A 64-year-old woman with type 1 diabetes has months of sinus symptoms and 4 days of oliguria. Urea and creatinine are elevated, anti-GBM antibodies are absent, C-ANCA is positive and urine contains RBC casts. EXAM TASKS State the diagnosis. Write the management plan.
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"granulomatosis with polyangiitis" AND "rapidly progressive glomerulonephritis" AND treatment
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PMID: 36927642
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Diagnosis
Granulomatosis with Polyangiitis (GPA) - formerly Wegener's Granulomatosis
presenting as Rapidly Progressive Glomerulonephritis (RPGN) - pauci-immune crescentic glomerulonephritis (Class III RPGN)
Diagnostic Reasoning
| Feature | Significance |
|---|---|
| Months of sinusitis/upper respiratory symptoms | Upper airway involvement (classic GPA triad - feature 1) |
| 4 days of oliguria + raised urea/creatinine | Acute kidney injury from RPGN (feature 2) |
| C-ANCA positive (anti-PR3) | Highly specific for GPA; found in ~70-90% of cases |
| RBC casts in urine | Pathognomonic of glomerular bleeding - confirms active glomerulonephritis |
| Anti-GBM antibodies absent | Excludes Goodpasture's disease (which would also cause RPGN) |
| Type 1 diabetes | Background context; does not exclude GPA but requires consideration in management |
GPA is a necrotizing granulomatous vasculitis of small- and medium-sized vessels primarily affecting the kidneys, upper and lower respiratory tracts. The renal lesion is pauci-immune crescentic GN, meaning little or no immune complex deposition on immunofluorescence. The absence of anti-GBM antibodies and presence of C-ANCA confirms the ANCA-associated vasculitis category rather than Goodpasture's or immune-complex GN.
Management Plan
This patient has organ-threatening (kidney) and potentially life-threatening disease, requiring immediate, aggressive treatment. Management is divided into induction and maintenance phases per EULAR 2022 recommendations (PMID 36927642).
Step 1 - Urgent Assessment and Investigations
- Renal biopsy - confirm pauci-immune crescentic GN, assess proportion of viable crescents vs. sclerotic glomeruli (guides prognosis and intensity of treatment)
- Urine microscopy (confirm RBC casts), 24-hour urine protein
- ANCA titres (confirm C-ANCA/PR3 by ELISA), anti-GBM antibodies (already done), ANA, complement levels (C3/C4)
- FBC, LFTs, LDH, coagulation screen
- Chest X-ray/HRCT chest - rule out pulmonary involvement, nodules, or haemorrhage (pulmonary-renal syndrome)
- ENT/sinus CT - document extent of upper airway disease
- Hepatitis B, C, and HIV serology (before immunosuppression)
- Blood cultures if infection suspected
- Monitor urine output and fluid balance closely
- Assess dialysis requirement (oliguria + rising creatinine)
Step 2 - Induction Therapy (Remission Induction)
Goal: suppress active vasculitis rapidly to salvage renal function.
Glucocorticoids:
- IV methylprednisolone 500-1000 mg/day x 3 days (pulse) - given first to achieve rapid anti-inflammatory effect
- Followed by oral prednisolone 1 mg/kg/day (max ~60-80 mg/day)
- Taper to target of ≤5 mg/day prednisolone equivalent within 4-5 months (EULAR 2022 recommendation to reduce cumulative steroid exposure)
Immunosuppressive induction - choose one:
- Rituximab 375 mg/m² IV weekly x 4 doses (preferred in many centres, especially for relapsing or fertile-age patients) - RAVE and RITUXVAS trials showed non-inferiority to cyclophosphamide for remission induction, with superiority in relapsing disease
- IV cyclophosphamide 15 mg/kg (or 500-750 mg/m²) every 2-3 weeks x 6 pulses - traditional standard, still widely used; pulse IV preferred over daily oral to reduce cumulative dose and side effects (bladder toxicity, myelosuppression)
In this 64-year-old with T1DM and severe renal impairment:
- Rituximab is often favoured given the patient's age and the desire to limit cyclophosphamide-related toxicity (infection risk, bladder toxicity, gonadal toxicity)
- If cyclophosphamide is used, reduce dose by 25-50% for eGFR <30 ml/min; use with MESNA for bladder protection
Avacopan (C5a receptor blocker):
- 30 mg orally twice daily - may be added as a steroid-sparing adjunct to rituximab or cyclophosphamide (ADVOCATE trial; approved by FDA/EMA for GPA/MPA)
- Particularly useful to reduce glucocorticoid burden in a diabetic patient (helps avoid steroid-driven hyperglycaemia)
Plasma exchange (PLEX):
- Consider in patients with RPGN and dialysis-dependent or near-dialysis AKI (creatinine rising rapidly, oliguria)
