Glomerulonephritis (Nephritic Spectrum) — Written Clinical Reasoning

SAQ 1 — Pulmonary-Renal Syndrome from ANCA-Associated Vasculitis (25 marks, 30 minutes)

Prompt: Outline your immediate and integrated management of this patient, including the emergency management, problem list, investigation interpretation, immunosuppression regimen with doses, the role of plasma exchange, prophylaxis, and the long-term management plan. Justify each decision with reference to evidence and guidelines. [1]

Model Answer

Immediate emergency management — pulmonary haemorrhage and respiratory failure (3 marks): [1]

This patient has life-threatening pulmonary haemorrhage from MPO-ANCA-associated vasculitis (microscopic polyangiitis). His SpO2 of 90% on room air with diffuse alveolar infiltrates and haemoptysis indicates active alveolar bleeding. Immediate management: [1]

1. Assess and secure the airway — he may deteriorate to respiratory failure. Notify ICU early. Supplemental oxygen to maintain SpO2 above 94%. If respiratory failure progresses, he will need intubation and mechanical ventilation.
2. Avoid anticoagulation and antiplatelet agents — pulmonary haemorrhage can be exacerbated. Stop any aspirin or anticoagulants.
3. Type and crossmatch blood — he may need transfusion for ongoing haemorrhage.
4. Treat the underlying vasculitis urgently — the pulmonary haemorrhage will not stop until the vasculitis is controlled. Begin induction immunosuppression immediately. [1]

Problem list (4 marks): [1]

1. Pulmonary-renal syndrome from MPO-ANCA-associated vasculitis (microscopic polyangiitis) — pulmonary haemorrhage and crescentic pauci-immune GN
2. Acute kidney injury, KDIGO stage 3 — creatinine 385 (4 times baseline), with crescents in 55% of glomeruli on biopsy
3. Mononeuritis multiplex (left foot drop) — vasculitic neuropathy, contributing to falls risk
4. Cutaneous vasculitis (palpable purpura)
5. Hypertension (BP 156/92) — likely secondary to renal disease and vasculitic activation
6. Anaemia of chronic disease and pulmonary haemorrhage (Hb 96)
7. Smoking-related lung disease — 40-pack-year history (increases risk of pulmonary haemorrhage in AAV)
8. Social: retired painter (solvent exposure is a risk factor for AAV) [1]

Investigation interpretation (4 marks): [1]

• ANCA (MPO positive): Confirms ANCA-associated vasculitis. MPO positivity (p-ANCA pattern) is typical of microscopic polyangiitis. PR3 would suggest GPA, but GPA presents with ENT disease and granulomatous lung lesions — this patient has no ENT involvement and diffuse pulmonary haemorrhage, consistent with MPA.
• Anti-GBM negative: Rules out Goodpasture syndrome and double-positive disease — this simplifies the plasma exchange decision (see below).
• Complement normal (C3 and C4 both normal): Consistent with pauci-immune vasculitis. Low complement would suggest lupus or cryoglobulinaemia.
• ANA negative: Excludes lupus nephritis.
• Renal biopsy: Pauci-immune necrotising and crescentic GN — the hallmark of AAV. Crescents in 55% of glomeruli indicate severe disease with a guarded renal prognosis.
• Chest CT: Diffuse ground-glass and alveolar infiltrates with haemoptysis confirms pulmonary haemorrhage. The diffuse pattern (not nodules or cavities) is consistent with capillaritis, not granulomatous disease. [1]

Induction immunosuppression regimen (5 marks): [1]

Per KDIGO 2021 and the RAVE and RITUXVAS trials, induction for organ-threatening AAV: [1]

