ANCA-associated glomerulonephritis

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

ANCA-associated glomerulonephritis is a renal manifestation of necrotising small-vessel vasculitis. Neutrophil activation by antibodies to proteinase 3 or myeloperoxidase damages glomerular capillaries, producing focal necrosis and crescents with few immune deposits. Loss of filtration can be rapid and irreversible, yet symptoms may be nonspecific fatigue, weight loss and dark urine. A routine creatinine without urinalysis can therefore miss the diagnostic pattern.

Diagnosis integrates phenotype, antigen-specific ANCA and tissue. Infection, anti-GBM disease, lupus, drug-induced vasculitis and malignancy can mimic the presentation or coexist. A biopsy is particularly valuable when ANCA is negative, infection is plausible, disease appears renal-limited or chronicity will change the balance of immunotherapy. In life-threatening pulmonary–renal disease, biopsy is expedited while supportive care and senior induction decisions proceed in parallel.

Care has two phases. Remission induction rapidly controls active vascular inflammation with rituximab or cyclophosphamide plus a carefully minimised glucocorticoid course or avacopan-based strategy. Maintenance prevents relapse, usually with scheduled rituximab under current BSR guidance. Across both phases, infection prevention, vaccination, fertility, immunoglobulins, blood counts, cardiovascular and bone health, malignancy surveillance and psychosocial support are treatment components rather than optional extras.

Key points

Granulomatosis with polyangiitis and microscopic polyangiitis commonly cause necrotising pauci-immune crescentic GN; eosinophilic granulomatosis with polyangiitis affects kidneys less often but remains in the differential.
PR3-ANCA is associated more often with GPA and relapse, while MPO-ANCA is associated more often with MPA and renal-limited disease; neither antibody defines phenotype perfectly.
Haematuria, red-cell casts, proteinuria and a creatinine rise can be clinically silent, so urinalysis and serial renal function belong in every suspected systemic-vasculitis assessment.
ENT inflammation, pulmonary nodules or haemorrhage, scleritis, purpura and mononeuritis multiplex are high-yield extra-renal clues, but renal-limited disease has none of them.
ANCA may be negative in biopsy-proven pauci-immune disease and may be positive in infection, inflammatory bowel disease or drug exposure; clinical probability and biopsy matter.
Kidney biopsy establishes the activity–chronicity balance and usually shows necrosis and crescents with little or no immune deposition on immunofluorescence.
Active GPA or MPA requires induction immunosuppression, with rituximab or intravenous pulsed cyclophosphamide as current BSR first-line options combined with glucocorticoid or avacopan strategy.
Reduced glucocorticoid exposure is preferred where suitable because infection and metabolic harm are major early causes of morbidity; the taper is planned from treatment day one.
Avacopan can replace much of the glucocorticoid burden for selected active GPA or MPA under NICE and specialist criteria, but it does not replace rituximab or cyclophosphamide induction.
Plasma exchange is not routine for every severe creatinine rise after PEXIVAS; nephrology individualises use for selected extreme renal risk, hypoxaemic alveolar haemorrhage or anti-GBM overlap.
Rituximab is the preferred BSR maintenance option after remission, typically for 24–48 months with individual relapse and infection review; azathioprine or methotrexate may be alternatives.
ANCA titre and B-cell count can inform context but clinical assessment, urine and kidney trajectory determine relapse; do not treat a laboratory rise in isolation.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Primary ANCA-associated vasculitis

Autoimmunity against proteinase 3 or myeloperoxidase underlies granulomatosis with polyangiitis, microscopic polyangiitis and some eosinophilic granulomatosis, with renal-limited disease also recognised.

