Anti-GBM disease

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

Anti-GBM disease is a rare but highly destructive small-vessel autoimmune disorder. Antibody binds a normally hidden basement-membrane epitope, activating complement and inflammatory injury. Glomeruli can be lost over days; alveolar capillary damage may cause fatal haemorrhage. Diagnosis and treatment must therefore proceed rapidly in parallel rather than waiting sequentially for each test.

Serum antibody testing is fast and strongly supportive, but a negative result does not absolutely exclude tissue-bound, low-level or unusual antibody. Biopsy defines activity, the proportion of normal glomeruli and chronic damage, and helps judge renal reversibility. Immunofluorescence showing linear IgG along the GBM is the classic discriminator. In an unstable pulmonary–renal presentation, biopsy logistics must not postpone senior treatment decisions.

Standard specialist therapy stops antibody production with glucocorticoid plus cyclophosphamide and removes existing antibody by plasma exchange. Infection screening, blood-count surveillance, fertility and bladder protection, Pneumocystis prophylaxis and renal dose adjustments accompany induction. Prognosis depends heavily on presenting creatinine, need for dialysis, biopsy chronicity and pulmonary involvement.

Key points

Anti-GBM disease is caused by pathogenic antibodies against the alpha-3 chain of type IV collagen in glomerular and alveolar basement membranes.
It typically produces rapidly progressive crescentic glomerulonephritis, pulmonary alveolar haemorrhage or both; isolated renal disease is common enough that absent lung symptoms do not reassure.
Visible haemoptysis is not required for alveolar haemorrhage; hypoxia, new bilateral opacities and a falling haemoglobin may be the only bedside cluster.
Request serum anti-GBM antibody urgently alongside ANCA because a clinically important double-positive group has both anti-GBM severity and later vasculitis relapse risk.
Kidney biopsy usually shows necrotising crescentic GN with strong linear IgG staining, distinguishing it from granular immune-complex and pauci-immune patterns.
Treatment is time-critical and generally combines plasma exchange, glucocorticoids and cyclophosphamide under a specialist protocol while pulmonary and renal complications are supported.
Plasma exchange removes circulating antibody and is usually continued until antibody becomes undetectable, with schedule and stopping criteria set by the renal centre.
Established dialysis dependence, extensive irreversible crescents and no pulmonary haemorrhage may make aggressive treatment futile, but this is a consultant decision requiring biopsy and trajectory.
Anti-GBM disease is usually monophasic once antibody is eradicated; prolonged maintenance immunosuppression is not routine unless the patient is also ANCA-positive.
Kidney transplantation is deferred until anti-GBM antibodies have remained undetectable for at least six months, with timing confirmed by the transplant service.
Smoking and hydrocarbon exposure can precipitate lung haemorrhage and should be addressed urgently without implying that exposure is required for diagnosis.

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

Anti-basement-membrane autoimmunity

Pathogenic autoantibodies target the alpha-3 chain of type IV collagen in glomerular and alveolar basement membranes, often without an identifiable initiating illness.

Pulmonary exposure modifiers

Smoking and hydrocarbon exposure can increase alveolar basement-membrane vulnerability and precipitate lung haemorrhage, although neither exposure is required for renal or pulmonary disease.

ANCA overlap

A clinically important subgroup has both anti-GBM antibodies and ANCA, combining severe initial glomerular injury with a greater later risk of vasculitis relapse.

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

1
Autoantibody binding
Circulating antibodies bind exposed collagen epitopes along glomerular and, in some patients, alveolar capillary basement membranes.
2
Linear inflammatory injury
Antibody and complement recruitment creates intense capillary inflammation, with strong linear IgG staining distinguishing this pattern on renal biopsy.
3
Necrosis and crescents
Severe glomerular inflammation produces necrosis and crescents, so viable glomeruli can be lost over days without prompt treatment.
4
Alveolar bleeding
Parallel injury to lung capillaries permits diffuse blood leakage into alveoli, impairing gas exchange even when haemoptysis is absent.

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

Rapid renal declineRed flag

Creatinine rising over days to weeks, glomerular haematuria, red-cell casts, proteinuria and oliguria is the characteristic renal emergency.

Occult alveolar haemorrhageRed flag

New hypoxia, diffuse alveolar shadowing and falling haemoglobin can indicate pulmonary bleeding even with no visible haemoptysis.

Pulmonary–renal syndrome

The combination of breathlessness or haemoptysis with an active nephritic sediment sharply raises anti-GBM and ANCA-associated vasculitis in the differential.

Isolated lung disease

Rare pulmonary-predominant disease may occur with preserved creatinine, particularly after smoking or inhalational exposure; urinalysis and serial renal tests remain necessary.

Dialysis-threatening presentationRed flag

Anuria, refractory potassium or acidosis, uraemic features and pulmonary oedema require immediate renal replacement assessment alongside disease-specific therapy.

Double-positive phenotype

Older age or systemic vasculitic features with both anti-GBM antibody and MPO- or PR3-ANCA predicts a need for later relapse-prevention planning.

