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Pulmonary-renal syndrome: a life threatening but treatable condition
  1. Stephen C West1,
  2. Nishkantha Arulkumaran1,
  3. Philip W Ind2,
  4. Charles D Pusey1
  1. 1Renal Section, Department of Medicine, Imperial College London, Hammersmith Hospital, London, UK
  2. 2Respiratory Section, Department of Medicine, Imperial College London, Hammersmith Hospital, London, UK
  1. Correspondence to Dr Nishkantha Arulkumaran, Renal Section, Department of Medicine, Hammersmith Hospital, 5th Floor Commonwealth Building, Ducane Road, London W12 0NN, UK; nish_arul{at}yahoo.com

Abstract

Pulmonary renal syndrome (PRS) describes the occurrence of renal failure in association with respiratory failure, characterised by autoimmune-mediated rapidly progressive glomerulonephritis (RPGN) and diffuse alveolar haemorrhage (DAH), respectively. PRS is associated with significant morbidity and mortality, and prompt diagnosis and treatment significantly improve outcomes. Prompt diagnosis of PRS requires a high index of suspicion, as clinical features are non-specific, and immunological testing aids the diagnosis in many cases. The diagnostic evaluation of DAH and RPGN is outlined in the context of the important differential diagnoses. The commonest causes of PRS include antineutrophil cytoplasm antibody (ANCA)-associated vasculitis and antiglomerular basement membrane disease. As such, more emphasis has been placed on these two conditions in addition to an overview of the less common causes of PRS. We provide a practical review of the diagnostic evaluation, current treatment strategies and clinical outcomes of PRS for renal, respiratory and general physicians.

  • General Medicine (see Internal Medicine)

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Introduction

The term ‘Pulmonary-Renal Syndrome’ (PRS), as first described by Goodpasture in 1919, is used to describe the occurrence of renal failure in association with respiratory failure, characterised by rapidly progressive glomerulonephritis (RPGN) and diffuse alveolar haemorrhage (DAH) secondary to an underlying autoimmune process.1 Corresponding histological features include glomerular crescents on renal biopsy and pulmonary capillaritis on lung biopsy.2 The most common causes of PRS in adults are antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) and antiglomerular basement membrane (anti-GBM) disease, accounting for 56–77.5% and 12.5–17.5% cases of PRS, respectively.3–5 A number of less common causes of PRS exist, making up less than 10% of all cases (table 1).

Table 1

Causes of PRS

Systemic small-vessel inflammation (‘vasculitis’) of the arterioles, capillaries and venules is associated with necrosis and disruption of the vessel walls. In the lungs, this results in extravasation of erythrocytes into the alveoli.32 Once DAH has developed, the histological appearance becomes increasingly similar across the various diseases, although clues as to the primary diagnosis can still be obtained.33 Fibrinoid necrosis of glomeruli, in association with ‘crescent’ formation on renal biopsy, is the hallmark of RPGN, and is described as focal and segmental necrotising glomerulonephritis (FSNGN). Disruption of the glomerular capillary walls with passage of immune cells and fibrin deposition in Bowman's space results in the formation of crescents. Obliteration of Bowman's space with crescents results in loss of renal function.32 RPGN is classified into three distinct immunopathological entities: antibody mediated (type 1), immune complex mediated (type 2) and pauci-immune (type 3). Types 1, 2 and 3 are seen with anti-GBM disease, systemic lupus erythematosus (SLE) and AAV, respectively.34

Differential diagnoses

A number of common clinical conditions may present with similar clinical features to PRS. These include low cardiac output states with pulmonary oedema and renal hypoperfusion, malignant hypertension with hypertensive renal and cardiac failure leading to pulmonary oedema, infectious diseases (including Legionella pneumonia, leptospirosis and malaria), and bronchopneumonia with sepsis-induced renal impairment. Furthermore, DAH may occur secondary to a number of non-autoimmune pathologies (box 1).

Box 1

Non-autoimmune causes of diffuse alveolar haemorrhage

  • Cardiac disease:

    • Congestive cardiac failure with AKI

    • Valvular heart disease

    • Atrial tumours35

  • Acute kidney injury with pulmonary oedema

  • Haemostatic abnormalities:

    • Thrombocytopenia

    • Uraemia

    • Anticoagulation/thrombolysis/antiplatelet agents

    • Disseminated intravascular coagulopathy

  • Barotrauma

  • Infection:

    • Leptospirosis35

    • Staphylococcus aureus36

    • Legionella pneumophila

    • Hantavirus

    • Malaria

  • Embolic phenomena:

