinopathy may not have diabetic nephropathy — biopsy to exclude MN or other primary glomerular disease.

Minimal change disease (MCD):

Focal segmental glomerulosclerosis (FSGS):

Diabetic nephropathy:

Amyloidosis (AL, AA):

Membranoproliferative GN (MPGN)/C3 glomerulopathy:

Key Differentials — Mimics and Secondary MN Causes

— Lupus class V: ANA+, anti-dsDNA, low C3/C4, "full-house" IF, mesangial deposits, tubuloreticular inclusions on EM

— Hepatitis B-associated MN: HBsAg+, common in endemic regions and children; treat HBV first

— Hepatitis C-associated MN: less common than HCV-associated MPGN; cryoglobulins variable

— Solid tumors (paraneoplastic): lung, colon, prostate, breast, renal cell, gastric — especially in patients >65; tumor antigens deposited subepithelially

— Medications: NSAIDs (chronic), penicillamine, gold, captopril, anti-TNF, mercury, bucillamine

— Infections: syphilis (congenital and secondary), schistosomiasis, malaria, filariasis

— Other autoimmune: Sjögren, rheumatoid arthritis, mixed connective tissue disease, IgG4-related disease, sarcoidosis

— Orthostatic proteinuria (young adults; only when upright; benign)

— Transient proteinuria with fever or exercise — repeat UA when well

— Heart failure — pre-renal proteinuria, BNP elevated, edema bilateral

— Cirrhotic ascites — albumin low from synthesis failure, not urinary loss; check spot UPCR

— Post-streptococcal GN: hematuria, HTN, edema, recent infection, low C3

— IgA nephropathy: synpharyngitic hematuria, normal complements

— ANCA vasculitis, anti-GBM: RPGN, hemoptysis, hematuria, RBC casts

Step 3 management: Always order ANA, dsDNA, C3, C4, HBsAg, anti-HCV, HIV, RPR, SPEP/UPEP, free light chains, and age-appropriate cancer screening in every newly diagnosed MN — calling it "primary" requires this workup to be negative.

Board pearl: IgG subclass staining on biopsy distinguishes primary MN (IgG4-dominant) from secondary MN (IgG1/IgG2/IgG3-predominant) — a frequently tested immunopathology pearl.

Secondary MN — must be excluded before calling primary:

Non-nephrotic mimics:

Acute glomerulonephritis with proteinuria but nephritic predominance:

Secondary Prevention, Discharge Plan, and Long-Term Management

— After remission, taper carefully — relapse rate 25–40% within 5 years

— Rituximab: redose based on CD19 reconstitution and rising anti-PLA2R

— CNIs: taper over 12+ months; abrupt withdrawal precipitates relapse

— Monitor anti-PLA2R q3–6 months — rising titer predicts relapse before proteinuria returns

— ACEi/ARB at maximum tolerated dose; BP target <130/80 (KDIGO 2021)

— Statin to LDL <100 (or <70 if established ASCVD)

— SGLT2 inhibitor if eGFR ≥20 and persistent proteinuria

— Low-sodium diet (<2 g/day), moderate protein (~0.8 g/kg/day), weight management

— Smoking cessation, exercise, alcohol moderation

— Continue while albumin <2.5–3.0 g/dL or while in active nephrotic syndrome

— Can be discontinued once remission achieved and albumin sustained >3.0

— INR monitoring for warfarin; bridge if procedures

— Pneumococcal (PCV20 or PCV15→PPSV23 at 1 year), influenza yearly, COVID-19 boosters per CDC, HBV if non-immune, Tdap every 10 years, zoster (Shingrix) in adults ≥50 — give before or during stable immunosuppression

— Avoid live vaccines (MMR, varicella, intranasal flu, yellow fever) on rituximab/cyclophosphamide

— Maintain age-appropriate screening; in anti-THSD7A+ patients, lower threshold for surveillance imaging

— If progression to ESRD, MN can recur in ~30–40% of allografts; monitor post-transplant anti-PLA2R

— Living donor transplant preferred where possible

Step 3 management: Discharge med list for a remitting MN patient: lisinopril, atorvastatin, furosemide (PRN), dapagliflozin, warfarin (if indicated), prednisone taper, calcium/vit D, PJP prophylaxis, and a pneumococcal vaccination plan.

