Nephrotic Syndrome Viva

Long Case Viva Defence

The patient

"Mrs Examiner, this is Mr James Wright, a 56-year-old engineer who presents to the renal outpatient clinic with three months of progressive anasarca and a new diagnosis of primary membranous nephropathy with nephrotic syndrome. His PCR is 680 mg/mmol, albumin 18 g/L, creatinine 95, anti-PLA2R strongly positive, and biopsy confirms stage II membranous nephropathy. He has past hepatitis B infection with anti-HBc positivity but is HBsAg negative. His main problems are: one, primary membranous nephropathy requiring cause-specific immunosuppression; two, hypoalbuminaemia at a threshold mandating anticoagulation; three, hypertension and hyperlipidaemia; four, hepatitis B reactivation risk with rituximab; and five, the need for ongoing surveillance for progression to CKD and for occult malignancy at his age." [1]

Problem list

1. Primary membranous nephropathy (anti-PLA2R positive, stage II on biopsy) with nephrotic syndrome
2. Hypoalbuminaemia at 18 g/L — thrombotic risk threshold met
3. Hypertension 148/92 and hyperlipidaemia
4. Past hepatitis B infection (anti-HBc positive) — reactivation risk with planned rituximab
5. Need for occult malignancy surveillance at age 56 [1]

Integrated management plan

"My plan addresses each problem. First, I confirm the diagnosis — the strongly positive anti-PLA2R and the biopsy are diagnostic of primary membranous nephropathy. I exclude secondary causes with ANA, complement, free light chains, viral serology — all normal here. I would still do an age-appropriate malignancy screen — chest X-ray, colorectal screening, prostate assessment — because solid tumour membranous is PLA2R-negative but paraneoplastic processes can rarely coexist, and I would re-screen at intervals." [1]

"Second, anti-proteinuric therapy for every patient — an ACE inhibitor at maximum tolerated dose. I would start ramipril 5 mg and titrate to 10 mg, accepting up to a 30 per cent creatinine rise, monitoring potassium, and not combining with an ARB. I would add an SGLT2 inhibitor for additional proteinuria reduction per KDIGO 2024. Blood pressure target less than 120/80 standardised." [1]

"Third, cause-specific immunosuppression. He meets the criteria — persistent nephrotic-range proteinuria and hypoalbuminaemia with a high anti-PLA2R titre and normal GFR. Per the MENTOR trial, my preferred first-line agent is rituximab 1 gram intravenously on day 1 and day 15, with a repeat course at 6 months if the titre remains high. MENTOR showed rituximab was non-inferior to cyclosporine at 6 months and superior at 24 months. Critically, before rituximab, I address his hepatitis B — anti-HBc positivity means past infection, and rituximab can reactivate hepatitis B with fulminant hepatitis. I would start prophylactic entecavir or tenofovir before rituximab and continue for at least 12 months, monitoring HBV DNA." [1]

"Fourth, complication prevention. His albumin is 18 — well below the 25 to 30 g/L threshold for prophylactic anticoagulation in membranous nephropathy, the highest-risk substrate. I would start a DOAC or warfarin for the duration of the nephrotic state. I would give pneumococcal and influenza vaccination now, avoid live vaccines during rituximab-induced B-cell depletion, and start atorvastatin for his hyperlipidaemia. For his oedema, salt restriction and frusemide 80 mg daily, adding a thiazide if resistant, aiming for 0.5 to 1 kg weight loss per day and avoiding over-diuresis." [1]

"Fifth, follow-up. I would monitor PCR, albumin, creatinine, and anti-PLA2R titre monthly. The anti-PLA2R titre fall precedes and predicts clinical remission — a falling titre confirms response. I would re-image for renal vein thrombosis if he develops any acute flank pain, haematuria, or sudden GFR fall, because renal vein thrombosis is commonest in membranous nephropathy." [1]

Probing Questions

Q1. Why rituximab over cyclophosphamide — what did MENTOR show?

"MENTOR, the Fervenza trial in the New England Journal in 2019, randomised patients with primary membranous nephropathy to rituximab 1 gram IV on days 1 and 15, with a second course at 6 months if needed, versus cyclosporine. Rituximab was non-inferior at 6 months in inducing complete or partial remission, and superior at 24 months in maintaining remission, largely because the cyclosporine group relapsed heavily after discontinuation. Rituximab also had a better safety profile — no nephrotoxicity, less hypertension, no cyclosporine-related cosmetic effects. This made rituximab the preferred first-line agent in most patients." [1]

Q2. When would you choose cyclophosphamide (modified Ponticelli) instead?

"Cyclical corticosteroid-cyclophosphamide — the modified Ponticelli regimen — is the alternative with the highest remission rate. STARMEN, the van de Logt trial in Kidney International 2020, showed it was superior to a sequential tacrolimus-rituximab regimen at 24 months. I would choose cyclophosphamide in a patient with aggressive disease — rapidly falling GFR, very high anti-PLA2R titre, or rituximab-resistant disease — or where rituximab is contraindicated. The trade-off is toxicity: cyclophosphamide carries gonadal toxicity, future malignancy risk, cytopenias, and infection, so I would counsel a young patient about fertility preservation, and it is generally not preferred in older multi-morbid patients." [1]

Q3. What is the mechanism of the hypercoagulable state in nephrotic syndrome?