    • Cholesterol emboli syndrome

    • Fat embolism36

    • Thromboembolic disease

  • Malignant hypertension with renal and cardiac failure leading to pulmonary oedema

  • Malignancy:

    • Primary lung

    • Metastatic

  • Toxins:

    • Paraquat poisoning

    • Solvents36

    • Cannabis36

    • ‘Crack’ cocaine

  • Idiopathic haemosiderosis

  • Lymphangioleiomyomatosis35

  • Pulmonary capillary haemangiomatosis35

Any cause of renal failure may result in oliguria and subsequent pulmonary oedema, mimicking PRS. Nevertheless, a high index of suspicion for PRS is crucial, as early diagnosis and treatment significantly alter the prognosis. Differentiating common causes of renal and respiratory failure from autoimmune PRS may be difficult, particularly as PRS may coexist with pneumonia or pulmonary oedema. Furthermore, there are no clinical features specific to PRS. If PRS is suspected, investigations to aid the diagnosis of DAH and FSNGN should be instigated without delay. A diagnostic algorithm summarising the key diagnostic features of PRS is provided in figure 1.

Figure 1

Diagnostic algorithm for pulmonary renal syndrome.

Diagnostic evaluation of DAH

Clinical features

DAH represents a broad clinical spectrum. It may develop acutely over a few days, or more insidiously, and may present as a mild illness or as fulminant respiratory failure. Features such as dyspnoea, haemoptysis, anaemia and hypoxia are neither sensitive nor specific. They may be attributed to complications of active vasculitis or its treatment, such as fluid overload or infection, and not all patients with DAH present with haemoptysis and/or dyspnoea.37 ,38 The nomenclature of vasculitides was revised recently at the 2nd Chapel Hill Consensus Conference.39 While it may take some time for the new definitions to become widely adopted, we have chosen to use them in this review.

Imaging

A plain chest radiograph (CXR) is a sensitive but non-specific diagnostic aid in DAH, with up to 13% of patients with DAH demonstrating no features of alveolar shadowing on CXR at presentation.37 ,40 ,41 Typically, opacities change rapidly, extending (increased alveolar bleeding) or resolving without scarring (reabsorption of blood) within 48 h (figure 2). Pleural effusions are not a feature and should suggest cardiac failure or fluid overload. Echocardiography may aid in the diagnosis of cardiogenic pulmonary oedema. High-resolution CT is superior to CXR in detecting DAH by the presence of localised ground-glass opacification or more extensive consolidation with air bronchograms, and is particularly valuable in cases of suspected DAH with normal CXR findings.42 ,43 There is no distribution of opacities specific to DAH, which may either be patchy or uniform.44 ,45

Figure 2

Chest radiograph (CXR) (left panel) demonstrating diffuse bilateral alveolar shadowing, predominantly in a perihilar distribution. Repeat CXR (right panel) 3 weeks later, on resolution of acute pulmonary haemorrhage.

Fibreoptic bronchoscopy and bronchoalveolar lavage

During an acute bleed, fresh blood may be visible within subsegmental airways on fibreoptic bronchoscopy (FOB), along with an increasingly haemorrhagic return on serial bronchoalveolar lavage (BAL). In subacute or recurrent DAH, the number of haemosiderin-laden macrophages on Prussian blue staining aids diagnosis.46 The upper limit of haemosiderin-laden macrophages in BAL fluid is taken as 5%.47 BAL may result in false negative results due to sampling error.48 Alternatively, there is the potential for a focal source of bleeding, such as an upper airway granuloma, to cause widespread aspiration of blood.44 FOB and BAL are particularly useful in cases where there is diagnostic difficulty, or when superadded infection is a concern.

Lung function testing

In the presence of intra-alveolar blood, there is lung restriction, and the alveolar uptake of inhaled carbon monoxide (CO) is increased, but clearance of its radioisotope (C15O) from a lung field is delayed.49 Thus, the ratio of uptake to clearance indicates recent DAH (in the previous 48–72 h). The obvious advantage to this method is that it is non-invasive. However, there are concerns about the value of measuring the transfer coefficient in the presence of coexisting pulmonary oedema, pneumonia or underlying lung disease (which all cause lung restriction but reduce CO uptake). Serial measurements, demonstrating opposing changes in vital capacity and CO transfer are required, as normal predicted values are wide. However, some authors consider this an impractical approach, as the method is technically demanding.50

Lung histology

Obtaining lung histology may be considered the gold standard test for diagnosing DAH secondary to small-vessel vasculitis. Capillaritis is the most common vascular lesion, present in 63% patients, with a similar incidence in P-ANCA and C-ANCA-positive cases.51 However, findings of capillaritis are not specific for the different types of small-vessel vasculitis. Anti-GBM disease typically presents with similar lesions.52 In granulomatosis with polyangiitis (GPA, formerly known as Wegener's granulomatosis), additional features of granulomatous inflammation with foci of necrosis may be present.53 Transbronchial biopsy may be prone to sampling error, and resultant pneumothorax may compromise already impaired lung function. Concerns about the practicality and safety of transbronchial video-assisted thoracoscopic, or open biopsy of the lung in the acute clinical situation, limit the applicability of this approach.