Board pearl: Rising anti-PLA2R titer = earliest warning of relapse — recheck and act on it before proteinuria returns.

Long-term immunosuppression strategy:

Cardiovascular and renal protection bundle (lifelong):

Anticoagulation management:

Vaccinations (boost annually/per schedule):

Cancer surveillance:

Transplant considerations:

Follow-Up, Monitoring, and Counseling

— Active disease/induction: every 2–4 weeks initially, then monthly

— Partial remission: every 1–3 months

— Complete remission: every 3–6 months for 2 years, then every 6–12 months indefinitely

— UPCR or 24-hour urine protein (track quantitatively)

— Serum creatinine and eGFR

— Serum albumin (drives anticoagulation decisions)

— Anti-PLA2R titer (q3–6 months during active disease)

— BP, weight, edema assessment

— Lipid panel (annually once stable)

— Cyclophosphamide: CBC weekly during therapy (nadir days 10–14), UA for hematuria (hemorrhagic cystitis), cumulative dose tracking (lifetime <36 g to limit bladder cancer risk)

— Rituximab: CD19/CD20 counts, IgG levels (hypogammaglobulinemia in long-term users), hepatitis B reactivation

— CNIs: trough levels (tacrolimus 5–7, cyclosporine 125–175), creatinine, K+, magnesium, BP, glucose

— Steroids: glucose, BP, weight, DEXA at 1 year, ophthalmologic exam (cataracts/glaucoma)

— Recognize DVT/PE symptoms — calf swelling, sudden dyspnea, chest pain, hemoptysis → ER

— Foamy urine return = possible relapse → call clinic

— Avoid NSAIDs lifelong (precipitate AKI, may worsen disease)

— Sick-day rules: hold ACEi/ARB and SGLT2i during volume depletion (vomiting, diarrhea)

— Contraception during cyclophosphamide and for 6+ months after rituximab

— Sperm/oocyte banking discussion before cyclophosphamide if fertility relevant

— Cardiac rehab not standard but graded exercise encouraged

— Dietitian referral for renal/cardiac diet

— Mental health screening — chronic illness depression common

Step 3 management: A patient calling 3 weeks post-rituximab with new calf swelling needs same-day duplex US and clinic visit — do not wait for the next scheduled appointment.

Board pearl: Anti-PLA2R turns negative before proteinuria normalizes — patience and serial monitoring beat premature regimen changes.

Outpatient follow-up cadence:

Monitoring labs at each visit:

Immunosuppression-specific monitoring:

Patient counseling priorities:

Rehabilitation/lifestyle:

Ethical, Legal, and Patient Safety Considerations

— Disclose infection risk, malignancy risk (especially cyclophosphamide → bladder cancer, hematologic malignancy), infertility (cyclophosphamide), teratogenicity (mycophenolate, cyclophosphamide), and reactivation of latent infections (TB, HBV, JC virus → PML with rituximab)

— Document discussion in chart; use teach-back to confirm understanding

— For rituximab: explicitly mention infusion reactions, hypogammaglobulinemia, and rare PML

— Offer sperm banking to males and oocyte/embryo cryopreservation to females before cyclophosphamide

— Discuss timing — referral can delay therapy, weigh against disease urgency

— Consider GnRH agonist (leuprolide) during cyclophosphamide for ovarian protection (evidence mixed but commonly used)

— Hepatitis B/C, HIV diagnoses → public health reporting per state law

— Tuberculosis if discovered during pre-immunosuppression screening

— Anticoagulation reconciliation at every hospital-to-clinic handoff — missed warfarin dosing or unrecognized DOAC interactions are common error sources

— Medication reconciliation for immunosuppressants and PJP prophylaxis — frequent omissions cause infection

