Vasculitic neuropathy and pulmonary-renal syndrome

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

Pulmonary haemorrhage can be clinically quiet until gas exchange deteriorates. Record serial oxygen need, respiratory rate and haemoglobin rather than waiting for visible haemoptysis. Chest radiograph gives speed; high-resolution CT better defines bilateral ground-glass and air-space change but is not specific. Bronchoscopy is useful when the airway is secure: sequentially more haemorrhagic lavage and haemosiderin-laden macrophages support diffuse alveolar haemorrhage, while microbiology tests competing infection.

The renal bedside data determine pace. Measure urine output, pressure and volume status and examine fresh urine for erythrocytes and casts. Request FBC, serial creatinine and electrolytes, albumin, CRP or ESR, coagulation, blood gas and quantified protein. Hyperkalaemia, acidosis, pulmonary oedema and uraemia are independent dialysis indications. Normal-sized kidneys and a short history suggest potentially reversible inflammation but do not predict response without biopsy.

Kidney biopsy is the preferred accessible organ in most pulmonary-renal presentations. Pauci-immune necrotising crescents support ANCA-associated disease, linear IgG supports anti-GBM disease and granular immunoglobulin or complement redirects toward lupus, cryoglobulinaemia or infection-related glomerulonephritis. Obtain tissue within twenty-four hours when feasible, but if alveolar haemorrhage and anti-GBM disease are strongly suspected, KDIGO advises starting treatment before confirmation.

For GPA or MPA, current BSR treatment combines glucocorticoid or avacopan with rituximab or intravenous pulsed cyclophosphamide. Prednisolone commonly begins at 50–75 mg daily or 1 mg/kg to a maximum of 75 mg in organ-threatening disease and follows a reduced taper to 5 mg by four to five months. Rituximab is preferred for relapse; fertility, cumulative cyclophosphamide, infection, renal severity and previous biologic exposure shape induction choice.

Plasma exchange ownership must be explicit. In ANCA disease, consider adjunctive exchange for severe renal involvement with creatinine above 300 micromol/L after weighing infection and bleeding risk; do not add it routinely for pulmonary haemorrhage alone. In anti-GBM disease, daily exchange of 40–50 mL/kg ideal body weight is combined with cyclophosphamide and glucocorticoid until antibodies are undetectable, except selected dialysis-dependent patients without lung haemorrhage and with irreversible biopsy damage.

Key points

Vasculitic neuropathy classically begins as acute or subacute painful, asymmetric sensory or sensorimotor loss affecting separate named nerves; mononeuritis multiplex can later look confluent and symmetrical.
Map individual movements, reflexes and sensory territories, then use nerve-conduction studies and EMG to demonstrate a multifocal axonal process and select a still-active nerve for biopsy.
Pathologically definite vasculitic neuropathy requires vessel-wall inflammation with vascular damage; a combined targeted nerve and muscle biopsy increases information but a negative sample cannot exclude patchy disease.
Pulmonary-renal syndrome means diffuse alveolar haemorrhage or pulmonary capillaritis with glomerulonephritis; ANCA vasculitis and anti-GBM disease are urgent causes, but lupus, cryoglobulinaemia, infection and medicines also occur.
Haemoptysis is not required for alveolar haemorrhage. Suspect it from falling haemoglobin, hypoxaemia, diffuse new opacity and progressively bloodier bronchoalveolar lavage after infection and cardiogenic causes are considered.
Send PR3-ANCA, MPO-ANCA and anti-GBM urgently with ANA, complement, cryoglobulins, hepatitis and cultures, but do not diagnose or exclude active vasculitis from one antibody result.

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

ANCA-associated small-vessel disease

Granulomatosis with polyangiitis and microscopic polyangiitis commonly combine pauci-immune glomerulonephritis with capillaritis, while eosinophilic disease frequently produces painful vasculitic neuropathy.

Anti-GBM autoantibody disease

Antibodies against the alpha-3 chain of type IV collagen attack glomerular and alveolar basement membranes, causing rapidly progressive nephritis with or without lung haemorrhage.

Immune-complex and secondary vasculitis

Lupus, cryoglobulinaemia, IgA vasculitis, infection, medicines and malignancy can injure glomerular, pulmonary and vasa-nervorum vessels through immune deposits or secondary inflammation.

Non-systemic vasculitic neuropathy

Vessel inflammation may remain confined to peripheral nerves and muscle after a careful search excludes another organ, infection, connective-tissue or clonal driver.

