Nephrotic Syndrome — Clinical Case

DCE Long Case

The patient (SASPOP)

• Symptoms: three months of progressive leg and abdominal swelling; one week of exertional dyspnoea
• Age: 56
• Sex: male
• Presentation: referred by GP after routine bloods showed albumin 18 g/L and a urine dipstick of 4+ protein
• Occupation: engineer
• Problems (presented as the opening statement): "Mrs Examiner, this is Mr James Wright, a 56-year-old engineer who presents with a three-month history of progressive anasarca and a one-week history of exertional dyspnoea, on a background of a new diagnosis of primary membranous nephropathy with nephrotic syndrome. His PCR is 680 mg/mmol, albumin 18, creatinine 95, anti-PLA2R strongly positive, and biopsy confirms stage II membranous nephropathy. He has past hepatitis B infection. The main problems are: the membranous nephropathy requiring cause-specific immunosuppression; hypoalbuminaemia at a threshold mandating anticoagulation; hypertension and hyperlipidaemia; hepatitis B reactivation risk with planned rituximab; and the need for occult malignancy surveillance at his age." [1]

Examination findings

• General: comfortable at rest, no respiratory distress, no cyanosis, no jaundice
• Cardiovascular: blood pressure 148/92 seated, JVP not elevated, heart sounds normal with a soft ejection systolic murmur, no gallop
• Respiratory: bibasal dullness to percussion consistent with small bilateral pleural effusions, fine basal crackles
• Abdomen: distended with shifting dullness (ascites), no palpable masses or ballotable kidneys, no hepatic stigmata, bowel sounds normal
• Limbs: striking pitting oedema to the mid-thighs bilaterally, sacral oedema, no calf tenderness
• General signs of secondary cause: no malar rash, no macroglossia, no periorbital purpura, no lymphadenopathy, no stigmata of chronic liver disease [1]

Investigation summary

• Urine: PCR 680 mg/mmol (nephrotic-range), bland microscopy with oval fat bodies, no blood
• Bloods: albumin 18 g/L, creatinine 95 micromol/L, eGFR greater than 60, normal C3 and C4, ANA negative, total cholesterol 9.2 mmol/L
• Anti-PLA2R antibody: strongly positive at 240 RU/mL (reference less than 20)
• Viral: HBsAg negative, anti-HBc positive (past infection), anti-HBs negative, anti-HCV negative, HIV negative
• Plasma cell screen: serum free light chains normal, serum electrophoresis no monoclonal band
• Biopsy: primary membranous nephropathy, stage II, no superimposed crescents or significant interstitial fibrosis
• Imaging: renal ultrasound normal-sized kidneys, no obstruction; echo normal LV function, no mural thrombus; CT pulmonary angiogram negative for pulmonary embolism [1]

Structured problem list

1. Primary membranous nephropathy with nephrotic syndrome — confirmed
2. Hypoalbuminaemia (18 g/L) — thrombotic risk threshold met
3. Hypertension (148/92) and hyperlipidaemia (cholesterol 9.2)
4. Past hepatitis B infection (anti-HBc positive) — reactivation risk with planned rituximab
5. Bilateral pleural effusions — likely a transudate from the nephrotic state
6. Need for occult malignancy surveillance at age 56 [1]

Integrated management plan

Problem 1 — Primary membranous nephropathy (cause-specific immunosuppression): [1]

He meets the criteria for immunosuppression — persistent nephrotic-range proteinuria and hypoalbuminaemia after three months, with a high anti-PLA2R titre and normal GFR. Per the MENTOR trial (Fervenza, NEJM 2019, PMID 31269364), the preferred first-line agent 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]. Alternative if rituximab contraindicated: cyclical corticosteroid-cyclophosphamide (modified Ponticelli) per STARMEN (PMID 33166580) [5].

Critical pre-treatment step: anti-HBc positivity indicates past hepatitis B. Rituximab can reactivate hepatitis B and cause fulminant hepatitis. Start prophylactic entecavir or tenofovir before rituximab and continue for at least 12 months (and at least 6 months after the last rituximab dose); monitor HBV DNA. [1]

Problem 2 — Anti-proteinuric therapy for every patient (KDIGO 2024): [1]

• ACE inhibitor at maximum tolerated dose — start ramipril 5 mg, titrate to 10 mg. Acceptable creatinine rise up to 30 per cent; monitor potassium. No dual ACEi/ARB.
• Add an SGLT2 inhibitor (dapagliflozin 10 mg or empagliflozin 10 mg) for additional proteinuria reduction [7].
• Blood pressure target less than 120/80 standardised; add amlodipine if needed.

Problem 3 — Thromboprophylaxis: [1]

His albumin is 18 g/L, well below the 25 to 30 g/L threshold for prophylactic anticoagulation in membranous nephropathy (the highest-risk substrate). Start prophylactic anticoagulation with a DOAC or warfarin for the duration of the nephrotic state. Counsel on bleeding risk. Re-image for renal vein thrombosis if any acute flank pain, haematuria, or sudden GFR fall occurs. [1]

Problem 4 — Complication prevention: [1]

• Pneumococcal (23-valent) and annual influenza vaccination now; avoid live vaccines during rituximab-induced B-cell depletion.
• Atorvastatin 40 mg daily for hyperlipidaemia; titrate.
• For oedema: salt restriction (less than 2 g sodium/day), frusemide 80 mg daily (high dose because albumin binding is reduced), add a thiazide if resistant. Aim for 0.5 to 1 kg/day weight loss; avoid over-diuresis. [1]

