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Q1: Definition and the three immunofluorescence types (3 min)
Examiner: Define rapidly progressive glomerulonephritis and classify it by immunofluorescence. Candidate: RPGN is a syndrome of rapid loss of renal function — loss of over 50 per cent of GFR within under 3 months — unified histologically by the finding of crescents (fibrin and proliferating parietal epithelial cells) in over 50 per cent of glomeruli on biopsy. Untreated, it progresses to end-stage kidney disease within days to weeks. By immunofluorescence there are three types. Type I is anti-GBM disease (about 10 to 20 per cent) — LINEAR IgG along the GBM, anti-alpha3(IV)NC1 antibody positive, Goodpasture syndrome with pulmonary haemorrhage, normal complement, and plasma exchange is essential. Type II is immune-complex (about 20 to 30 per cent) — GRANULAR deposits from lupus nephritis, post-infectious GN with crescents, or IgA nephropathy; complement is low in lupus and post-infectious. Type III is pauci-immune (about 60 to 70 per cent) — minimal or no immunoglobulin deposition, ANCA-associated vasculitis (granulomatosis with polyangiitis and microscopic polyangiitis), normal complement, anti-PR3 (c-ANCA) for GPA and anti-MPO (p-ANCA) for MPA. Type III is the commonest cause of RPGN in adults.
Q2: Pathogenesis of crescent formation and why treatment is urgent (3 min)
Examiner: Walk me through crescent formation and why speed matters. Candidate: Whatever the trigger — anti-GBM antibody, immune-complex deposition, or ANCA-mediated pauci-immune injury — severe capillary-wall inflammation RUPTURES the glomerular basement membrane. The breach allows fibrin, macrophages and plasma proteins to enter Bowman's space, and this stimulates parietal epithelial cells (and detached podocytes that adopt a proliferative phenotype) to divide into a crescent-shaped cellular and fibrocellular mass that compresses and ultimately obliterates the glomerular tuft. Crescents evolve from cellular (early, potentially salvageable) to fibrocellular to fibrous (irreversible). This evolution is why treatment is so urgent: once the crescent becomes fibrous, no amount of immunosuppression will recover that glomerulus. Hence the cardinal rule of RPGN — treat empirically with high-dose IV methylprednisolone BEFORE the biopsy result returns, because the window for salvage is narrow (days to weeks) and the damage is largely irreversible.
Q3: ANCA vasculitis — the NET/alternative-complement model and induction (3 min)
Examiner: Explain the pathogenesis of ANCA vasculitis and outline induction therapy. Candidate: ANCA are IgG autoantibodies against neutrophil granule proteins — myeloperoxidase (MPO, p-ANCA) and proteinase 3 (PR3, c-ANCA). The pathogenesis is the NET-alternative-complement amplification loop. Cytokines (IL-1, TNF) from infection or inflammation PRIME resting neutrophils to translocate MPO and PR3 to the cell surface; circulating ANCA bind and cross-link these, activating the neutrophil via Fc-gamma receptors. The activated neutrophil degranulates, releasing reactive oxygen species, proteases and neutrophil extracellular traps (NETs) — DNA-histone-protein webs that damage the endothelium. NETs activate the ALTERNATIVE complement pathway, generating C5a, which recruits more primed neutrophils in a self-amplifying loop, producing necrotising small-vessel vasculitis and crescentic GN. Because the antibody targets soluble neutrophil proteins rather than fixed tissue, little immunoglobulin deposits in the glomerulus — hence the pauci-immune immunofluorescence. This model explains why avacopan, a C5a receptor blocker, works as a steroid-sparing agent (ADVOCATE trial). Induction is methylprednisolone 500 to 1000 mg IV daily for 3 days then oral prednisolone 1 mg/kg/day, PLUS rituximab 375 mg/m2 weekly for 4 weeks (RAVE — non-inferior to cyclophosphamide and superior in relapse) OR cyclophosphamide 2 mg/kg/day oral. Plasma exchange is added only for dialysis-dependent crescentic ANCA with rapidly falling GFR or life-threatening alveolar haemorrhage (PEXIVAS narrowed routine use). PJP prophylaxis with co-trimoxazole throughout.