1. Methylprednisolone pulses: 500 to 1000 mg IV daily for 3 days, to rapidly suppress inflammation. This is followed by oral prednisone 1 mg/kg/day (approximately 60 to 80 mg). PEXIVAS established that a reduced-dose steroid tapering schedule is noninferior to the traditional high-dose approach, with fewer serious infections — taper prednisone to below 10 mg by 3 months.
2. Rituximab: 375 mg/m2 IV weekly for 4 weeks (or 1 g IV x2 two weeks apart). RAVE demonstrated rituximab is noninferior to cyclophosphamide for induction and superior in relapsing disease. RITUXVAS confirmed rituximab (with two cyclophosphamide pulses) is equivalent to standard cyclophosphamide in renal AAV. Rituximab is preferred for this patient as it avoids cyclophosphamide toxicity (infertility, malignancy, cytopenia) and allows future maintenance with the same agent.
3. Alternative — cyclophosphamide: If rituximab is unavailable or contraindicated, IV cyclophosphamide 15 mg/kg (adjusted for age and renal function) every 2 to 3 weeks for 3 to 6 months. [1]

Plasma exchange decision (3 marks): [1]

This patient has life-threatening pulmonary haemorrhage. The decision regarding plasma exchange is nuanced: [1]

• PEXIVAS (2020) found that plasma exchange did not reduce the composite of death or ESKD in AAV overall. This has reduced the routine use of plasma exchange.
• However, for life-threatening pulmonary haemorrhage, many units still use plasma exchange on the rationale that rapid removal of circulating ANCA and inflammatory mediators may help control alveolar bleeding, even though the evidence is weaker than for renal-limited disease.
• His creatinine of 385 (not yet dialysis-dependent or above 500) does not meet the MEPEX severity threshold for renal benefit.
• Decision: I would discuss with the nephrology and vasculitis multidisciplinary team. Given the severity of the pulmonary haemorrhage, I would favour plasma exchange (one plasma volume exchange daily or alternate-day, with 5% albumin replacement) for the first 7 to 10 sessions, in addition to rituximab and corticosteroids. If his renal function deteriorates to dialysis dependence or his creatinine exceeds 500, this further supports plasma exchange per the MEPEX subgroup benefit. [1]

Prophylaxis and supportive care (3 marks): [1]

• Pneumocystis jirovecii prophylaxis: Trimethoprim-sulfamethoxazole 800/160 mg three times weekly for the duration of high-dose corticosteroid therapy (equivalent to prednisone 20 mg or more for more than 4 weeks) and for as long as CD19 B-cell counts are suppressed after rituximab. This is critical — PJP is a leading cause of death in immunosuppressed vasculitis patients.
• Gastrointestinal protection: Proton pump inhibitor for gastric protection during high-dose corticosteroid therapy.
• Bone protection: Calcium and vitamin D supplementation; bisphosphonate if high fracture risk.
• Venous thromboembolism prophylaxis: This is challenging given his pulmonary haemorrhage — discuss with haematology. AAV with active disease carries a high VTE risk, but anticoagulation may worsen pulmonary bleeding. Mechanical prophylaxis until haemorrhage is controlled, then reassess.
• Blood pressure control: ACE inhibitor or ARB once the acute phase is stabilising and renal function is recovering — to control hypertension and reduce proteinuria.
• Vaccinations: Ensure pneumococcal, influenza, hepatitis B vaccination status is up to date before rituximab suppresses the vaccine response. Avoid live vaccines during immunosuppression. [1]

Long-term management and follow-up (3 marks): [1]

• Maintenance immunosuppression: After 3 to 6 months of induction remission, transition to maintenance. For PR3-positive or relapsing disease, rituximab (1 g x2 or 500 mg x2 every 4 to 6 months for at least 18 to 24 months) is preferred. For MPO-positive disease, azathioprine (1 to 2 mg/kg/day) or rituximab are options. Given his MPO positivity and single presentation, azathioprine is a reasonable first-line maintenance, with rituximab if he relapses.
• Monitoring: Monthly clinical review (BVAS, weight, blood pressure), blood tests (creatinine, CRP, ANCA titre, FBC for cytopenia from immunosuppression), and urinalysis (proteinuria, haematuria). Rising ANCA titre or recurrent haematuria may herald relapse.
• Renal prognosis: With crescents in 55% of glomeruli and a creatinine of 385, he has approximately a 30 to 50% chance of progressing to ESKD despite treatment. If he recovers renal function, he needs lifelong monitoring for relapse and CKD progression. If he reaches ESKD, transplantation is possible after disease remission is sustained (typically 6 to 12 months of quiescent disease).
• Smoking cessation: Critical to reduce the risk of future pulmonary haemorrhage and cardiovascular disease. [1]

