MBBS SAQ
Membranous Nephropathy & FSGS — Short Answer Questions (NEET-PG / INICET)
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SAQ 1 — A 56-year-old man presents with nephrotic-range proteinuria (6 g/day), albumin 22 g/L, and normal renal function. Renal biopsy shows thickened GBM with silver-stain spikes and granular IgG4/C3 deposits. Discuss the diagnosis, the next investigations, and the management
Diagnosis: Primary membranous nephropathy — thickened GBM with spikes (silver stain), granular capillary-wall IgG4 and C3 (immunofluorescence), subepithelial deposits with spike-and-dome on electron microscopy. Confirm with serum anti-PLA2R antibody (positive in ~70 to 80%, IgG4 subclass) — its titre tracks disease activity and guides treatment.
Next investigations (to exclude secondary causes and assess risk):
- Anti-PLA2R titre (primary); anti-THSD7A if negative (cancer-associated).
- ANA, anti-dsDNA, complement C3/C4 (lupus class V); HBsAg, anti-HCV, HIV.
- Malignancy screen (age over 50 mandatory): CT chest/abdomen/pelvis, age-appropriate colonoscopy, PSA, mammography — within the first 1 to 3 years.
- Serum electrophoresis and free light chains (exclude myeloma/AL amyloid); TSH (autoimmune thyroiditis).
- Renal ultrasound, baseline FBC, glucose/HbA1c, lipid profile, TB screen and vaccination status before any immunosuppression.
Management (KDIGO 2021 risk-stratified):
- Shared nephrotic care: ACE inhibitor or ARB (titrate to blood pressure and proteinuria); prophylactic anticoagulation (albumin under 25 g/L — the highest thrombotic-risk nephrotic cause, renal vein thrombosis); statin for hyperlipidaemia; salt restriction and loop diuretic ± amiloride/spironolactone for oedema; vaccinate (pneumococcal, influenza, hepatitis B) before immunosuppression.
- Risk stratify: proteinuria 4 to 8 g/day with normal renal function = moderate risk — 6 months of maximal conservative therapy, then immunosuppress if proteinuria persists over 8 g/day, renal function declines, or complications occur.
- First-line immunosuppression (if high-risk): rituximab 1 g IV at days 1 and 15 (MENTOR, NEJM 2019 — non-inferior to cyclosporine with lower relapse), OR the modified Ponticelli regimen (alternating methylprednisolone/prednisolone with cyclophosphamide over 6 months). Screen for hepatitis B and TB before rituximab.
- Monitor anti-PLA2R titre and proteinuria — a falling titre predicts remission.
SAQ 2 — A 50-year-old man with membranous nephropathy (albumin 19 g/L) develops sudden severe left flank pain with macroscopic haematuria. Discuss the diagnosis, the mechanism, and the management
Diagnosis: Left renal vein thrombosis — sudden flank/loin pain with macroscopic haematuria in a severely hypoalbuminaemic nephrotic patient (risk highest in membranous nephropathy). Left-sided is commoner because the left renal vein is longer and passes between the aorta and superior mesenteric artery.
Mechanism (the nephrotic hypercoagulable state):
- Urinary loss of antithrombin III (the key thrombin inhibitor).
- Increased hepatic fibrinogen and factor VIII synthesis (driven by low oncotic pressure).
- Platelet activation, hemoconcentration and hyperviscosity.
- Loss of plasminogen and increased plasminogen-activator inhibitor-1.
Risk rises sharply when albumin is under 25 g/L — hence prophylactic anticoagulation is indicated at this threshold in membranous.
Management:
- Image with renal Doppler ultrasound or CT venography to confirm the thrombus.
- Anticoagulate — LMWH (loading) then warfarin (INR 2 to 3), or a direct oral anticoagulant (apixaban, rivaroxaban), for at least the duration of nephrotic-range proteinuria.
- Treat the underlying membranous nephropathy (immunosuppression per risk stratification) to induce remission and lower the thrombotic risk.
- Screen for pulmonary embolism (often silent) and other DVT.