Diagnostic evaluation of renal vasculitis

Clinical features of acute renal failure are non-specific and can include oliguria, peripheral or pulmonary oedema and hypertension. Serum creatinine may not always be elevated at presentation in PRS. Urine should be sent for dipstick analysis, microscopy and protein:creatinine ratio estimation. Ultimately, a renal biopsy should be carried out to confirm the diagnosis of FSNGN.

Urine dipstick and microscopy

An active urinary sediment (ie, the presence of blood and protein on urine dipstick) is suggestive of an active glomerulonephritis. In the presence of congestive cardiac failure, urine analysis may reveal mild proteinuria.54 The urinary sediment is generally bland in ‘flash pulmonary oedema’ secondary to renovascular disease. Urinary findings on microscopy in sepsis-induced acute kidney injury include renal tubular cells, hyaline, epithelial and mixed cellular casts and calcium oxalate crystalluria,55 and urine protein estimation may reveal non-nephrotic range proteinuria.56 In PRS, haematuria tends to be microscopic. Urine microscopy typically reveals red cell casts and dysmorphic erythrocytes (suggestive of a glomerular source of bleeding), and the urine protein:creatinine ratio tends to be in the non-nephrotic range.

Renal biopsy

Renal biopsy should be sought when an autoimmune cause of PRS is suspected. Renal histology typically reveals FSNGN with crescents (figure 3). In the case of AAV, immunofluoresence may reveal few or no antibody deposits (hence, ‘pauci-immune’ GN).57 In anti-GBM disease, characteristic linear deposits of immunoglobulin G (IgG) antibodies along the basement membrane are seen on immunohistochemistry.34 Other causes of autoimmune PRS have different patterns of antibody deposition within the glomeruli, including widespread granular deposits of various immunoglobulins in SLE.

Figure 3

Light microscopy of renal biopsy showing disruption of normal glomerular architecture with partial obliteration of Bowman's space by a cellular crescent.

Specific causes of PRS

ANCA-associated vasculitis

AAV comprises three distinct clinical entities; GPA, microscopic polyangiitis (MPA) and eosinophilic GPA (previously Churg-Strauss syndrome).39 The UK incidence of GPA, MPA and eosinophilic GPA (EGPA) is 9.7, 8 and 2.7 per million, respectively.58 AAV affects people aged 65 years and over more commonly.58 DAH occurs in 8–36% of patients with AAV.37 ,40 ,45

The targets of ANCA are proteinase 3 (PR3) and myeloperoxidase (MPO) within neutrophil and monocyte granules, which become exposed on the cell surface when neutrophils and monocytes are activated by proinflammatory cytokines.34 ,59 ,60 Binding of ANCA causes further activation of these cells. Infections may induce production of ANCA,61 and Staphylococcus aureus nasal carriage is associated with relapse of GPA.62 Drugs and toxins, including propolythiouracil, hydralazine, cocaine and silica may also induce ANCA, with resolution following cessation of exposure.35 ,61 Patients with AAV have a predilection for Th17 responses, which have been linked to autoimmunity.34 ,63

ANCA do not bind directly within the kidney or lung, as evidenced by the paucity of immune complex or antibody deposition within affected organs. Despite this, there is good in vivo and in vitro evidence that MPO-ANCA59 ,63 ,64 are pathogenic, though a similar role for PR3-ANCA is less conclusive.34 ,59 ,60 ,62 Activated neutrophils in small vessels release reactive oxygen species and proteolytic enzymes in response to ANCA binding which damages adjacent tissue. The negative charge on the GBM and fenestrated endothelium may result in leucostasis, resulting in the concentration of their cytotoxic products.65 It is unclear why pulmonary involvement occurs in some cases but not others.