Q4: Anti-GBM (Goodpasture) — emergency management (2 min)
Examiner: A 24-year-old man has haemoptysis, rapidly progressive renal failure and a strongly positive anti-GBM antibody. Talk me through the emergency management. Candidate: This is anti-GBM disease presenting as a pulmonary-renal syndrome — a medical emergency. The pathogenic antibody is IgG against the non-collagenous domain of the alpha-3 chain of type IV collagen (alpha3(IV)NC1) in the GBM and alveolar BM, producing linear IgG on IF and crescents on light microscopy. Management is triple therapy: (i) plasma exchange — daily or alternate-day 4-litre exchanges with 5 per cent albumin (and fresh frozen plasma if bleeding or within 72 hours of biopsy), continued until the anti-GBM antibody is undetectable, typically 2 to 3 weeks or 9 to 12 sessions; (ii) methylprednisolone pulse 500 to 1000 mg IV daily for 3 days then oral prednisolone 1 mg/kg/day tapering; and (iii) cyclophosphamide 2 mg/kg/day oral (dose-reduced for age and renal function). Concurrently, oxygen and airway/respiratory support for the pulmonary haemorrhage, PJP prophylaxis with co-trimoxazole, gastric protection, and urgent renal biopsy once coagulation is corrected to confirm linear IgG. Prognosis is guarded — oligoanuria at presentation carries an over 50 per cent ESKD risk; for future transplant, the antibody must be undetectable for at least 6 months.
Q5: Trials — RAVE, MEPEX, PEXIVAS, MAINRITSAN (2 min)
Examiner: Which trials shape your induction and maintenance of ANCA vasculitis? Candidate: Four trials are pivotal. RAVE (Stone 2010) compared rituximab 375 mg/m2 weekly for 4 weeks with cyclophosphamide-azathioprine for ANCA induction and found rituximab non-inferior overall and SUPERIOR in relapsing disease — establishing rituximab as first-line induction. RITUXVAS (Jones 2010/2015) confirmed rituximab non-inferiority in renal-limited ANCA with sustained remission at 2 years. MEPEX (Jayne 2007) found plasma exchange superior to methylprednisolone pulse for renal recovery in severe renal ANCA — the historical basis for plasma exchange in dialysis-dependent disease. PEXIVAS (Walsh 2020, 704 patients) showed plasma exchange did NOT reduce the composite of death or ESKD in severe ANCA, narrowing its routine use to anti-GBM or double-positive disease, dialysis-dependent crescentic ANCA with rapidly falling GFR, and life-threatening diffuse alveolar haemorrhage. For maintenance, MAINRITSAN (Guillevin 2014) found rituximab 500 mg at day 0, 14, then 6, 12 and 18 months superior to azathioprine for preventing relapse — establishing rituximab as preferred maintenance. Finally, ADVOCATE showed avacopan (a C5a receptor blocker) is steroid-sparing and non-inferior for sustained remission.
Q6: High-yield exam pearls (2 min)
Examiner: Give me your top pearls for RPGN. Candidate: (1) RPGN = renal emergency; crescents on biopsy; AKI over days to weeks with RBC casts — the cardinal microscopy finding that confirms glomerular bleeding. (2) Three IF types: Type I anti-GBM (linear IgG, Goodpasture, pulmonary haemorrhage); Type II immune-complex (granular; lupus, post-infectious, IgA); Type III pauci-immune (ANCA — GPA, MPA; commonest in adults). (3) PR3 = c-ANCA = GPA (ENT and lung); MPO = p-ANCA = MPA (renal-predominant). (4) Anti-GBM targets alpha3(IV)NC1. (5) Four drug causes of ANCA: hydralazine, propylthiouracil, levamisole-cocaine, minocycline. (6) Crescents in over 50 per cent of glomeruli defines RPGN histologically; fibrous crescents are irreversible — treat empirically before biopsy. (7) Plasma exchange for anti-GBM and selected ANCA; RAVE = rituximab first-line; PEXIVAS restricted routine plasma exchange; MAINRITSAN = rituximab for maintenance. (8) Double-positive (ANCA + anti-GBM) = manage as anti-GBM; wait 6 months with antibody undetectable before transplant.