"The classical teaching is that antithrombin — molecular weight 58 kilodaltons, small enough to leak through the damaged glomerular barrier — is lost in the urine, reducing anticoagulant capacity. Other contributors include urinary loss of free protein S, hepatic upregulation of fibrinogen and factor VIII in response to low oncotic pressure, platelet activation and aggregation, and impaired fibrinolysis. Modern multi-cohort work, including the Kerlin study in JASN 2023, has nuanced this — antithrombin levels do not perfectly correlate with thrombotic risk, and the mechanism is more complex than the single-factor model. For the exam, the antithrombin loss remains the expected answer for why nephrotic syndrome is hypercoagulable." [1]

Q4. He develops acute right flank pain and gross haematuria on day 14. What do you do?

"Renal vein thrombosis is the leading diagnosis — membranous nephropathy is the highest-risk substrate. I would arrange urgent CT renal venography, which demonstrates the filling defect in the renal vein; ultrasound is insensitive and is not adequate. I would check a coagulation panel and exclude bleeding risk. If RVT is confirmed, I would start therapeutic anticoagulation — heparin transitioned to warfarin or a DOAC — for at least the duration of the nephrotic state, often long-term. I would also reassess the underlying membranous — uncontrolled proteinuria perpetuates the thrombotic risk, so accelerating the immunosuppression to achieve remission is part of the long-term solution." [1]

Q5. His anti-PLA2R titre is rising at 6 months despite rituximab. What next?

"A rising anti-PLA2R titre predicts clinical relapse and indicates immunological non-response to the first rituximab course. My options are: a second course of rituximab; switching to cyclical corticosteroid-cyclophosphamide per STARMEN, which is the highest-remission alternative; or a calcineurin inhibitor, though this is third-line given inferiority to rituximab in MENTOR. I would also reassess — is this truly primary membranous, or have I missed a secondary cause? A re-biopsy may be warranted if the picture is changing, to look for superimposed crescents (suggesting a dual diagnosis with anti-GBM or ANCA) or interstitial fibrosis and tubular atrophy that would change the prognostic calculus." [1]

Short Case Discussion — Oedema Examination

The instruction

"Examine this patient's abdomen and legs, paying particular attention to oedema." [1]

The routine

"I would introduce myself, position the patient supine at 45 degrees, expose from the chest to the knees with consent, and examine from the end of the bed. I would assess for general signs — pallor of anaemia, a sallow uraemic complexion, Cushingoid features if on steroids, a malar rash or alopecia suggesting lupus, macroglossia and periorbital purpura suggesting amyloid, lymphadenopathy suggesting lymphoma. I would inspect the face for periorbital oedema, then the neck for the JVP. I would examine the hands for nail changes, the arms for fistulae or arthrography. Then I would examine the abdomen — inspect for distension from ascites, ballot the kidneys (palpable ballotable kidneys suggest polycystic or amyloid infiltration), assess for shifting dullness and a fluid thrill, and listen for renal artery bruits. I would examine for peripheral and sacral oedema, checking for pitting, and I would examine the calves for deep venous thrombosis. I would assess the chest for pulmonary oedema and pleural effusion." [1]

Presentation template

"I have examined Mr Wright. He is comfortable at rest. There is striking periorbital and dependent pitting oedema to the mid-thighs bilaterally, with sacral oedema and clinically detectable ascites with shifting dullness. There is no pallor, no Cushingoid habitus, no malar rash, no macroglossia, and no palpable lymphadenopathy. The JVP is not elevated. The abdomen is soft; there are no palpable masses or ballotable kidneys. There is no peripheral stigmata of chronic liver disease. Examination of the calves shows no calf tenderness to suggest deep venous thrombosis. In summary, this man has a pure nephrotic oedema picture with anasarca and ascites. My leading differential is a glomerular cause of nephrotic syndrome — most commonly membranous nephropathy at his age, and I would quantify the proteinuria, check the anti-PLA2R antibody, and proceed to renal biopsy." [1]

Discussion

"The distribution of oedema is clinically informative. Periorbital oedema, particularly in the morning, is characteristic of nephrotic syndrome — the lax periorbital tissue accumulates fluid overnight. Dependent oedema reflects gravity. Anasarca indicates severe disease. The key discriminations are cardiac (raised JVP, gallop, basal crackles), hepatic (stigmata of chronic liver disease, ascites with a low serum-ascites albumin gradient), and nephrotic (hypoalbuminaemia, heavy proteinuria). I would quantify the proteinuria with a protein-to-creatinine ratio, check the albumin, renal function, and complement, and screen for secondary causes before biopsy. In the short case, the discriminating question is always: is this pure nephrotic oedema, or is there a cardiac, hepatic, or multi-system cause?" [1]