Problem 5 — Malignancy surveillance: [1]

A solid tumour membranous is PLA2R-negative, but paraneoplastic processes can rarely coexist. Age-appropriate screening — chest X-ray, colorectal screening, prostate assessment — and re-screen at intervals. [1]

Problem 6 — Follow-up: [1]

Monitor PCR, albumin, creatinine, anti-PLA2R titre, blood pressure monthly during immunosuppression. Anti-PLA2R titre fall precedes and predicts clinical remission. Long-term surveillance for progression to CKD; refer for transplant workup early if proteinuria persists and GFR falls. [1]

Communication and shared decision-making

• Explain the diagnosis in plain language: an autoimmune attack on a kidney filter protein (PLA2R), causing protein to leak into the urine and producing the swelling.
• Explain the immunosuppression options — rituximab (preferred, less toxic, MENTOR-supported) versus cyclophosphamide (more aggressive, more toxicity). Discuss the rituximab infusion reactions, infection risk, and the critical need for hepatitis B prophylaxis.
• Explain the anticoagulation rationale — the swollen, protein-leaking state makes the blood sticky, and we thin it until the kidney heals.
• Discuss the realistic prognosis — one-third of membranous undergoes spontaneous remission, one-third has persistent proteinuria, one-third progresses; immunosuppression improves these odds.
• Offer written information and a renal nurse specialist contact. [1]

DCE Short Case — Oedema and Abdominal Examination

The instruction

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

Systematic examination routine

1. End of bed: general appearance, comfort, pallor, Cushingoid features (if on steroids), sallow uraemic complexion, malar rash and alopecia (lupus), macroglossia and periorbital purpura (amyloid), lymphadenopathy (lymphoma, Hodgkin with MCD), needle-track marks (HIV risk)
2. Hands: nail changes (half-and-half nails of CKD), leptocutaneous signs
3. Face: periorbital oedema (characteristic of nephrotic syndrome, particularly in the morning), conjunctival pallor of anaemia
4. Neck: JVP (elevated in cardiac oedema; normal or low in nephrotic), carotid pulse
5. Chest: pulmonary oedema, pleural effusion (transudate from the nephrotic state), pericardial rub
6. Abdomen: inspect for distension from ascites; palpate for ballotable kidneys (polycystic, amyloid infiltration), hepatosplenomegaly; assess for shifting dullness and fluid thrill (ascites); listen for renal artery bruits
7. Limbs: peripheral pitting oedema, distribution (periorbital, dependent, sacral, anasarca), calf tenderness (deep venous thrombosis), arterial pulses
8. Close: blood pressure (often raised), urinalysis if available (4+ protein, no blood) [1]

Key physical signs in a nephrotic patient

• Periorbital oedema — lax periorbital tissue accumulates fluid overnight
• Dependent pitting oedema — gravity-dependent, may reach anasarca
• Ascites — shifting dullness, fluid thrill
• Pleural effusion — bibasal dullness, reduced breath sounds
• Pallor — anaemia from inflammation, iron loss (urinary transferrin), or bone marrow infiltration (amyloid)
• Signs of the underlying cause — malar rash, macroglossia, stigmata of chronic liver disease, lymphadenopathy, retinopathy (diabetes) [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, no periorbital purpura, and no palpable lymphadenopathy. The JVP is not elevated. The heart sounds are normal with a soft ejection systolic murmur. There are small bilateral pleural effusions. The abdomen is distended with shifting dullness; there are no palpable masses or ballotable kidneys. The calves show no deep venous tenderness. In summary, this man has a pure nephrotic oedema picture with anasarca and ascites. My leading differential is a glomerular cause of nephrotic syndrome, and at his age with this severity I would prioritise primary membranous nephropathy. I would quantify the proteinuria with a protein-to-creatinine ratio, check the anti-PLA2R antibody, and proceed to renal biopsy." [1]

Discussion questions

Q: What is the mechanism of the oedema in nephrotic syndrome? A: Two mechanisms coexist. The classical "underfill" mechanism — hypoalbuminaemia lowers plasma oncotic pressure, fluid shifts to the interstitium, effective circulating volume falls, the kidney retains sodium. The modern "overfill" mechanism — the damaged glomerulus leaks proteases (plasmin) that activate epithelial sodium channels in the collecting duct, driving primary renal sodium retention. The practical implication: a loop diuretic alone may not suffice; combination with a thiazide or potassium-sparing agent may be needed. [1]

Q: Why is nephrotic syndrome hypercoagulable? A: Multifactorial — urinary loss of antithrombin (58 kDa, small enough to leak), loss of free protein S, hepatic upregulation of fibrinogen and factor VIII, platelet activation, impaired fibrinolysis. Renal vein thrombosis is the signature complication, commonest in membranous nephropathy. [1]

Q: How would you confirm renal vein thrombosis if he developed flank pain? A: CT renal venography or magnetic resonance venography. Ultrasound is insensitive. Treat with therapeutic anticoagulation. [1]

Q: What vaccinations does he need? A: Pneumococcal (23-valent polysaccharide, with 13-valent conjugate in some schedules), annual influenza, hepatitis B (especially given his past infection status), and varicella in children. Avoid live vaccines during active immunosuppression. [1]

Q: Why is the ACE inhibitor given to every nephrotic patient regardless of blood pressure? A: ACE inhibitors reduce proteinuria by lowering intraglomerular pressure and stabilising the slit diaphragm, independent of blood pressure. Reducing proteinuria protects podocytes and slows progression to CKD. The same logic applies to ARBs and SGLT2 inhibitors. [1]