— Holding ACEi/ARB during AKI/hospitalization without restart plan is a Joint Commission–flagged transition failure — ensure restart plan documented at discharge

— Vaccination status communication between nephrology, PCP, and infusion center

— In low-risk MN with high spontaneous remission rate, discuss observation vs immediate immunosuppression — patient values matter

— Elderly patient with limited life expectancy and slowly progressive disease may reasonably decline immunosuppression

— Document contraception counseling for women of reproductive age on teratogens

— Pre-conception nephrology visit ideal — adjust regimens proactively

— Rituximab cost/insurance prior authorization — may delay therapy; document medical necessity

— Specialty pharmacy coordination for biologics

Step 3 management: Before cyclophosphamide in a 32-year-old woman, document fertility counseling, contraception, baseline pregnancy test, vaccination update, and TB/HBV screening — missing any of these is a board-favorite negligence stem.

Informed consent for immunosuppression:

Fertility preservation:

Mandatory and recommended reporting:

Transition-of-care safety pitfalls (high-yield Step 3):

Shared decision-making:

Pregnancy planning ethics:

Health-system access:

High-Yield Associations and Rapid-Fire Facts

— Anti-PLA2R antibodies → primary MN (~70–80%)

— Anti-THSD7A → primary MN (~3–5%, stronger malignancy link)

— "Spike and dome" on silver stain → MN

— Subepithelial deposits on EM → MN

— IgG4-dominant IF staining → primary MN

— "Full-house" IF + tubuloreticular inclusions → lupus membranous (class V)

— Hepatitis B → MN in children (HCV → MPGN more often)

— Solid tumors (lung, colon, prostate, breast) → paraneoplastic MN, especially >65

— NSAIDs → MN or MCD

— Gold, penicillamine → drug-induced MN

— Syphilis (congenital and secondary) → MN

— Renal vein thrombosis — most associated with MN of all glomerulopathies

— Highest VTE rate when albumin <2.5 g/dL

— Vitamin D deficiency (loss of DBP), hypothyroidism (loss of TBG), iron deficiency (loss of transferrin)

— MENTOR trial: rituximab superior to cyclosporine at 24 months

— Modified Ponticelli regimen: alternating monthly steroids and cyclophosphamide over 6 months

— STARMEN trial: tacrolimus + rituximab vs cyclophosphamide + steroids — mixed results

— Low → conservative

— Moderate → rituximab or CNI

— High/very high → rituximab or cyclophosphamide-based Ponticelli

Board pearl: Memorize the deposit location map: subepithelial = MN; subendothelial = MPGN/lupus IV; mesangial = IgA/lupus II; intramembranous = dense deposit disease.

Key distinction: IgG subclass matters — IgG4 dominant = primary MN; IgG1/2/3 = secondary/lupus MN.

Pathognomonic associations:

Disease–MN linkages:

Complication hot list:

Treatment trial pearls:

KDIGO 2021 risk-driven framework:

Vaccinations before immunosuppression: pneumococcal, influenza, HBV, COVID-19, Shingrix

Drugs to avoid lifelong in MN patients: NSAIDs, nephrotoxic herbal supplements, live vaccines on rituximab

Natural history rule of thirds: 1/3 remit, 1/3 stable, 1/3 progress

Cancer screening triggers: age >65, anti-THSD7A+, weight loss, smoking history

Board Question Stem Patterns

— 55-year-old man with 6 weeks of progressive lower-extremity edema, foamy urine, BP 138/86, albumin 2.4, creatinine 1.0, UPCR 7 g/g, bland sediment

— Next step: check anti-PLA2R, hepatitis serologies, ANA, age-appropriate cancer screening, then renal biopsy → MN

— Treatment: start ACEi, statin, sodium restriction, anticoagulation assessment, observe 6 months if low-risk

— 72-year-old smoker with new nephrotic syndrome; PLA2R negative

— Next step: low-dose chest CT, colonoscopy → discover lung adenocarcinoma → treat tumor, MN often remits