Exposure-associated vasculitis

Hydralazine, propylthiouracil and levamisole-adulterated cocaine can generate complex ANCA phenotypes; a precise medicine and substance history helps separate these from primary disease.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
ANCA-mediated neutrophil activation
Antibodies to proteinase 3 or myeloperoxidase activate neutrophils, initiating small-vessel inflammation that can damage glomerular capillaries.
2
Capillary endothelial injury
Activated neutrophils damage glomerular capillaries, producing focal necrosis, haematuria and a potentially rapid, irreversible loss of filtration.
3
Crescent formation
Glomerular capillary injury produces crescents with few immune deposits; extensive crescentic disease can cause rapidly worsening kidney function.
4
Pauci-immune multisystem vasculitis
Immunofluorescence shows little immunoglobulin despite intense inflammation, while equivalent small-vessel injury can affect lungs, nerves, skin, eyes and upper airways.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Renal-limited vasculitis

An asymptomatic creatinine rise with glomerular haematuria, casts and moderate proteinuria may be the entire presentation; absence of rash or respiratory disease does not lower urgency.

Pulmonary haemorrhageRed flag

Dyspnoea, hypoxia, diffuse opacities and falling haemoglobin may represent alveolar bleeding even without haemoptysis and demand critical pulmonary–renal assessment.

Granulomatous ENT disease

Persistent bloody nasal crusting, sinus inflammation, otitis, hearing loss, subglottic symptoms or destructive lesions support GPA and require ENT assessment.

Mononeuritis multiplexRed flag

Painful, asymmetric, stepwise motor or sensory deficits such as foot drop indicate nerve infarction and are organ-threatening even when creatinine is normal.

Ocular or orbital threatRed flag

Scleritis, visual change, proptosis or painful ophthalmoplegia may threaten sight and needs same-day ophthalmology and vasculitis-team review.

Drug or cocaine exposure

Hydralazine, propylthiouracil and levamisole-adulterated cocaine can produce complex ANCA phenotypes; a non-judgemental medicine and substance history is diagnostic.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Urinalysis, microscopy, ACR and PCRFirst step
Why
Identify glomerular blood, casts and protein and establish a baseline for renal response.
Interpretation and limitations
Dysmorphic red cells or casts support active GN; haematuria can persist from damage, so interpret later changes with creatinine and protein trend.
02
Serial creatinine, electrolytes and urine output
Why
Measure the rate and physiological consequences of filtration loss.
Interpretation and limitations
Rapid change, potassium, acidosis and fluid overload set urgency; a normal result today does not exclude early vasculitis if urine is active.
03
PR3-ANCA and MPO-ANCA immunoassay
Why
Support diagnosis and characterise a relapse-associated phenotype.
Interpretation and limitations
A compatible high-specificity result is useful, but positive does not equal active vasculitis and negative does not exclude biopsy-proven pauci-immune GN.
04
Anti-GBM antibody
Why
Detect double-positive pulmonary–renal disease requiring an anti-GBM plasma-exchange pathway.
Interpretation and limitations
Always request in severe crescentic GN; dual positivity changes both immediate treatment and later maintenance planning.
05
Full blood count, CRP and infection screen
Why
Assess anaemia, eosinophilia, inflammation and infection before immunosuppression.
Interpretation and limitations
CRP and constitutional symptoms cannot separate vasculitis from infection; culture and image a suspected source before treatment when stability permits.
06
Chest imaging and respiratory assessment
Why
Find nodules, cavities, infiltrates, airway stenosis or alveolar haemorrhage.
Interpretation and limitations
Radiology is not specific; bronchoscopy may help distinguish haemorrhage and infection when respiratory and critical-care teams judge it safe.
07
Kidney biopsy
Why
Confirm pauci-immune necrotising crescentic GN and quantify normal glomeruli, active lesions and scar.
Interpretation and limitations
Activity supports potential reversibility, while extensive global sclerosis and interstitial fibrosis temper renal expectations without negating extra-renal treatment needs.
08
Pre-immunosuppression safety tests
Why
Establish hepatitis, tuberculosis, immunoglobulin, vaccination, pregnancy and fertility baselines and infection prophylaxis needs.
Interpretation and limitations
Collect promptly without creating avoidable treatment delay; abnormal findings shape agent choice and specialist risk mitigation.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Infection-related glomerulonephritis

Fever, murmur, prosthetic material, positive cultures or a deep source favour infection; endocarditis may also produce ANCA, making microbiology essential before immunosuppression.

Anti-GBM disease

Pulmonary–renal disease occurs in both, but circulating anti-GBM antibody and linear glomerular IgG identify anti-GBM disease; some patients are double-positive.

