ANCA Associated Glomerulonephritis

ANCA-associated glomerulonephritis is pauci-immune necrotising and crescentic glomerulonephritis due to small vessel vasculitis with antineutrophil cytoplasmic antibodies against proteinase 3 or myeloperoxidase. It accounts for most cases of rapidly progressive glomerulonephritis in adults over 50 and for 50 to 60% of crescentic glomerulonephritis.

The clinical syndromes are microscopic polyangiitis (mainly MPO-ANCA), granulomatosis with polyangiitis (mainly PR3-ANCA, with upper respiratory tract granulomas), and eosinophilic granulomatosis with polyangiitis (MPO-ANCA in 30%, kidney disease less common). Annual incidence is about 2 to 3 cases in each 100 000 people.

Without treatment, mortality exceeds 80% within a year; with treatment, 5-year survival is 75 to 85%, and 20 to 25% of patients with kidney involvement reach kidney failure.

Pathophysiology. ANCA activate primed neutrophils, causing degranulation, oxidative burst, neutrophil extracellular trap formation and complement activation through the alternative cascade (C5a), with injury to small vessels and glomerular capillaries.

• Prodrome of fever, weight loss, malaise, arthralgia and myalgia.
• Kidney: haematuria, proteinuria (usually under 3 g daily), rapidly rising creatinine, oliguria, hypertension (mild).
• Lung: haemoptysis, nodules, cavities, pulmonary haemorrhage, interstitial lung disease (MPO-ANCA).
• Upper airway (granulomatosis with polyangiitis): epistaxis, nasal crusting, sinusitis, saddle nose, subglottic stenosis, hearing loss, orbital mass.
• Skin: purpura, ulcers; eye: scleritis, episcleritis; nerve: mononeuritis multiplex; gut: pain, bleeding; heart: pericarditis, cardiomyopathy.

Red flags

• Pulmonary haemorrhage, hypoxia or haemoptysis.
• Creatinine above 500 micromol/L, oliguria or dialysis requirement.
• Neurological deficit (mononeuritis, central nervous system disease).
• Gastrointestinal bleeding or perforation; cardiac involvement.
• Relapse on tapering, or after withdrawal of rituximab.

• ANCA by indirect immunofluorescence plus antigen specific immunoassay for PR3 and MPO (10 to 15% are ANCA-negative); creatinine and eGFR trend, urinalysis with microscopy, protein:creatinine ratio, full blood count, CRP, eosinophil count, immunoglobulins, complement, anti-GBM antibody (double positivity in 5%), hepatitis B and C, HIV.
• Chest CT and sinus CT; echocardiography; nerve conduction studies if neuropathy.
• Biopsy: pauci-immune focal necrotising glomerulonephritis with crescents (classified as focal, crescentic, mixed or sclerotic by percentage of normal glomeruli, crescents and sclerosis; the sclerotic class carries the worst renal prognosis); skin, nasal or lung biopsy if needed.
• Disease activity score (Birmingham Vasculitis Activity Score), ANCA titre trend, CD19 B-cell count and immunoglobulin G level before rituximab.

Differential diagnosis

• Drug induced ANCA vasculitis (hydralazine, propylthiouracil, minocycline, levamisole adulterated cocaine), infective endocarditis, systemic lupus erythematosus, anti-GBM disease, cryoglobulinaemia, thrombotic microangiopathy, polyarteritis nodosa (no ANCA, no glomerulonephritis), tuberculosis, malignancy.

Remission induction (organ- or life threatening disease)

• Glucocorticoid: methylprednisolone 500 mg intravenously daily for 1 to 3 days (or 1 g in severe disease), then prednisolone 1 mg/kg daily (maximum 60 mg), reduced to 20 mg by week 6 and 5 mg by 6 months. In older adults or those at high infection risk, use a reduced dose schedule.
• Rituximab 375 mg/m² intravenously weekly for 4 doses, or 1 g on days 1 and 15. It is preferred in relapsing disease, PR3-ANCA, children, women of child bearing age, and frail patients.
• Alternatively, cyclophosphamide intravenously 15 mg/kg (maximum 1.2 g) every 2 weeks for 3 doses, then every 3 weeks for 3 to 6 months. Reduce to 12.5 mg/kg at age 60 to 70 and 10 mg/kg over age 70, and by a further 20% if creatinine is above 300 micromol/L.
• Oral cyclophosphamide alternative: 2 mg/kg daily (maximum 200 mg) for 3 months (1.5 mg/kg above age 60; 1 mg/kg above age 75).
• For severe disease, combine rituximab with two doses of intravenous cyclophosphamide 15 mg/kg.
• Avacopan 30 mg orally twice daily with food for 12 months, allowing faster steroid taper. Monitor liver tests and neutrophil count; avoid if active hepatitis B or severe hepatic impairment.
• Plasma exchange (7 exchanges of 60 mL/kg over 14 days) for pulmonary haemorrhage, anti-GBM positivity, or selected patients with creatinine above 300 micromol/L.
• Sodium bicarbonate, antihypertensives and dialysis for complications.

Remission maintenance

• Rituximab 500 mg intravenously every 6 months for 18 months after induction, or azathioprine 2 mg/kg daily (check thiopurine methyltransferase), or mycophenolate mofetil 1 g twice daily. Use methotrexate 15 to 25 mg weekly only if eGFR is above 60 mL/min/1.73 m².
• Continue maintenance for 24 to 48 months, longer in PR3-ANCA, previous relapse or persistent ANCA.
• Relapse: re-induce with rituximab 1 g on days 1 and 15 (or 375 mg/m² weekly for 4 doses) plus steroid pulses.

Prophylaxis and supportive care

• Co-trimoxazole 480 mg orally daily (960 mg three times weekly if eGFR above 30; atovaquone 1500 mg daily for sulphonamide allergy).
• Proton pump inhibitor; calcium and vitamin D.
• Hepatitis B screening and entecavir prophylaxis if core antibody positive.
• Pneumococcal and influenza vaccination.
• IgG monitoring, with immunoglobulin replacement if IgG is under 4 g/L with recurrent infections.
• Blood pressure under 130/80 mmHg; ramipril 2.5 mg daily to 10 mg daily after recovery from acute injury; dapagliflozin 10 mg daily (eGFR at least 25) for chronic proteinuric kidney disease.

Dialysis dependent disease. Continue induction for 3 months. If there is no recovery of kidney function and no extrarenal activity, stop immunosuppression and offer maintenance dialysis or transplantation (wait for 6 to 12 months of remission).

Monitoring. Creatinine and urinalysis weekly during induction, then monthly; ANCA, CD19 count and IgG every 3 to 6 months; infection surveillance; BVAS at each review.

Referral and escalation. Same day nephrology and rheumatology; respiratory and critical care for pulmonary haemorrhage; ENT for subglottic stenosis.

Special groups

• Elderly: reduced dose steroids, rituximab induction, and aggressive infection prophylaxis.
• Pregnancy: azathioprine and low dose steroids for maintenance; avoid cyclophosphamide, mycophenolate and methotrexate; rituximab only if essential.
• Children: methylprednisolone 10 to 30 mg/kg (maximum 1 g) for 3 days, rituximab 375 mg/m² weekly for 4 doses or cyclophosphamide 500 mg/m² monthly.
• Transplant: recurrence is uncommon; transplant after at least 6 months of remission.