Diagnostic evaluation of AAV

Clinical features of vasculitis are non-specific and include arthritis, fever, malaise, scleritis and myalgia.57 Features suggestive of a vasculitic aetiology include cutaneous manifestations (palpable purpuric rash or pyoderma gangrenosum, occurring in 40–60% of patients), and peripheral neuropathy or mononeuritis multiplex. Upper airway involvement (epistaxis, destruction of the nasal cartilage, and hoarse voice) occur in up to 90% of patients with GPA, but some features of upper airway disease also occur in up to 50% of patients with EGPA and 35% of patients with MPA.57 The clinical triad of peripheral blood eosinophilia, asthma and vasculitis characterises patients with EGPA. Details of the definitions of AAV are given in the paper from the Chapel Hill Consensus Conference.39

DAH is one of the most serious manifestations of AAV, and occurs in 8–36% of patients.66–68 An active urinary sediment is a common finding, with 97% of patients having microscopic haematuria, and 79% of patients having proteinuria.41 Renal impairment is the most common severe presentation of AAV occurring in up to 70% of patients.65 ,68 The mean serum creatinine at presentation in reported series varies from 212 to 554 μmol/l.37 ,69 ,70 Between 25% and 57% of patients with AAV and DAH require renal replacement therapy (RRT) at presentation.37 ,38 ,40 ,41 ,70 ,71 Among patients with AAV and DAH, most studies report histological evidence of features of pauci-immune, FSNGN on renal biopsy.37 ,41 ,69

Approximately 95% of patients with AAV have detectable ANCA.72 ,73 ANCA with a cytoplasmic distribution on immunofluorescence (C-ANCA, directed against proteinase-3) tend to correspond to the clinical syndrome of GPA, whereas ANCA with a perinuclear distribution (P-ANCA, directed against MPO) are more frequent in the clinical syndrome of MPA.

Management of AAV

DAH in AAV does not invariably require the same treatment in all patients. Rather, the severity of involvement of different organs, age of the patient, and previous immunosuppression history, should all be factors in deciding on the best treatment for a particular patient. Treatment is divided into induction of remission and maintenance.

Induction treatment of AAV with glucocorticoids and cyclophosphamide has significantly improved the outcome.74 ,75 Intravenous methylprednisolone is sometimes included in the induction treatment, but is associated with increased rates of infection.76 The chimeric monoclonal anti-CD20 antibody, rituximab, is as effective as cyclophosphamide in inducing remission in newly diagnosed AAV with renal involvement and in relapsing disease, even in patients with ‘advanced’ renal failure and alveolar haemorrhage.66 ,78

Plasmapheresis as an adjunctive therapy to cyclophosphamide and oral prednisolone improves renal recovery in severe renal vasculitis.79 The institution of plasmapheresis, in addition to immunosuppression, has been reported to be a safe and effective treatment to resolve DAH associated with AAV,70 and is currently being evaluated in the ongoing multicentre randomised controlled trial, PEXIVAS.80

DAH and serum creatinine of >200 μmol/l at presentation are independently associated with induction-refractory disease.81 Among patients with induction-refractory disease, massive alveolar haemorrhage is associated with a higher mortality. Rituximab,82 intravenous immunoglobulin,83 deoxyspergualin,77 infliximab,84 alemtuzumab85 and antithymocyte globulin have been reported to be effective in treating refractory AAV.

Maintenance of disease remission may be difficult, as relapse of AAV is frequent.86 Induction treatment of DAH with high-dose glucocorticoids should be tapered over several months together with intravenous or oral cyclophosphamide for 3–6 months.72 Pulsed intravenous cyclophosphamide achieves a lower cumulative dose and less toxicity, while achieving similar efficacy to daily oral cyclophosphamide.87 Glucocorticoids are generally continued at a low dose for the first 2 years, when chances of disease relapse are higher.88 Stopping steroid treatment altogether in the context of a persistent positive ANCA titre may result in disease relapse.89 The continued use of cyclophosphamide as maintenance treatment should be avoided, as complications of cyclophosphamide are related to the cumulative dose.87 Sepsis, malignancy, haemorrhagic cystitis and cytopenias are complications associated with cyclophosphamide.73 ,90 ,91 Azathioprine is effective in maintenance, but mycophenolate mofetil can be used in patients sensitive to azathioprine.92 Co-trimoxazole, at a prophylaxis dose may also reduce the relapse rate in GPA.93

Outcome of AAV

DAH is one of the strongest predictors of mortality in AAV, increasing the relative risk by up to 8.6-fold;40 ,68 1- and 5-year survival among patients with DAH associated with MPO-AAV were reported by Lauque as 82% and 68%, respectively.41 Factors consistently associated with mortality in the general AAV cohort include end-stage renal failure, age and maximum creatinine in the first month.65 ,94–96 Most patients who present with DAH requiring RRT remain dialysis-dependent at 1 year.41 ,70 The existing literature shows variable rates of DAH recurrence, ranging from 10%70 to 31%.41

