Nephrotic Syndrome — Written Clinical Reasoning

SAQ 1 — Integrated Membranous Nephropathy Management (20 marks, 30 minutes)

Prompt: Outline your integrated management plan for this patient, addressing the diagnostic confirmation, cause-specific immunosuppression, anti-proteinuric therapy, complication prevention (thrombosis, infection, hyperlipidaemia), and follow-up. Justify each decision with reference to evidence. [1]

Model Answer

Problem list (4 marks): [1]

1. Primary membranous nephropathy with nephrotic syndrome — anti-PLA2R strongly positive, biopsy-confirmed stage II
2. Hypoalbuminaemia (18 g/L) — high thrombotic risk threshold
3. Hypertension (148/92) and hyperlipidaemia (cholesterol 9.2) — cardiovascular and progression risk
4. Past hepatitis B infection (anti-HBc positive) — reactivation risk with rituximab
5. No renal vein thrombosis on imaging — but ongoing risk; anticoagulation threshold met
6. Risk of progression to CKD over time — requires surveillance [1]

Step 1 — Confirm the diagnosis and exclude secondary causes (2 marks): [1]

The strongly positive anti-PLA2R antibody (Beck 2009, PMID 19571079) is highly specific for primary membranous nephropathy [4]. The biopsy confirms the diagnosis and excludes superimposed crescents or interstitial fibrosis that would alter prognosis. The negative ANA, normal complement, normal free light chains, and negative viral serology exclude lupus, amyloid, and viral-associated disease. A malignancy screen is warranted at his age — chest X-ray, age-appropriate colorectal and prostate screening — because solid tumour membranous is PLA2R-negative but a paraneoplastic process can rarely coexist; re-screen at intervals.

Step 2 — Anti-proteinuric and antihypertensive therapy for every patient (3 marks): [1]

• ACE inhibitor or ARB at maximum tolerated dose (KDIGO 2024, PMID 38490803) [7]. Start ramipril 5 mg daily and titrate to 10 mg over weeks. Acceptable creatinine rise is up to 30 per cent; monitor potassium. Do NOT combine ACEi and ARB (ONTARGET harm).
• Blood pressure target less than 120/80 standardised, per KDIGO 2024 for proteinuric CKD. Add amlodipine if needed.
• Consider an SGLT2 inhibitor (dapagliflozin 10 mg or empagliflozin 10 mg) for additional proteinuria reduction across glomerular aetiologies, given the KDIGO 2024 endorsement [7].

Step 3 — Cause-specific immunosuppression (5 marks): [1]

This patient meets the criteria for immunosuppression — persistent nephrotic-range proteinuria (PCR 680) and hypoalbuminaemia (18 g/L) after the natural history of three months, with a high anti-PLA2R titre and normal GFR. The preferred first-line agent per MENTOR (Fervenza, NEJM 2019, PMID 31269364) is rituximab 1 g IV on day 1 and day 15, with a repeat course at 6 months if the anti-PLA2R titre remains high and proteinuria persists [2]. MENTOR showed rituximab was non-inferior to cyclosporine at 6 months and superior at 24 months, with fewer relapses and less nephrotoxicity.

Critical pre-treatment step: the anti-HBc positivity indicates past hepatitis B infection. Rituximab can reactivate hepatitis B and cause fulminant hepatitis — give prophylactic antiviral therapy with entecavir or tenofovir starting before rituximab and continuing for at least 12 months (and at least 6 months after the last rituximab dose), and monitor HBV DNA. Counsel the patient on infusion reactions and opportunistic infection. [1]

Alternative if rituximab contraindicated or refused: cyclical corticosteroid-cyclophosphamide (modified Ponticelli) for 6 months — the regimen with the highest remission rate per STARMEN (PMID 33166580) [5], but at greater toxicity (steroid and cyclophosphamide adverse effects, fertility, future malignancy). Cyclosporine is inferior to rituximab and now third-line.

Step 4 — Complication prevention (4 marks): [1]

Step 5 — Monitoring and follow-up (2 marks): [1]

• Monitor PCR, albumin, creatinine, anti-PLA2R titre, and blood pressure monthly during immunosuppression.
• Anti-PLA2R titre fall precedes and predicts clinical remission — a falling titre confirms response; a rising titre predicts relapse.
• Reassess immunosuppression, anticoagulation, and vaccination at each visit.
• Long-term surveillance for progression to CKD; refer for transplant workup early if proteinuria persists and GFR falls. [1]

SAQ 2 — Investigation Interpretation (10 marks)

Prompt: A 28-year-old woman presents with nephrotic syndrome (PCR 480, albumin 20 g/L). C3 is low at 0.50 g/L, C4 is low at 0.06 g/L. She has a malar rash and arthralgia. ANA is positive at 1:640 and anti-dsDNA is positive. Interpret these findings and outline the diagnosis-specific management. [1]

Model Answer

Diagnosis: This is class V (membranous) lupus nephritis. The clinical triad of nephrotic syndrome, low C3 AND low C4 (classical pathway activation), and a multi-system autoimmune phenotype (malar rash, arthralgia, positive ANA and anti-dsDNA) is the classic presentation. Low C3 and low C4 together distinguish lupus (and cryoglobulinaemia, endocarditis, hepatitis C MPGN) from conditions with isolated low C3 (post-streptococcal, C3 glomerulopathy). [1]

Confirmatory test: Renal biopsy with immunofluorescence showing "full house" deposition (IgG, IgA, IgM, C3, C1q) — the C1q positivity is the discriminator from primary membranous nephropathy, which is C1q-negative. Light microscopy may show membranous thickening with mesangial hypercellularity; electron microscopy shows subepithelial and mesangial deposits. The ISN/RPS class (V, membranous, with or without class III/IV overlap) determines the intensity of immunosuppression. [1]

Differential of low C3 AND low C4: lupus, cryoglobulinaemia (hepatitis C), subacute bacterial endocarditis, hepatitis C-associated MPGN. The malar rash and positive ANA/dsDNA make lupus the leading diagnosis; cryoglobulins, HCV serology, and blood cultures would exclude the alternatives if the picture were ambiguous. [1]

Management: Per KDIGO 2024 lupus nephritis update, class V lupus nephritis with nephrotic syndrome is treated with mycophenolate mofetil plus corticosteroids, or a calcineurin inhibitor (tacrolimus, or voclosporin) plus corticosteroids, with belimumab as add-on therapy. Hydroxychloroquine is given to all lupus patients for its renal-protective effect. Blood pressure control with an ACE inhibitor or ARB; consider an SGLT2 inhibitor for proteinuria. Sun protection and rheumatology co-management. Monitor C3, C4, anti-dsDNA, and proteinuria for disease activity. [1]

The key contrast with primary membranous nephropathy: primary membranous is PLA2R-positive, C1q-negative, complement usually normal, and treated with rituximab (MENTOR). Lupus membranous is PLA2R-negative, C1q-positive, complement low, and treated with mycophenolate or calcineurin inhibitor plus corticosteroids — not rituximab first-line. [1]