Lupus or immune-complex nephritis

Low complement, ANA or dsDNA activity and granular full-house deposits favour lupus, whereas ANCA disease is typically pauci-immune on biopsy.

Thrombotic microangiopathy

Thrombocytopenia, schistocytes and biochemical haemolysis suggest small-vessel thrombosis rather than primary necrotising vasculitis, although severe hypertension and overlapping renal injury can blur the picture.

Additional chapter-specific clues

Infection mimic

Fever, murmur, prosthetic material, positive cultures or a deep source can produce ANCA and GN; immunosuppression before source evaluation can cause major harm.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Suspected renal AAVSecure diagnosis at emergency speedFirst stepAKI or falling eGFR accompanies active glomerular urine findings with or without systemic vasculitic features.

1Admit according to organ threat, assess lungs, nerves, eyes, ENT, skin and cardiovascular state, and treat hyperkalaemia, acidosis, sepsis or respiratory failure immediately.
2Send PR3, MPO, anti-GBM, complement, ANA, cultures and focused infection tests, obtain chest imaging and review medicines and cocaine exposure.
3Arrange urgent kidney biopsy when safe and hold a renal–rheumatology treatment discussion; do not let a negative ANCA delay biopsy in a convincing syndrome.

02Organ-threatening inductionSuppress inflammation and protect against treatmentBiopsy or compelling clinicopathological evidence shows active GPA or MPA threatening kidney, lung, nerve, eye or another organ.

1Select rituximab or intravenous pulsed cyclophosphamide with the vasculitis team, accounting for relapse, fertility, age, infection, prior exposure, malignancy and access.
2Pair induction with the agreed reduced-dose glucocorticoid regimen or eligible avacopan strategy, documenting the taper, response targets and rescue plan from the outset.
3Provide Pneumocystis prophylaxis, vaccination and infection advice, gastric and bone protection where indicated, blood-count monitoring and reproductive counselling.

03Possible alveolar haemorrhageSeparate haemorrhage, infection and oedemaHypoxia, new diffuse lung shadowing or falling haemoglobin develops during suspected AAV.

1EscalationEscalate oxygenation and critical-care support, assess blood loss and fluid state, and obtain microbiology because haemorrhage and infection can coexist.
2Use CT and bronchoscopy selectively with respiratory specialists, while checking anti-GBM antibody and reviewing anticoagulants or bleeding contributors.
3DefinitiveGive definitive vasculitis induction promptly; consider plasma exchange only through senior specialist criteria for selected hypoxaemic haemorrhage, extreme renal risk or anti-GBM overlap.

04MaintenancePrevent relapse without indefinite toxicityClinical remission follows rituximab- or cyclophosphamide-based induction.

1PreferredAlternativeTransition to scheduled rituximab as the preferred BSR maintenance option, or an appropriate alternative when contraindicated, ensuring induction exposure is not accidentally continued.
2Plan approximately 24–48 months according to PR3 phenotype, prior relapse, organ damage, infection risk, immunoglobulins and the person's preferences.
3Monitor symptoms, urine and kidney function rather than treating ANCA rise alone, and investigate infection, chronic damage and medicine toxicity before labelling relapse.

Key medicines and prescribing safety5 treatments · regimens, roles and cautions

B-cell depletion induces GPA or MPA remission and is the preferred current BSR maintenance option after induction.

Rituximab

Induction and maintenance use a specialist intravenous protocol with premedication, screening and scheduled re-dosing.

Infusion reaction, hepatitis B reactivation, hypogammaglobulinaemia, late neutropenia and serious infection require screening, immunoglobulin review and vaccine planning.

Provides rapid remission induction for organ- or life-threatening GPA or MPA when selected over rituximab.

Intravenous cyclophosphamide

Pulse dose and interval follow the vasculitis protocol with reductions for age, eGFR, cytopenia and cumulative exposure.

Myelosuppression, sepsis, infertility, teratogenicity, bladder toxicity and later malignancy require blood counts, hydration, contraception and fertility discussion.

Rapidly controls vascular inflammation while rituximab or cyclophosphamide takes effect.

Glucocorticoid

Use the specialist reduced-exposure induction schedule with any intravenous pulses and oral taper specified from day one.