Anti-GBM disease

The incidence of anti-GBM disease is around one per million, with a bimodal incidence showing peaks in the third and seventh decades.97 Clinical manifestations of anti-GBM disease are varied with 60–80% suffering from both pulmonary and renal involvement, 20–40% with isolated renal disease and <10% with isolated pulmonary disease.98 More than 75% of patients with lung haemorrhage have a history of tobacco use.99 ,100

The vast majority of anti-GBM antibodies bind to the non-collagenous-1 (NC1) domain of the α3 chain of type IV collagen, but the α5 chain can also be targeted.101 This antigen is found in various organs,101–103 but may be particularly accessible in the kidney and lung explaining the observed clinical features.104 The trigger to abnormal antibody production remains unclear, though there is evidence that auto-reactive T-cells may play a role in pathogenesis.2 ,105 More than 80% of individuals with anti-GBM disease are HLA-DR15 (previously HLA-DR2) or DR4-positive.97

Diagnostic evaluation of anti-GBM disease

Haemoptysis is the commonest presenting feature in anti-GBM disease, occurring in 65–94% of cases.106 Other presenting features include cough, dyspnoea, fatigue, fever, nausea and vomiting, gross haematuria and chest pain.99 ,102 ,106 ,107 Arthritis and myalgia are usually absent.97 Findings on clinical examination are non-specific, and include pallor, and crackles and wheezes on chest auscultation.99 ,107

Anti-GBM disease accounts for up to 20% of patients presenting with acute renal failure due to RPGN.97 Renal involvement occurs in up to 90% of patients ranging from abnormal urinalysis with haematuria alone, to severe renal injury requiring RRT.108–110 Urinalysis is usually abnormal with most patients having haematuria (macroscopic in up to 35%), red cell casts and proteinuria.99 ,107 ,108 Patients with concurrent DAH tend to have more severe renal injury than those without DAH.111 RRT, at presentation, is required in 12–55% of cases, and correlates with the need for long-term RRT.99 ,100 ,108 ,111 Renal biopsy remains the gold standard investigation, typically revealing FSNGN with linear deposition of anti-GBM antibodies along the basement membrane on immunofluoroscence.111 Circulating anti-GBM antibodies are found in up to 92% of cases using ELISAs.99 Although false positives and negatives are rare, accuracy may be further improved by western blotting.112

Management of anti-GBM disease

Induction therapy consists of corticosteroids, cyclophosphamide and plasmapheresis.111 Methylprednisolone may be considered as adjunctive treatment in life-threatening DAH.107 There is a lack of data from large randomised clinical trials to evaluate these treatments.

Plasmapheresis may be superior to methylprednisolone as an adjunct to cyclophosphamide.97 Patients with renal injury (but dialysis-independent) undergoing plasmapheresis have better renal recovery than those who historically received methylprednisolone.110 Furthermore, the use of methylprednisolone may be associated with more infective complications.97 A plasmapheresis course of 14 daily exchanges, or until anti-GBM antibody is undetectable, should be considered.113 This results in the resolution of DAH in around 90% of patients.111 Rituximab, cyclosporine A and mycophenolate mofetil have been tried successfully following treatment failure or intolerance.114–117 Anti-GBM disease rarely relapses (<3%),111 so long-term maintenance therapy is therefore not usually required. Corticosteroids are withdrawn over 6–9 months, and cyclophosphamide over 2–3 months.111 Where maintenance is required for persisting anti-GBM antibody, azathioprine has been used. In patients intolerant of cytotoxic treatment, rituximab may be considered.114

Outcome of anti-GBM disease

The outcome of Goodpasture's disease is favourable if patients are independent of dialysis at presentation, with 90% surviving the initial illness.97 The presence of DAH is a risk factor for early mortality.111 Levy et al reported that patients who presented with a creatinine concentration less than 500μmol/l had 100% patient survival and 95% renal survival at 1 year, by contrast with patients presenting dialysis-dependent who had 65% patient survival and 8% renal survival at 1 year.111 The extent of crescents on biopsy correlates with renal function at presentation and renal outcome. Renal function does not appear to deteriorate beyond the initial insult in successfully treated patients.107 ,111

‘Double-positive’ disease

Double-positive disease represents a sub-group of AAV and anti-GBM disease where both antibodies are present. Five to fourteen percent of ANCA-positive patients have detectable anti-GBM, and 30–43% of anti-GBM-positive patients have detectable ANCA.7 ,118–120 The predominant ANCA type in double-positive disease is MPO-ANCA (82%). All reported patients with double-positive disease have renal involvement, and 41–83% have concurrent pulmonary involvement.6 ,7 Renal recovery is unlikely in those with severe renal disease at presentation.7