- EULAR 2022: "Plasma exchange may be considered in patients with rapidly progressive glomerulonephritis" - though the PEXIVAS trial (2020) showed PLEX did not significantly reduce end-stage renal disease or death at 2 years, it may still be offered on a case-by-case basis, particularly if there is concurrent pulmonary haemorrhage
- If alveolar haemorrhage is found on imaging, PLEX is more strongly indicated
Step 3 - Supportive / Adjunctive Measures
| Intervention | Rationale |
|---|---|
| Renal replacement therapy (haemodialysis) if needed | Oliguria + uraemia; dialysis-dependent AKI may recover with aggressive treatment |
| Antifungal/PCP prophylaxis (Co-trimoxazole 480 mg daily or trimethoprim-sulfamethoxazole DS 3x/week) | Mandatory during high-dose immunosuppression |
| Proton pump inhibitor | Gastroprotection with high-dose steroids |
| Bone protection (calcium, vitamin D; bisphosphonate) | Steroid-induced osteoporosis prevention |
| Tight glycaemic control | Type 1 diabetes + high-dose steroids = significant hyperglycaemia risk; requires insulin dose adjustment and close monitoring |
| Blood pressure control (ACEi/ARB if proteinuric and not anuric) | Renoprotection |
| Avoid NSAIDs and nephrotoxic drugs | Preserve residual renal function |
| Ophthalmology referral | Exclude orbital/ocular GPA involvement |
Step 4 - Maintenance Therapy (once remission achieved, typically at 3-6 months)
- Rituximab is first-line for maintenance in GPA (500 mg IV every 6 months x 2 years, then review) - per EULAR 2022
- Alternatives: azathioprine 2 mg/kg/day or mycophenolate mofetil 2-3 g/day (less preferred in PR3-ANCA GPA due to higher relapse rates)
- Methotrexate is an alternative but should be avoided with significantly reduced GFR
- Continue low-dose prednisolone taper; aim for steroid-free maintenance with rituximab if possible
- Monitor ANCA titres (rising titres may predict relapse), renal function, urinalysis
- Duration of maintenance: minimum 24 months; many centres continue 3-5 years given high relapse risk in PR3-positive GPA
Prognosis Note
The EULAR 2022 guidelines note that early diagnosis and prompt treatment are critical - 5-year kidney and patient survival with adequate immunosuppression is 65-75%. Dialysis-dependent renal failure at presentation may still recover with aggressive early therapy. PR3-ANCA (C-ANCA) positivity predicts higher relapse rates compared to MPO-ANCA, so long-term monitoring is essential. - Comprehensive Clinical Nephrology, 7th Edition, p. 361
Key sources: EULAR 2022 Recommendations (PMID 36927642) | Brenner and Rector's The Kidney p. 3096 | Comprehensive Clinical Nephrology, 7th Edition p. 361
In best brief short way..clinical features, investigation and management .in short best way
GPA (Wegener's Granulomatosis) - Quick Reference
Clinical Features
Upper Respiratory (ENT)
- Chronic sinusitis, epistaxis, nasal crusting/ulceration
- Saddle-nose deformity, subglottic stenosis, otitis media
Lower Respiratory
- Cough, haemoptysis, dyspnoea
- Nodules, cavities, infiltrates on CXR
Renal
- Haematuria, RBC casts, proteinuria
- RPGN → oliguria → AKI
Other
- Eye: proptosis, scleritis
- Skin: purpura, ulcers
- Systemic: fever, weight loss, arthralgia
Investigations
| Test | Expected Finding |
|---|---|
| C-ANCA (anti-PR3) | Positive (~90% in systemic GPA) |
| Anti-GBM | Negative (excludes Goodpasture's) |
| Urinalysis | RBC casts, proteinuria |
| Urea/Creatinine | Elevated (AKI) |
| FBC | Anaemia, leukocytosis |
| CXR/HRCT chest | Nodules, cavities, infiltrates |
| Sinus CT | Mucosal thickening, bone erosion |
| Renal biopsy | Pauci-immune crescentic GN (gold standard) |
Management
Induction (remission induction)
- IV methylprednisolone 500-1000 mg x 3 days → oral prednisolone 1 mg/kg/day (taper to ≤5 mg by 4-5 months)
- Rituximab (preferred) OR IV cyclophosphamide x 6 pulses
- Avacopan 30 mg BD - steroid-sparing add-on (especially useful in diabetics)
- Plasma exchange - consider if dialysis-dependent RPGN or pulmonary haemorrhage
Maintenance (once remission at ~3-6 months)
- Rituximab 500 mg IV every 6 months (first-line)
- Alternatives: azathioprine or MMF
- Duration: minimum 24 months (longer in PR3-positive)
Supportive
- PCP prophylaxis (co-trimoxazole)
- PPI + bone protection
- Tight glycaemic control (diabetic patient)
- Dialysis if needed (may recover with treatment)
Key point: PR3/C-ANCA GPA has a high relapse rate - long-term ANCA monitoring is mandatory.
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