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

1
Vasa-nervorum infarction
Inflammation narrows and thromboses the small arteries supplying peripheral nerves, producing patchy axonal loss that begins painfully and asymmetrically before deficits converge.
2
Pulmonary capillary rupture
Alveolar capillaritis disrupts the blood-gas barrier, filling airspaces with erythrocytes and causing diffusion failure, anaemia and radiographic opacities.
3
Crescentic glomerular injury
Necrotising capillary-wall damage lets fibrin enter Bowman's space, driving crescent formation, haematuria, protein leakage and rapid loss of filtration.
4
Antibody-pattern distinction
ANCA activates primed neutrophils with few immune deposits, anti-GBM antibody binds linearly to basement membrane, and immune complexes create granular deposits with complement activation.
5
Irreversibility with delay
Alveolar blood can clear and inflamed glomeruli may recover, but established glomerular sclerosis and infarcted axons cannot be restored by later immunosuppression.

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

Mononeuritis multiplex

Severe burning pain followed by sensory loss and weakness in one named nerve, then another non-contiguous nerve, is the classic evolving vasculitic pattern.

Diffuse alveolar haemorrhageRed flag

New bilateral opacity, hypoxaemia and falling haemoglobin with or without haemoptysis requires urgent capillaritis and bleeding assessment.

Rapidly progressive glomerulonephritisRed flag

Creatinine rising over days to weeks with dysmorphic haematuria, casts and proteinuria indicates destructive glomerular inflammation until proved otherwise.

Anti-GBM phenotypeRed flag

Pulmonary haemorrhage plus severe crescentic nephritis, often after smoking or hydrocarbon exposure, should trigger immediate anti-GBM testing and treatment consideration.

Red flags requiring action

Hypoxaemia, increasing work of breathing, falling haemoglobin or diffuse new ground-glass or air-space opacity suggests alveolar haemorrhage even when haemoptysis is absent.
Oliguria, rapidly rising creatinine, severe hypertension, hyperkalaemia, acidosis or pulmonary oedema requires immediate nephrology and renal-replacement assessment.
Anti-GBM disease is suspected when alveolar haemorrhage accompanies rapidly progressive glomerulonephritis; treatment must begin before confirmation if waiting would cause organ loss.
New foot drop, wrist drop, asymmetric weakness, sphincter symptoms or rapidly ascending deficit requires urgent localisation and exclusion of cord, cauda equina and compressive disease.
Fever, shock, murmur, indwelling-device infection or cavitating pneumonia can mimic vasculitis; obtain cultures and deliver sepsis treatment without postponing respiratory support.

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
Immediate oxygenation, haemoglobin and urine assessmentFirst step
Why
Grade respiratory and renal threat before aetiological results return.
Interpretation and limitations
Trend oxygen requirement, arterial gas, haemoglobin, urine output, sediment, creatinine, potassium and acid-base status; worsening physiology overrides a superficially stable single value.
02
Urgent PR3, MPO and anti-GBM assays
Why
Separate major antibody-associated pulmonary-renal pathways rapidly.
Interpretation and limitations
Positive anti-GBM with a compatible syndrome supports immediate exchange-based treatment; ANCA specificity supports AAV but neither titre nor negativity replaces tissue and clinical probability.
03
Reference kidney biopsy
Why
Define deposit pattern, active crescents and irreversible scarring.
Interpretation and limitations
Request light microscopy, immunofluorescence and electron microscopy: pauci-immune, linear and granular patterns direct fundamentally different induction and maintenance plans.
04
High-resolution chest CT and bronchoscopy
Why
Characterise alveolar filling and test haemorrhage against infection and oedema.
Interpretation and limitations
Diffuse ground-glass change is non-specific; sequentially bloodier lavage supports haemorrhage, and lavage culture is essential before intensifying immunosuppression.
05
Nerve-conduction studies and EMG
Why
Demonstrate multifocal axonal injury, exclude primary demyelination and select biopsy tissue.
Interpretation and limitations
Unequal reduced sensory and motor amplitudes with denervation across separate nerves supports ischaemic axonopathy; early studies may require repeat testing.
06
Infection and immune-complex screen
Why
Identify mimics and secondary causes before disease-specific immunosuppression.
Interpretation and limitations
Blood cultures, hepatitis and HIV tests, ANA, dsDNA, complement, cryoglobulins and immunofixation are selected and interpreted with rash, fever, complement and organ phenotype.

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

Sepsis and endocarditis

Infection can cause pulmonary infiltrates, immune-complex nephritis, embolic neuropathy and positive ANCA; cultures and source assessment are essential before attributing every feature to autoimmunity.

Cardiogenic oedema or acute lung injury

Pulmonary oedema, aspiration and ARDS produce bilateral opacity and hypoxaemia but lack the integrated haemoglobin, bronchoscopy, urinary and serological pattern of capillaritis.

Pulmonary embolism and anticoagulant bleeding

Embolism causes acute hypoxaemia and haemoptysis, while anticoagulation can create alveolar bleeding; neither independently explains an active glomerular sediment.