It is postulated that GBM damage from AAV exposes the antigens which leads to the production of GBM autoantibodies. This is supported by the fact that a number of double-positive patients have antibodies against components of GBM other than the classical α3-chain of type IV collagen.7 However, double-positive patients become ANCA-negative faster than typical AAV, and relapses are relatively uncommon.7 Renal histology usually demonstrates typical linear staining of the GBM for IgG, and features consistent with AAV may coexist.6

Induction treatment of double-positive disease should be similar to the treatment of anti-GBM disease, with high-dose corticosteroids, cyclophosphamide and plasmapheresis.6 ,7 ,120 ,121 Relapses of vasculitis have been reported and, thus, maintenance therapy with prednisolone and azathioprine should be considered.6 Long-term renal function is dependent on renal function at presentation. It is unclear how the long-term outcome of double-positive disease compares with anti-GBM disease.7 ,120 ,121

Less common causes of PRS

Antiphospholipid syndrome

Antiphospholipid syndrome (APS) is a disease characterised by vascular thrombosis, recurrent miscarriages and the presence of antiphospholipid antibodies: lupus anticoagulant, anticardiolipin antibody or anti-β2 glycoprotein-I antibody.122 APS is associated with other autoimmune diseases, especially SLE and rheumatoid arthritis.122 Renal disease occurs in <10% of patients with primary APS.11 A thrombotic microangiopathy (TMA) is the most common finding on renal histology. Patients typically present with subnephrotic proteinuria, impaired renal function and hypertension.11 DAH presents either as part of the ‘Catastrophic APS’ (CAPS) or as a distinct entity.12 The underlying pathological process involves a TMA, and occasional capillaritis. Patients are classically men, and middle-aged.123

PRS associated with APS requires prompt treatment with corticosteroids.12 Plasmapheresis and/or intravenous immunoglobulins should be adjuncts in severe or in steroid-unresponsive disease.12 In CAPS, patients with proven thrombosis, or evidence of microthrombi, should be cautiously anticoagulated once acute haemorrhage has been controlled.12 ,124 Aspirin should be considered even in the absence of thrombi.124 The mortality of CAPS is significant, with up to 33% patients not surviving the acute illness despite aggressive treatment.117

Lupus vasculitis

DAH is a rare manifestation of lupus vasculitis (LV).8 It occurs either in the presence of capillaritis or with minimal inflammatory response and undamaged lung structure.125 DAH is more likely to occur as an initial feature rather than later in the disease course.125 Lupus nephritis coexists in 40–100% of patients, and haematopoietic system involvement occurs in more than 90% of patients.8

PRS requires prompt induction treatment with cyclophosphamide, corticosteroids and consideration of plasmapheresis.123 ,126 There should also be a thorough search for infection and consideration of empirical broad-spectrum antibiotics, as this approach has been shown to lower mortality.126 Rituximab has been successful in the treatment of refractory LV,9 but its precise role in treatment of PRS has not been established. Historically, outcomes were poor with only 8% surviving the acute illness. This has markedly improved with aggressive treatment, with >60% survival at 1 year in recent series.8

IgA vasculitis (previously Henoch-Schönlein Purpura)

IgA vasculitis (IgAV) is a small-vessel vasculitis commonly associated with IgA nephropathy. Ninety percent of cases occur in those under 10 years old.10 IgAV classically consists of the triad of a purpuric rash, abdominal pain and arthritis, though other features can be present.10 DAH is a rare complication of IgAV, seen more often among adults.127

In the absence of severe respiratory failure, corticosteroids should be the first-line treatment. However, in the context of aggressive disease with severe respiratory failure or refractory disease, treatment should include pulsed intravenous cyclophosphamide in addition to corticosteroids.127 The use of plasmapheresis in the treatment of DAH is limited to case reports.127 Advancing age and the severity of respiratory failure determine the prognosis of IgAV-associated PRS.127

Essential cryoglobulinaemic vasculitis

Cryoglobulins are immunoglobulins that precipitate when exposed to lower temperatures. Cryoglobulinaemic vasculitis (CV), usually containing a monoclonal IgM and a polyclonal IgG, leads to systemic small-vessel vasculitis. A clinical picture similar to CV can occur in association with hepatitis C virus (hepatitis C virus-associated cryoglobulinaemic vasculitis) or as a cancer-associated vasculitis (particularly with lymphoma).13 ,14 DAH occurs in 3.2% of cases of CV, and is associated with membranoproliferative glomerulonephritis in 90% of cases.13 ,14 DAH is most commonly associated with the mixed immunoglobulin subtype of CV.14 CV is associated with low or undetectable C4 levels with preserved C3.13 Constitutional symptoms include purpura, arthralgia, fever and neuropathy.14