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
Urgent serum anti-GBM antibodyFirst step
Why
Detect the disease-defining circulating autoantibody and establish a baseline for clearance.
Interpretation and limitations
A positive compatible result supports immediate treatment; repeat or tissue assessment may be needed when suspicion remains high despite a negative assay.
02
PR3-ANCA and MPO-ANCA
Why
Identify double-positive disease and inform long-term relapse strategy.
Interpretation and limitations
ANCA does not replace anti-GBM testing or biopsy; dual positivity combines the acute anti-GBM emergency with future AAV behaviour.
03
Urinalysis, microscopy and PCR
Why
Confirm glomerular bleeding and quantify protein loss.
Interpretation and limitations
Dysmorphic red cells and red-cell casts support crescentic GN; a bland result should prompt reconsideration but cannot stabilise a critically ill patient by itself.
04
Creatinine, electrolytes and blood gas
Why
Measure renal trajectory and detect dialysis-threatening hyperkalaemia or acidosis.
Interpretation and limitations
The rate of change and clinical complications matter more than an isolated creatinine; involve critical care for combined respiratory and metabolic failure.
05
Full blood count, coagulation and haemolysis screen
Why
Quantify blood loss, procedural safety and alternative causes of anaemia.
Interpretation and limitations
A falling haemoglobin without external bleeding supports occult alveolar loss; correct coagulopathy before biopsy when clinically possible.
06
Chest radiograph or CT
Why
Assess diffuse alveolar opacities and competing infection or oedema.
Interpretation and limitations
Imaging is not specific; rapidly changing bilateral air-space shadowing with anaemia and GN strengthens pulmonary haemorrhage.
07
Kidney biopsy with immunofluorescence
Why
Confirm crescentic injury, linear IgG and the amount of salvageable renal tissue.
Interpretation and limitations
The percentages of crescents, normal glomeruli and interstitial fibrosis help frame recovery; biopsy should be expedited but performed safely.
08
Infection and immunosuppression screen
Why
Find active infection and establish hepatitis, tuberculosis, vaccination and reproductive baselines before induction.
Interpretation and limitations
Do not delay emergency therapy unnecessarily; use simultaneous screening and prophylaxis with renal, infection and pharmacy advice.

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

ANCA-associated vasculitis

ENT, skin or nerve disease and pauci-immune biopsy favour ANCA vasculitis, while anti-GBM antibody and linear IgG support anti-GBM disease; overlap testing is important.

Lupus nephritis

Systemic lupus features, low complement and granular immune-complex deposits favour lupus rather than linear anti-basement-membrane staining.

Infection-related glomerulonephritis

Positive cultures, endocarditis features or an active deep infection with granular immune deposits supports infection-related disease, in which blind immunosuppression may be harmful.

Pulmonary oedema or infection

Cardiogenic congestion and pneumonia can mimic alveolar haemorrhage; falling haemoglobin, diffuse bleeding on respiratory assessment and the glomerular urine pattern increase pulmonary–renal probability.

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

01Pulmonary–renal emergencyDiagnose and treat in parallelFirst stepActive GN accompanies haemoptysis, hypoxia, diffuse opacities or otherwise unexplained falling haemoglobin.

1Admit, support airway and oxygenation, stop avoidable anticoagulants after senior risk review, and treat life-threatening hyperkalaemia, acidosis or pulmonary oedema.
2Send anti-GBM antibody, ANCA, cultures and baseline immune-treatment tests immediately and arrange urgent renal biopsy when safe.
3With senior nephrology, begin the centre anti-GBM protocol when suspicion is strong, coordinating plasma exchange, glucocorticoid, cyclophosphamide and critical-care support.

02InductionRemove antibody and stop productionSerology or biopsy supports active treatable anti-GBM disease.

1Use plasma exchange at the renal centre's prescribed volume and replacement schedule, monitoring fibrinogen, calcium, access and haemodynamic complications.
2Administer glucocorticoid and cyclophosphamide according to age, kidney function and severity, with antiemetic, gastric, bone, fertility, bladder and infection safeguards.
3Follow anti-GBM antibody serially and continue or stop exchange using specialist criteria, while judging kidney and lung response independently.

03Low recovery potentialIndividualise treatment limitsThe patient is dialysis-dependent with very advanced histological destruction but has no pulmonary haemorrhage.

1Confirm dialysis need, reliable biopsy chronicity and absence of active lung haemorrhage; exclude a recent trajectory or normal glomeruli suggesting salvageable tissue.
2Discuss potential benefit and substantial treatment toxicity with senior nephrology and the patient, rather than declaring futility from creatinine alone.
3If intensive immunotherapy is not pursued, provide dialysis, symptom, vaccination and transplant-planning care and continue antibody surveillance as advised.

04After remissionSeparate monophasic from relapsing riskAntibody is undetectable and active pulmonary and renal injury has settled.

