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Membranous Nephropathy & FSGS — Viva Questions
Rapid-fire examiner prompts with model answers. Each answer should be delivered in 30-60 seconds.
Definition & classification
Q. What is membranous nephropathy? An antibody-mediated subepithelial immune-complex glomerular disease causing non-selective proteinuria and the nephrotic syndrome — the commonest primary glomerular cause of nephrotic syndrome in Caucasian adults.
Q. What antibody defines primary membranous nephropathy? IgG4 anti-PLA2R (M-type phospholipase A2 receptor) antibody — positive in 70 to 80% of primary cases (Beck, NEJM 2009). Anti-THSD7A is a second, rarer antigen (~2 to 5%) with a strong cancer association.
Q. Define FSGS. Focal segmental glomerulosclerosis — a podocytopathy defined histologically by focal (some glomeruli) and segmental (part of the tuft) sclerosis with diffuse foot-process effacement on EM.
Q. Name the Columbia FSGS variants in order of prognosis, best to worst. Tip > cellular > NOS > perihilar > collapsing. Collapsing is the worst (HIV, APOL1); tip is the best (often steroid-responsive).
Aetiology & secondary causes
Q. List the secondary causes of membranous nephropathy. Solid-organ malignancy (lung, colon, stomach, prostate, breast — over 50), hepatitis B and C, lupus class V, drugs (NSAIDs, gold, penicillamine, captopril), syphilis, autoimmune thyroiditis, sarcoidosis.
Q. List the aetiological classes of FSGS. Primary (circulating permeability factor — suPAR, CLCF-1), genetic (APOL1, NPHS1/2, TRPC6, INF2), virus-associated (HIV — collapsing, HIVAN), drug-induced (heroin, pamidronate, interferon), and adaptive/structural (obesity, reduced renal mass, reflux, sickle cell).
Pathophysiology
Q. Walk through the mechanism of primary membranous nephropathy. Circulating IgG4 anti-PLA2R crosses the GBM and binds PLA2R on the podocyte, forming subepithelial immune complexes in situ. Complement is activated via the lectin and alternative pathways, generating C5b-9 (membrane attack complex) on the podocyte, which releases oxidants and proteases, effaces foot processes and damages the slit diaphragm. New basement-membrane spikes form between the deposits (silver stain; Ehrenreich-Churg stages I to IV), producing proteinuria.
Q. Why is the nephrotic patient hypercoagulable, and why is the risk highest in membranous? Urinary loss of antithrombin III, increased hepatic fibrinogen and factor VIII, platelet activation, and hemoconcentration. Risk rises sharply when albumin is under 25 g/L; membranous nephropathy has the highest thrombotic risk of any nephrotic cause (up to a third develop renal vein thrombosis, DVT or PE).
Diagnosis & investigations
Q. What does the renal biopsy show in membranous nephropathy? Thickened GBM with silver-stain spikes (light microscopy); granular capillary-wall IgG4 and C3 (immunofluorescence); subepithelial deposits with spike-and-dome and foot-process effacement (electron microscopy).
Q. What does the renal biopsy show in FSGS? Focal, segmental sclerosis with hyalinosis and synechiae to Bowman capsule (LM); nonspecific IgM and C3 in sclerotic segments (IF); diffuse foot-process effacement in primary FSGS (EM). An adequate sample (at least 10 to 20 glomeruli) is required because FSGS is focal.
Q. Outline the serological workup of an adult with nephrotic syndrome. Anti-PLA2R (membranous); ANA, anti-dsDNA, complement C3/C4 (lupus); HBsAg, anti-HCV, HIV; serum electrophoresis and free light chains (myeloma/AL amyloid); anti-GBM and ANCA if crescents or rapid GFR decline; TSH. Malignancy screen (CT CAP, colonoscopy, PSA, mammography) in membranous over 50.
Management
Q. What is the shared (nephrotic) care for ALL patients with membranous or FSGS? ACE inhibitor or ARB (antiproteinuric cornerstone); salt restriction and loop diuretic ± amiloride/spironolactone; statin; anticoagulation when albumin is under 25 g/L (especially membranous); vaccination (pneumococcal, influenza, hepatitis B) before immunosuppression.
Q. Describe the modified Ponticelli regimen. Alternating monthly cycles over 6 months: months 1, 3, 5 — IV methylprednisolone 1 g daily for 3 days then oral prednisolone 0.5 mg/kg/day; months 2, 4, 6 — oral cyclophosphamide 2 to 2.5 mg/kg/day. (The original used chlorambucil; cyclophosphamide is now preferred.)
Q. What is the MENTOR trial and its conclusion? Fervenza et al., NEJM 2019 — rituximab (1 g IV at days 1 and 15) was non-inferior to cyclosporine in membranous nephropathy, with a significantly lower relapse rate and better renal preservation. Rituximab is now first-line or preferred for high-risk membranous.
Q. How do you treat primary FSGS? Maximal conservative therapy (ACE inhibitor/ARB) plus a prolonged high-dose steroid trial — oral prednisolone 1 mg/kg/day (maximum 80 mg) for at least 12 to 16 weeks (4 to 6 months), confirming adherence — then taper if response; if steroid-resistant after a full trial, a calcineurin inhibitor (ciclosporin or tacrolimus) for at least 6 months.
Q. When do you NOT use immunosuppression in FSGS? In genetic FSGS (steroid-resistant, does not recur after transplant) and in adaptive/secondary FSGS (treat the cause — weight loss, reflux correction, manage reduced renal mass).
Complications & scenarios
Q. A nephrotic patient develops sudden left flank pain and haematuria. Diagnosis and management? Renal vein thrombosis — image with renal Doppler ultrasound or CT venography and anticoagulate (LMWH-bridged warfarin or a DOAC) for at least the duration of nephrotic-range proteinuria. Prophylactic anticoagulation is indicated when albumin is under 25 g/L in membranous.
Q. A patient develops massive proteinuria 5 days after a renal transplant for FSGS. What is happening? Recurrent FSGS (occurs in 30 to 50% of transplants, often within days) — mediated by a circulating permeability factor. Treat with plasma exchange and rituximab, and intensify immunosuppression. Genetic FSGS does not recur.
Q. Why are nephrotic patients prone to infection, and how is it prevented? Urinary loss of IgG and alternative-complement factors B and D impairs opsonisation of encapsulated organisms (pneumococcus, H. influenzae, E. coli) — spontaneous bacterial peritonitis, cellulitis, pneumococcal sepsis. Prevent by vaccination (pneumococcal, influenza, hepatitis B) before immunosuppression, and treat suspected infection promptly with empirical broad-spectrum antibiotics.
Pearls
Q. Membranous nephropathy in a 60-year-old smoker — what must you screen for, and when? Occult solid-organ malignancy (lung, colon, stomach, prostate, breast) and hepatitis B and C, within the first 1 to 3 years of diagnosis. Check anti-THSD7A if anti-PLA2R is negative (strong cancer association).
Q. Frothy urine + collapsing FSGS + AKI in a young Black man — diagnosis and immediate action? HIV-associated nephropathy (HIVAN). Urgent HIV test, start antiretrovirals plus an ACE inhibitor — the combination that transformed a previously near-universal ESKD outcome. Consider APOL1.