Diabetic or compressive neuropathy

Length-dependent symmetrical sensory loss, root pain or entrapment follows different anatomy from abrupt painful deficits affecting separate named nerves.

Thrombotic microangiopathy

Anaemia, thrombocytopenia, schistocytes, hypertension and kidney injury can accompany systemic illness but indicate microvascular thrombosis rather than primary crescentic glomerulonephritis.

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

01Immediate stabilisationProtect lungs and kidneysFirst stepHypoxaemia, alveolar opacity and active glomerular urine occur together.

1Admit to a monitored setting, support oxygenation and circulation and treat hyperkalaemia, acidosis, overload and infection or major bleeding immediately.
2Draw antibody, complement, viral and culture samples before exchange or immunosuppression when this does not delay organ rescue.
3Arrange CT, bronchoscopy when safe and kidney biopsy within 24 hours, coordinating respiratory, nephrology, rheumatology and critical care.

02ANCA first-line inductionStop pauci-immune capillaritisFirst lineBiopsy and phenotype support organ-threatening GPA or MPA.

1Begin glucocorticoid using the reduced BSR taper or an avacopan-containing specialist plan and provide infection, bone, gastric and metabolic safeguards.
2Select intravenous pulsed cyclophosphamide or licensed-dose rituximab; prefer rituximab for relapsing disease and individualise fertility and severe-renal considerations.
3Consider plasma exchange for creatinine above 300 micromol/L after risk assessment, but do not use it routinely for pulmonary haemorrhage without severe renal disease.

03Anti-GBM emergency standardRemove antibody and stop productionAnti-GBM disease is strongly suspected or confirmed with pulmonary or salvageable renal injury.

1Start high-dose glucocorticoid and daily plasma exchange without waiting for biopsy when clinical suspicion is high and delay threatens recovery.
2Add oral cyclophosphamide under the anti-GBM protocol and exchange 40–50 mL/kg ideal body weight until circulating antibody becomes undetectable.
3Use biopsy prognosis to identify selected dialysis-dependent patients without alveolar haemorrhage for whom treatment harm may outweigh unlikely renal recovery.

04Neuropathy routeConfirm activity and preserve functionPainful asymmetric sensory or motor deficits evolve with or without another systemic organ.

1Exclude compression and central disease, map named nerves and obtain urgent nerve-conduction studies, EMG and systemic vasculitis testing.
2Use a safer involved organ for biopsy when available; otherwise arrange targeted nerve and adjacent muscle biopsy before prolonged immunosuppression when feasible.
3Treat the defined systemic vasculitis or severe non-systemic vasculitic neuropathy and begin orthosis, analgesia, foot protection and rehabilitation immediately.

Key medicines and prescribing safety6 treatments · regimens, roles and cautions

One of two BSR-recommended induction options for active GPA or MPA and the preferred option in active relapsing disease; other vasculitic-neuropathy causes require their own evidence.

Rituximab for GPA or MPA induction

Give 375 mg/m2 intravenously once weekly for 4 weeks with glucocorticoid under the licensed adult GPA and MPA induction regimen; use infusion premedication and specialist administration.

Screen HBsAg and anti-HBc, active infection, immunoglobulins and vaccines, monitor infusion reaction and delayed neutropenia and give the alert card. Pregnancy normally requires benefit-risk specialist use; product information advises effective contraception for 12 months after treatment.

Licensed C5a-receptor blockade that can replace much oral glucocorticoid exposure in selected AAV induction; it is not standalone treatment for pulmonary-renal disease or anti-GBM disease.

Avacopan

Take 30 mg orally twice daily with food alongside a rituximab- or cyclophosphamide-based regimen for severe active GPA or MPA; specialist treatment is generally evaluated within the licensed 52-week evidence period. Reduce to 30 mg once daily with a strong CYP3A4 inhibitor.

Check liver tests before treatment and every 4 weeks for the first 6 months, screen hepatitis B and active infection and avoid strong CYP3A4 inducers. Stop for serious hepatic injury or angioedema. Avoid pregnancy and use effective contraception during treatment and for 2 weeks afterwards; decide breastfeeding individually.

A BSR-recommended induction alternative to rituximab for organ-threatening GPA or MPA; it is used within a named vasculitis protocol rather than as an unadjusted fixed dose.

Intravenous pulsed cyclophosphamide for AAV

A standard specialist CYCLOPS schedule gives 15 mg/kg intravenously at weeks 0, 2 and 4, then every 3 weeks to remission over 3 to 6 months, with dose reductions for age, kidney function and cytopenia.

Specialist use is off-label for many product presentations. Check FBC before each pulse, renal function, urinalysis, infection and cumulative exposure; provide hydration and uroprotection as protocolled and address gonadal preservation. Avoid pregnancy and breastfeeding and follow product-specific post-treatment contraception intervals.