SAQ 3 — A 35-year-old woman presents with nephrotic syndrome; biopsy shows focal segmental glomerulosclerosis (tip variant). Outline the management and the prognosis, and list the secondary/adaptive causes of FSGS to screen for
Management:
- Maximal conservative therapy — ACE inhibitor or ARB (antiproteinuric cornerstone), blood pressure target under 130/80 (under 125/75 with proteinuria), salt restriction, loop diuretic ± amiloride/spironolactone for oedema, statin for hyperlipidaemia, anticoagulation if albumin is low, vaccinate.
- Prolonged high-dose steroid trial — oral prednisolone 1 mg/kg/day (maximum 80 mg/day) for at least 12 to 16 weeks (often 4 to 6 months), then taper. The tip variant is often steroid-responsive (best-prognosis Columbia variant).
- If steroid-resistant (after a full trial, confirmed adherence) — calcineurin inhibitor: ciclosporin 3 to 5 mg/kg/day or tacrolimus 0.05 to 0.1 mg/kg/day for at least 6 months; monitor trough levels and renal function. Mycophenolate or rituximab are alternatives for frequently-relapsing/steroid-dependent disease.
- Screen for and treat secondary/adaptive causes (below) — these do not usually need immunosuppression.
Prognosis: tip variant = best prognosis of all Columbia variants, often steroid-responsive (behaves like minimal change disease); steroid-responsive FSGS generally has a good prognosis, while steroid-resistant primary FSGS progresses to ESKD in 50% or more over 5 to 10 years. Collapsing variant has the worst prognosis.
Secondary/adaptive causes of FSGS to screen for:
- Adaptive (hyperfiltration): obesity, reduced renal mass (unilateral agenesis, nephrectomy, reflux nephropathy), sickle cell disease, cyanotic congenital heart disease.
- Virus-associated: HIV (HIVAN, collapsing variant), parvovirus B19, CMV.
- Drug-induced: heroin, pamidronate, interferon, lithium, anabolic steroids.
- Genetic (steroid-resistant, no transplant recurrence): APOL1 (West-African ancestry), NPHS1 (nephrin), NPHS2 (podocin), TRPC6, INF2, ACTN4, WT1.
SAQ 4 — Compare and contrast the pathophysiology and histology of membranous nephropathy and FSGS
Membranous nephropathy — immune-complex (antibody-mediated) disease:
- Circulating IgG4 autoantibodies against the podocyte M-type phospholipase A2 receptor (PLA2R) (70 to 80%) or THSD7A (2 to 5%) cross the GBM and form subepithelial immune complexes in situ.
- Complement is activated via the lectin (mannan-binding lectin) and alternative pathways (not classical, because IgG4 does not fix complement classically), generating the C5b-9 membrane attack complex on the podocyte.
- Sublytic C5b-9 triggers oxidants/proteases and cytoskeletal rearrangement → foot-process effacement and proteinuria.
- Histology: thickened GBM with silver-stain spikes (LM); granular capillary-wall IgG4 and C3 (IF); subepithelial deposits with spike-and-dome (EM). Ehrenreich-Churg stages I to IV.
FSGS — podocytopathy (podocyte injury):
- A circulating permeability factor (primary: suPAR, CLCF-1, anti-CD40 candidates) OR genetic/structural injury (APOL1, NPHS1/2, TRPC6, INF2; adaptive hyperfiltration) drives podocyte detachment and apoptosis.
- The exposed GBM adheres to Bowman capsule (synechia) → the segment scarifies; collapsing variants collapse further tufts.
- Histology: focal, segmental sclerosis with hyalinosis and adhesions (LM); nonspecific IgM/C3 in sclerotic segments (IF); diffuse foot-process effacement in primary FSGS, often focal in adaptive (EM). Columbia variants: collapsing, tip, cellular, perihilar, NOS.
Shared: both produce nephrotic syndrome, share complications of proteinuria (oedema, hypercoagulability, infection, hyperlipidaemia), and need biopsy plus RAAS blockade, anticoagulation when albumin is low, and vaccination. They differ in immunosuppression strategy (risk-stratified rituximab/Ponticelli for membranous; prolonged steroid trial then CNI for FSGS).