1Stop induction medicines according to the specialist course and monitor renal recovery, urine findings, infection and late treatment toxicity.
2If ANCA-negative, avoid unnecessary chronic maintenance; if double-positive, transition to an AAV relapse-prevention strategy with rheumatology and nephrology.
3For kidney failure, discuss transplantation only after antibodies have remained undetectable for at least six months and the transplant centre confirms candidacy.

Key medicines and prescribing safety4 treatments · regimens, roles and cautions

Rapidly removes circulating anti-GBM antibody during active renal or pulmonary disease.

Plasma exchange

Exchange volume, frequency, replacement fluid and stopping point follow the specialist renal protocol and antibody trend.

Central access, bleeding, low fibrinogen, hypocalcaemia, hypotension, infection and medicine removal require daily multidisciplinary review.

Suppresses new pathogenic antibody production as part of combined induction treatment.

Cyclophosphamide

Use the centre's oral or intravenous induction regimen adjusted for age, kidney function, blood count and cumulative exposure.

Myelosuppression, infection, infertility, teratogenicity, bladder toxicity and malignancy risk require prophylaxis, contraception, counselling and laboratory monitoring.

Rapidly suppresses inflammatory glomerular and alveolar capillary injury while definitive antibody control takes effect.

Glucocorticoid

Severe disease commonly begins with specialist intravenous methylprednisolone then oral prednisolone and a defined taper.

Screen and monitor infection, glucose, blood pressure, mood, gastrointestinal and bone risk; never use as isolated definitive therapy for active anti-GBM disease.

Reduces opportunistic Pneumocystis pneumonia risk during cyclophosphamide and high-dose glucocorticoid treatment.

Pneumocystis prophylaxis

Use the local renal-adjusted first-line or alternative regimen during substantial combined immunosuppression.

Check sulfonamide allergy, blood count, potassium, renal function and interactions; alternatives have their own haematological and inhalational limitations.

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

Irreversible kidney failure

Extensive crescent formation can rapidly eliminate viable glomeruli, leaving permanent dialysis dependence despite subsequent removal of circulating antibody.

Hypoxaemic respiratory failure

Diffuse alveolar haemorrhage can fill airspaces, causing severe oxygenation failure, acute anaemia and a need for critical respiratory support.

Uraemic and electrolyte emergencies

Abrupt loss of filtration may produce hyperkalaemia, acidosis, fluid overload, pericarditis or encephalopathy alongside the immune disease.

Later vasculitis relapse

Isolated anti-GBM disease is usually monophasic, but double-positive patients retain an ANCA-associated relapse risk requiring longer specialist surveillance.

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

Measure anti-GBM antibody serially using the same laboratory method where possible to guide plasma-exchange duration and confirm sustained negativity.
Track creatinine, urine output, potassium, bicarbonate, fluid state and dialysis requirement daily during the destructive phase.
Follow oxygen need, chest imaging trend and haemoglobin closely because alveolar bleeding can recur without visible haemoptysis.
During plasma exchange monitor access, coagulation, fibrinogen and calcium and review timing of medicines that may be removed by the procedure.
During cyclophosphamide and steroid therapy use protocol blood counts, infection surveillance, glucose, blood pressure and bladder and reproductive safeguards.
After remission check ANCA status, urinalysis and kidney trajectory and maintain longer relapse surveillance for double-positive patients.

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

No haemoptysis does not reassure

A substantial fraction of alveolar haemorrhage presents through hypoxia, diffuse opacities and anaemia before any blood is coughed up.

Linear staining is the signature

Anti-GBM antibody binds evenly along the basement membrane, producing linear IgG rather than granular immune deposits or pauci-immune fluorescence.

Double positivity changes follow-up

The immediate illness behaves like anti-GBM disease, but later relapse behaves more like ANCA vasculitis and usually warrants maintenance planning.

Dialysis is not the sole decision

Initial dialysis dependence predicts poor renal recovery, yet pulmonary haemorrhage remains independently treatable and biopsy may show a subgroup with salvageable glomeruli.

Antibody can be assay-negative

Strong clinical and linear-biopsy evidence can occasionally identify disease when routine circulating-antibody assay is negative or weak, demanding laboratory discussion.

Transplant timing is immunological

Waiting for sustained antibody negativity reduces recurrence risk; the transplant centre also assesses general fitness and the consequences of preceding induction therapy.

11Common pitfallsFrequent interpretation and management errors.

01
Excluding pulmonary haemorrhage because the patient denies haemoptysis.
02
Waiting for every serology result before alerting nephrology to a rapidly progressive pulmonary–renal syndrome.
03
Treating a positive anti-GBM assay without confirming clinical compatibility or considering biopsy and false positivity.
04
Forgetting ANCA testing and missing the long-term relapse implications of double-positive disease.
05
Continuing plasma exchange without monitoring fibrinogen, calcium, access complications and antibody trend.
06
Assuming long-term maintenance immunosuppression is routine for every ANCA-negative monophasic case.