Suppresses new anti-GBM antibody production; the regimen differs from pulsed ANCA induction and follows KDIGO specialist practice rather than a generic vasculitis prescription.

Anti-GBM oral cyclophosphamide

Give 2 to 3 mg/kg orally once daily, usually reduced to 2 mg/kg above age 55 and adjusted for kidney function and leucopenia, for approximately 2 to 3 months with plasma exchange and glucocorticoid.

Monitor FBC several times early, renal and liver function, haematuria and infection and provide Pneumocystis prevention when appropriate. Gonadal, bladder, marrow and malignancy toxicity is cumulative; cyclophosphamide is contraindicated in pregnancy in relevant UK product information and breastfeeding must stop.

Provides rapid capillaritis control while rituximab, cyclophosphamide and plasma exchange address the causal immune process; precise pulse use depends on infection and severity.

Methylprednisolone then prednisolone

For critical pulmonary-renal inflammation, specialists may give methylprednisolone 500 to 1000 mg intravenously once daily for up to 3 days, then oral prednisolone about 1 mg/kg daily within the disease-specific reduced taper.

Culture and treat infection, monitor glucose, pressure, mental state, fluid, gastrointestinal and bone risk and provide adrenal and steroid-card advice. Minimise cumulative exposure; prednisolone is generally the preferred systemic steroid in pregnancy when organ threat requires it, under specialist care.

The reference antibody-removal component of anti-GBM treatment, started immediately with glucocorticoid when suspicion is high and combined with cyclophosphamide.

Anti-GBM plasma exchange

Exchange 40 to 50 mL/kg ideal body weight daily against 5% albumin, adding fresh frozen plasma at the end when alveolar haemorrhage or recent kidney biopsy increases bleeding risk; continue until anti-GBM antibody is undetectable.

Coordinate line infection, citrate hypocalcaemia, pressure, fibrinogen, coagulation and blood-component reactions. Obtain serology first if safe and schedule removable immunosuppressants after exchange; apheresis cannot suppress fresh antibody production alone.

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

Respiratory failure

Continuing alveolar bleeding causes refractory hypoxaemia, airway obstruction by clot, ventilation requirement, secondary infection and death.

Kidney failure

Severe crescentic disease can require acute dialysis and leave chronic kidney disease, transplantation need, anaemia and cardiovascular risk despite immunological remission.

Fixed motor disability

Axonal infarction may leave foot or wrist drop, sensory ataxia, neuropathic pain, ulcer risk and falls requiring orthoses and prolonged rehabilitation.

Relapse and cumulative damage

ANCA-associated disease can recur in different organs; repeated inflammatory episodes and treatment exposure accumulate airway, renal, neurological and vascular impairment.

Immunosuppressive toxicity

Glucocorticoid, cyclophosphamide and rituximab can cause severe infection, marrow suppression, infertility, bladder injury, malignancy, hypogammaglobulinaemia and fetal harm.

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

During alveolar haemorrhage trend oxygen requirement, respiratory rate, blood gases, haemoglobin, platelet and coagulation status and radiographic clearing rather than haemoptysis alone.
Measure urine output, creatinine, eGFR, potassium, bicarbonate, pressure, urine sediment and protein daily in unstable glomerulonephritis and reassess dialysis indications repeatedly.
Repeat objective named-muscle power, sensory maps, reflexes, gait and functional tasks; new nerve-territory loss indicates activity even when pain fluctuates.
Follow anti-GBM antibody during exchange until undetectable and confirm continued negativity; dual ANCA-positive disease then needs an AAV maintenance plan.

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

Haemoptysis may be absent

Alveolar blood can remain distal or the patient may be too breathless to expectorate, making serial haemoglobin and oxygenation more dependable clues.

Biopsy patterns own treatment

Pauci-immune, linear and granular immunofluorescence distinguish ANCA, anti-GBM and immune-complex pathways that cannot safely share one protocol.

Plasma exchange has two rules

It is standard antibody removal in anti-GBM disease but selective, not routine, adjunctive treatment in modern ANCA-associated vasculitis.

Double positivity predicts two phases

ANCA plus anti-GBM disease needs aggressive anti-GBM-style early treatment and AAV-style maintenance because later relapse resembles ANCA disease.

11Common pitfallsFrequent interpretation and management errors.

01
Waiting for haemoptysis before considering diffuse alveolar haemorrhage in a hypoxaemic anaemic patient with new bilateral opacity.
02
Starting immunosuppression for a positive ANCA without cultures, tissue strategy or assessment for endocarditis and other infection.
03
Using a negative nerve biopsy to exclude a highly patchy vasculitic process without reviewing target selection and other-organ evidence.
04
Applying the anti-GBM plasma-exchange rule indiscriminately to ANCA pulmonary haemorrhage without severe kidney involvement.