— Known MN patient presents with acute left flank pain, gross hematuria, and rising creatinine

— Diagnosis: renal vein thrombosis → CT venography or Doppler US → anticoagulate

— Young woman with malar rash, arthralgias, nephrotic syndrome, low C3/C4, ANA+, dsDNA+, biopsy with full-house IF

— Diagnosis: lupus class V membranous → hydroxychloroquine + immunosuppression for SLE

— Asian immigrant child or young adult with nephrotic syndrome, HBsAg+, normal complements

— Treatment: entecavir or tenofovir first; immunosuppression generally avoided

— Woman with known MN on lisinopril and mycophenolate planning pregnancy

— Next step: stop ACEi and MMF, switch to labetalol + azathioprine ± tacrolimus, achieve remission before conception

— MN patient in remission; routine follow-up shows rising anti-PLA2R but stable proteinuria

— Action: increase monitoring; consider retreatment if titer continues to rise

— MN with proteinuria 9 g/day for 9 months despite max ACEi, declining eGFR

— Best choice: rituximab (MENTOR) or modified Ponticelli (high-risk)

Step 3 management: The most commonly missed stem element is age-appropriate cancer screening before immunosuppression in older MN patients — always select that option when listed.

Board pearl: "Subepithelial deposits with IgG4 dominance" in a vignette = primary MN with anti-PLA2R; pick rituximab or conservative observation based on risk category.

Pattern 1 — The classic primary MN stem:

Pattern 2 — The paraneoplastic stem:

Pattern 3 — The thrombotic complication stem:

Pattern 4 — The lupus mimic:

Pattern 5 — The hepatitis B stem:

Pattern 6 — The pregnancy stem:

Pattern 7 — The relapse detection stem:

Pattern 8 — The treatment selection stem:

One-Line Recap

Membranous nephropathy is an antibody-mediated (anti-PLA2R in ~75%) podocyte injury producing subepithelial immune deposits and nephrotic syndrome in adults, managed by risk-stratified conservative therapy (RAAS blockade, statin, diuretics, anticoagulation when albumin <2.5) advancing to rituximab or modified Ponticelli for moderate-to-high-risk disease, with mandatory exclusion of secondary causes (lupus, hepatitis B/C, malignancy, drugs) before labeling it primary.

— Low risk → conservative (ACEi/ARB + statin + diuretic + SGLT2i) × 6 months

— Moderate risk → rituximab or CNI

— High/very high risk → rituximab or modified Ponticelli (alternating monthly steroids + cyclophosphamide × 6 months)

— Refractory → switch class, consider obinutuzumab

Board pearl: When a Step 3 stem features adult + insidious nephrotic syndrome + bland sediment + unprovoked VTE, the answer is membranous nephropathy — send anti-PLA2R, screen for cancer/hepatitis/lupus, biopsy, and risk-stratify before immunosuppression.

Step 3 management: The three highest-yield action items are (1) age-appropriate cancer screening in patients >65, (2) anticoagulation when albumin <2.5 g/dL with risk factors, and (3) vaccinate (pneumococcal, influenza, HBV, COVID, Shingrix) before starting rituximab or cyclophosphamide.

Workup essentials: UPCR or 24-hr protein, eGFR, albumin, anti-PLA2R, ANA/dsDNA/C3/C4, HBV/HCV/HIV/RPR, SPEP/UPEP, age-appropriate cancer screening, renal biopsy showing "spike and dome" with subepithelial IgG4 deposits.

Treatment ladder by KDIGO 2021 risk:

Complications to anticipate: renal vein thrombosis, PE/DVT (highest VTE risk of any GN — anticoagulate when albumin <2.0–2.5), infection from Ig loss, AKI, accelerated atherosclerosis, progression to ESRD in ~1/3.

Monitoring: Anti-PLA2R falls before proteinuria — serial titers q3–6 months guide treatment duration and predict relapse; lifelong follow-up because ~30% relapse and MN recurs in ~30% of allografts.