SAQ 2 — Complement Interpretation and Classification (15 marks, 20 minutes)

Prompt: A 42-year-old woman presents with oedema, hypertension, and proteinuria of 3.5 g/day. Her creatinine is 145. C3 is 0.45 g/L (low), C4 is 0.08 g/L (low). ANA is positive at 1:640; anti-dsDNA is positive. Discuss the differential diagnosis based on the complement profile, what the biopsy is likely to show, and outline the classification and treatment approach. [1]

Model Answer

Complement interpretation (4 marks): [1]

The low C3 AND low C4 indicates classical complement pathway activation. This narrows the differential significantly: [1]

• Lupus nephritis: The most likely diagnosis, given the positive ANA and anti-dsDNA, proteinuria, and low C3/C4. Lupus activates the classical pathway via immune complex deposition.
• Endocarditis-associated GN: Also low C3 and C4 — exclude with blood cultures and echocardiography.
• Cryoglobulinaemic GN: Typically hepatitis C-associated, with low C3 and very low C4 (often undetectable).
• Membranoproliferative GN (immune complex type): Can show low C3 and C4. [1]

The normal complement differential includes IgA nephropathy, ANCA vasculitis, and anti-GBM disease — these are effectively excluded by the low complement. [1]

Expected biopsy findings (4 marks): [1]

Given the lupus serology, the biopsy is likely to show lupus nephritis. The pattern depends on the class: [1]

• Light microscopy: In class IV (diffuse proliferative, the most common severe class), expect endocapillary and mesangial proliferation, wire-loop lesions (subendothelial deposits), karyorrhexis, and possibly crescents.
• Immunofluorescence: The classic "full house" pattern — IgG, IgA, IgM, C3, C1q all positive (granular). Full house deposition is highly specific for lupus nephritis.
• Electron microscopy: Mesangial, subendothelial, and subepithelial deposits. The combination of subendothelial deposits (which correlate with active proliferative disease) and subepithelial deposits is characteristic. [1]

Classification and treatment (7 marks): [1]

The ISN/RPS classification (2003, updated 2018) guides treatment: [1]

• Class III (focal proliferative, less than 50%): Indication for immunosuppression if active.
• Class IV (diffuse proliferative, 50% or more): The most clinically important class. Requires urgent induction with mycophenolate mofetil (target 2 to 3 g/day) or Euro-Lupus cyclophosphamide (500 mg IV q2weekly x6), plus corticosteroids (methylprednisolone pulses then oral prednisone tapering). Given her Caucasian background and the equivalence data from the Euro-Lupus Nephritis Trial, either MMF or low-dose cyclophosphamide is appropriate.
• Class V (membranous): If pure class V, the approach differs — MMF with calcineurin inhibitors, or rituximab. If mixed III/IV + V, treat the proliferative component. [1]

The PEXIVAS-reduced-dose steroid strategy applies here too — taper steroids rapidly to minimise toxicity. [1]

Maintenance: After 6 months of induction, transition to maintenance with MMF (1 to 2 g/day) or azathioprine, for at least 2 to 3 years. ALMS maintenance data support MMF superiority over azathioprine. [1]

Monitoring: Serial C3, C4, anti-dsDNA titres, proteinuria, and creatinine. Rising anti-dsDNA with falling complement may herald a renal flare. [1]

Counselling: Discuss fertility implications if cyclophosphamide is chosen (consider egg or sperm preservation; azathioprine and MMF are teratogenic and must be avoided in pregnancy — switch to azathioprine before conception). Discuss the risks of long-term immunosuppression (infection, osteoporosis, cardiovascular disease) and the need for hydroxychloroquine, which reduces lupus flares and should be continued throughout. [1]