Induction treatment usually includes corticosteroids, plasmapheresis and cyclophosphamide. Rituximab has been successfully used for the treatment of severe cryoglobulinaemic vasculitis.129

Behcet's disease

Behcet's disease (BD) is a multisystem disorder characterised by repeated oral and genital ulcers with relapsing uveitis. Pulmonary involvement is reported in 1–18% of cases, although DAH contributes to <2% of these reports.20 Pulmonary artery aneurysms are the commonest pulmonary pathology accounting for 34% of cases.20 Pulmonary embolism is less common. The initial investigation of choice for haemoptysis in BD should be thoracic CT angiography to rule out a ruptured pulmonary artery aneurysm.20

Patients with pulmonary artery aneurysms are treated with either cyclophosphamide or methotrexate and corticosteroids. Embolisation of the pulmonary artery aneurysm is carried out if bleeding occurs. Azathioprine is used for maintainence therapy after a year of disease remission.130 Thrombi are commonly found in the pulmonary arteries. However, the use of anticoagulation is controversial, as it may worsen bleeding from pulmonary artery aneurysms, and thrombi may not resolve as they are usually organised and closely adherent to the vessel wall.20

Renal disease in BD has no direct association with pulmonary disease. The majority of renal disease consists of amyloidosis, glomerulonephritis and vascular lesions. Immunosuppression regimens, similar to those used for other pulmonary manifestations have been used to treat DAH. There are no clinical trials supporting this approach due to the rarity of the condition. Long-term outcomes depend upon the degree of renal involvement.19

Systemic sclerosis

Systemic sclerosis (SSc) is a connective tissue disorder characterised by inflammation, fibrosis and degeneration of the blood vessels, skin and visceral organs. PRS in SSc is rare and may present in three ways: TMA, SSc-associated small-vessel vasculitis, and a Goodpasture-like syndrome induced by high-dose D-penicillamine treatment.22 ,131 There is increasing recognition of a subset of SSc associated with MPO-ANCA and vasculitis.131

Differentiating between the various subtypes of PRS is vital, as corticosteroids potentially trigger and worsen TMA.22 Patients with TMA may benefit from plasmapheresis, which has also been effective in thrombocytopenic purpura associated with SSc. SSc associated with small-vessel vasculitis or D-penicillamine, should be treated with corticosteroids (especially if ANCA-positive), together with cyclophosphamide and consideration of plasmapheresis.22 Rituximab has been used with promising early results.131 Outcomes are poor regardless of the subtype of the PRS, with mortality rates up to 90% over 2 years.22

Rheumatoid vasculitis (previously systemic rheumatoid vasculitis)

Rheumatoid vasculitis (RV) describes a subgroup of patients with rheumatoid arthritis and clinical manifestations of vasculitis. Historically, RV occurs in up to 5.4% of those with rheumatoid arthritis, however, there is evidence that this incidence is declining.18 DAH is an uncommon complicating factor of RV and relates to an underlying capillaritis.17 Renal involvement varies from isolated urinary abnormalities to severe renal impairment. The commonest renal manifestations are amyloidosis and glomerulonephritis,18 with some patients being ANCA-positive.16

The mainstay of treatment is corticosteroids. Cyclophosphamide results in a more rapid remission and fewer relapses, compared with azathioprine, D-penicillamine, or high-dose prednisolone. However, no treatment has been shown to be superior in terms of survival benefit.18

Mixed connective tissue disease

Mixed connective tissue disease (MCTD) is an autoimmune disease, with clinical features of SLE, SSc and rheumatoid arthritis (RA). PRS associated with MCTD is very rare, and may be due to the SLE-like component of the disease.17 It is more likely to occur in children and those with a low complement level.28 Due to the rarity of the condition, treatment follows the regimens for other autoimmune causes of PRS, including corticosteroids and cyclophosphamide.17

Poststreptococcal glomerulonephritis

Poststreptococcal glomerulonephritis (PSGN) is one of the commoner types of postinfectious glomerulonephritis. PRS related to PSGN is a very rare occurrence, usually presenting approximately 10 days after streptococcal pharyngitis, or 2 weeks after an episode of impetigo. Frank haematuria, oedema and hypertension are commonly present. Case reports describe favourable outcomes with high-dose corticosteroid treatment, resulting in rapid resolution of DAH in all cases and renal disease in the majority.30

