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Stem
A 24-year-old man presents to the emergency department with a 5-day history of worsening haemoptysis (about 30 mL of blood-streaked sputum per day), breathlessness and dark 'cola-coloured' urine. His creatinine was 0.9 mg/dL one month ago at a routine check and is now 4.6 mg/dL. On examination he is tachypnoeic (respiratory rate 28/min), oxygen saturation 90 per cent on room air, blood pressure 158/96 mmHg, with bilateral basal crackles. Urine dipstick: blood 3+, protein 1+. Phase-contrast microscopy shows dysmorphic red cells and red-cell casts. Haemoglobin 9.2 g/dL (microcytic, iron-deficient pattern); platelets normal; schistocytes absent. Serum C3 and C4 are normal. ANA and anti-dsDNA negative. ANCA (anti-PR3, anti-MPO) negative. Anti-GBM antibody is strongly positive. Chest X-ray shows bilateral perihilar alveolar infiltrates. Bronchoalveolar lavage returns progressively bloodier aspirates.
Questions
a) What is the most likely diagnosis, and which two features support the pulmonary-renal syndrome? (2 marks)
Anti-GBM disease (Goodpasture syndrome) — Type I rapidly progressive (crescentic) glomerulonephritis. The diagnosis is supported by (i) the strongly positive anti-GBM antibody (IgG against the non-collagenous domain of the alpha-3 chain of type IV collagen, alpha3(IV)NC1) and (ii) the pulmonary-renal syndrome — rapidly progressive crescentic GN (rising creatinine with RBC casts) with diffuse alveolar haemorrhage (haemoptysis, bilateral alveolar infiltrates, progressively bloodier BAL, iron-deficiency anaemia). The normal complement and negative ANCA exclude immune-complex and pauci-immune causes; linear IgG on biopsy would confirm Type I.
b) Outline the immunopathogenesis of the renal and pulmonary injury. (3 marks)
IgG autoantibodies are produced against the alpha3(IV)NC1 antigen — the non-collagenous domain of the alpha-3 chain of type IV collagen — which is normally sequestered within the mature glomerular basement membrane and the alveolar basement membrane (both share this target). The antibodies deposit in a continuous, ribbon-like LINEAR pattern along the GBM and alveolar BM. Binding activates complement (C3) and triggers Fc-receptor-mediated neutrophil and macrophage injury, which ruptures the capillary wall. In the kidney this allows fibrin and macrophages into Bowman's space, stimulating parietal epithelial cells to proliferate into crescents that compress and obliterate the tuft (over 50 per cent crescents defines RPGN histologically). In the lung it produces capillaritis and alveolar haemorrhage. Because the antibody is tissue-fixed and circulates, removing circulating antibody by plasma exchange is central to treatment — a distinction from pauci-immune ANCA disease. Smoking and respiratory infection increase the risk of pulmonary bleeding.
c) Outline the immediate and definitive management. (4 marks)
Immediate (resuscitative): high-flow oxygen and close airway/respiratory monitoring; secure anaesthetic/ITU support if respiratory failure worsens; treat the pulmonary haemorrhage with protective ventilation if intubated; treat hyperkalaemia and fluid overload if present. Crucially, start high-dose immunosuppression IMMEDIATELY — do not wait for biopsy.
Definitive — triple therapy:
- Plasma exchange — daily or alternate-day, 4-litre exchanges with 5 per cent human albumin (add fresh frozen plasma if bleeding or within 72 h of biopsy), continued until the anti-GBM antibody is undetectable (typically 2 to 3 weeks, 9 to 12 sessions).
- Glucocorticoid — methylprednisolone 500 to 1000 mg IV daily for 3 days then oral prednisolone 1 mg/kg/day tapering.
- Cyclophosphamide 2 mg/kg/day oral (dose-reduce for age and renal function) to suppress ongoing antibody production.
Add PJP prophylaxis (co-trimoxazole 480 mg daily), gastric protection, and bone/glucose monitoring. Urgent renal biopsy should be arranged once coagulation is corrected (the IF pattern — linear IgG — confirms Type I).
d) State the expected prognosis and the rule governing future renal transplantation. (1 mark)
Prognosis is guarded: anti-GBM disease with oligoanuria or dialysis-dependence at presentation carries an over 50 per cent risk of end-stage kidney disease, and pulmonary haemorrhage carries significant early mortality. However, if the acute episode is weathered with prompt triple therapy, the disease is usually monophasic (relapse is rare while the antibody stays negative). For future transplantation, the anti-GBM antibody must be undetectable for at least 6 months before transplant to minimise recurrence in the graft.