Infection, diabetes, psychiatric effects, hypertension, gastrointestinal and bone harm increase with exposure; failure to taper should prompt disease and adherence review.

C5a-receptor blockade can substantially reduce glucocorticoid exposure during active GPA or MPA induction.

Avacopan

The usual licensed adult regimen is 30 mg orally twice daily with food under specialist criteria.

Use with rituximab or cyclophosphamide, not as sole induction; monitor liver tests, infection and major CYP3A4 interactions and follow local duration policy.

Prevents Pneumocystis pneumonia and may reduce some bacterial infections during intensive induction.

Pneumocystis prophylaxis

Use renal-adjusted co-trimoxazole or a protocol alternative throughout the defined high-risk immunosuppression period.

Monitor potassium, creatinine and blood count and check sulfonamide allergy and interactions; prophylactic dosing is not vasculitis relapse treatment.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Rapidly progressive kidney failure

Extensive necrosis and crescents can destroy filtration over days to weeks, leaving dialysis dependence when active injury is not controlled before chronic scarring develops.

Pulmonary haemorrhage

Alveolar capillary injury may cause hypoxaemia, falling haemoglobin and diffuse opacities without visible haemoptysis, creating a critical pulmonary–renal emergency.

Neurological and sensory loss

Nerve infarction can produce painful mononeuritis and permanent weakness, while ocular, orbital or upper-airway inflammation may threaten sight, hearing or airway patency.

Relapsing chronic damage

Recurrent vasculitis can accumulate renal and extrarenal scarring; persistent haematuria alone may instead reflect old glomerular damage and requires contextual interpretation.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Track creatinine, eGFR, urine PCR and microscopic or dipstick blood against the pre-treatment trajectory; recovery and persistent damage may evolve at different rates.
At every review actively ask about breathlessness, haemoptysis, ENT change, red eye, neuropathic deficit, rash, constitutional symptoms and infection exposure.
During induction monitor full blood count, liver profile, immunoglobulins, glucose and regimen-specific toxicity at protocol intervals, with lower thresholds during renal impairment.
Before each rituximab course review infection, vaccination timing, immunoglobulin trend and hepatitis risk rather than re-dosing solely from the calendar.
Use ANCA and B-cell results as supporting data; do not escalate immunotherapy for an isolated rise without clinical evidence of active disease.
Reassess cardiovascular, bone, fertility, malignancy, mood and work impact because survival with AAV leaves substantial cumulative disease and treatment burden.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Pauci-immune describes staining

The term means little immunoglobulin or complement on biopsy immunofluorescence; it does not mean the inflammatory lesion is mild or immunologically inactive.

Normal creatinine can conceal activity

A person with substantial renal reserve may have active glomerular haematuria before serum creatinine rises, making routine urine surveillance decisive.

Phenotype beats acronym

PR3 and MPO help with probability and relapse planning, but organ involvement and biopsy activity determine immediate threat more reliably than GPA or MPA labels alone.

Haematuria can outlast vasculitis

Persistent microscopic blood after treatment may come from scarred glomeruli; worsening proteinuria, casts and eGFR plus systemic features are more persuasive for renal relapse.

Dialysis changes the balance

Renal-limited disease that remains dialysis-dependent has lower relapse but high infection risk, so maintenance may be reduced only after individual extra-renal and recovery review.

Upper-airway damage is not always activity

Crusting, hearing loss and stenosis can reflect infection or fixed damage; examination, imaging and specialist ENT assessment prevent unnecessary immunosuppression.

11Common pitfallsFrequent interpretation and management errors.

01
Excluding pauci-immune glomerulonephritis because PR3- and MPO-ANCA are negative.
02
Calling fever and a positive ANCA vasculitis before obtaining cultures and excluding endocarditis.
03
Using glucocorticoid alone for organ-threatening GPA or MPA without definitive induction therapy.
04
Giving routine plasma exchange to every patient with severe renal impairment without specialist selection.
05
Treating an isolated ANCA rise as relapse while ignoring infection, chronic damage and the clinical examination.
06
Omitting Pneumocystis, vaccination, fertility and immunoglobulin safeguards from the induction plan.