Polymyositis and dermatomyositis

Dermatomyositis and polymyositis are autoimmune inflammatory myopathies, DAH is a rare feature.25 Primary renal disease does not occur as a direct consequence of polymyositis, but secondary damage can occur from rhabdomyolysis and myoglobinuria.26 Treatments have been based on those used for other causes of autoimmune DAH, including high-dose corticosteroids and cyclophosphamide.25 ,26

Drug-associated DAH

Many drugs can cause DAH. Some drugs trigger an immunological process with crescentic glomerulonephritis and DAH. Examples include hydralazine, propylthiouracil, penicillamine, allopurinol, carbimazole, methimazole and all-trans-retinoic acid. It is not unusual for patients to have detectable ANCA, with some patients being positive for both MPO and PR3.35 Treatment involves stopping the offending agent, which usually leads to improvement in clinical features, and corticosteroid therapy if this does not occur.2

Conclusion

PRS is defined as concurrent autoimmune induced DAH and RPGN. The commonest causes include AAV and anti-GBM disease, although it can rarely occur in a number of other diseases. Regardless of the aetiology, PRS is a severe clinical condition conferring high morbidity and mortality. A high index of suspicion is required, as there are no specific clinical features. Once the diagnosis is suspected, appropriate immunological investigations should be undertaken, usually followed by renal biopsy. Prompt diagnosis and initiation of therapy has a positive effect on outcomes. Potent immunosuppression forms the foundation of treatment, with plasmapheresis as a potential adjunct. Outcomes, which historically were poor, are improving for the majority of patients with PRS.

Main messages

  • Pulmonary renal syndrome (PRS) is a clinical syndrome characterised by diffuse alveolar haemorrhage (DAH) and rapidly progressive glomerulonephritis (RPGN).

  • Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is the commonest cause of PRS, followed by antiglomerular basement membrane disease.

  • There is no specific diagnostic test specific for DAH, but a combination of tests may point to the diagnosis.

  • Renal biopsy revealing focal and segmental necrotising glomerulonephritis aids the diagnosis of RPGN and the cause of PRS.

  • Immunological testing should be carried out early, but should not delay treatment where diagnosis has been made by clinical features and other relevant investigations.

  • Treatment of PRS in AAV is divided into induction and maintenance. Induction treatment aims to treat active disease, and maintenance treatment aims to prevent recurrence of active disease once remission has been achieved.

Current research questions

  • The long-term consequence of diffuse alveolar haemorrhage (DAH) on lung function needs to be determined.

  • The role of plasma exchange in DAH associated with antineutrophil cytoplasm antibody (ANCA)-associated vasculitis is unclear, and is currently being evaluated by the randomised controlled trial, PEXIVAS.

  • Existing immunotherapy for treatment of vasculitis is associated with significant long-term complications. Ongoing research into the most efficacious therapeutic regimens associated with the least side effects is especially important.

Key references

  • Niles JL, Böttinger EP, GR Saurina, et al. The syndrome of lung hemorrhage and nephritis is usually an ANCA-associated condition. Arch Intern Med 1996;156: 440–45.

  • Watts RA, Lane SE, Bentham G, et al. Epidemiology of systemic vasculitis: a ten-year study in the United Kingdom. Arthritis Rheum 2000;43:414–9.

  • Jennette JC, Falk RJ, Bacon PA, et al. 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. Published Online First: 8 October 2012. doi:10.1002/art.37715

  • Salama AD, Levy JB, Lightstone L, et al. Goodpasture's disease. Lancet 2001;358:917–20.

  • de Prost N, Parrot A, Cuguemelle E, et al. Diffuse alveolar hemorrhage in immunocompetent patients: Etiologies and prognosis revisited. Respir Med. 2012;106:1021–32.

Multiple choice questions (Answers after the references)

  1. ANCA-associated vasculitis is associated with diffuse alveolar haemorrhage in almost all cases.

  2. ANCA-associated vasculitis is typically associated with multiple immune deposits on renal biopsy.

  3. In anti-GBM disease, maintenance treatment with azathioprine is generally required to prevent relapse of the illness.

  4. Up to 90% of patients with DAH will have features of diffuse alveolar shadowing on chest radiography.

  5. In the diagnostic evaluation of renal vasculitis, urine protein estimation typically reveals nephrotic range proteinuria.

ANSWERS

  1. False (diffuse alveolar haemorrhage occurs in up to 36% of patients with ANCA-associated vasculitis).

  2. False (renal histology typically lacks immune deposits).

  3. False (maintenance treatment is often not required, but may be considered if anti-GBM antibodies persist).

  4. True.

  5. False (urine protein is typically in the subnephrotic range).

References

Footnotes

  • Contributors SCW, NA: writing manuscript, literature search. PWI, CDP: editing manuscript.

  • Funding None.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.