Pulmonary renal vasculitis syndromes

doi:10.1016/j.autrev.2010.05.012

Autoimmunity Reviews

Volume 9, Issue 10, August 2010, Pages 657-660

https://doi.org/10.1016/j.autrev.2010.05.012 Get rights and content

Abstract

The term pulmonary renal vasculitis syndrome describes a clinical syndrome of diffuse alveolar haemorrhage (DAH) complicating acute glomerulonephritis that often heralds severe, life-threatening systemic vasculitis requiring urgent, aggressive therapy. “Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis” and glomerular basement membrane (“Goodpasture's”) disease are the commonest causes but other pathologies including systemic lupus erythematosus and the anti-phospholipid syndrome are also implicated. Such patients hence present most commonly to rheumatologists and nephrologists but usually require input from a number of specialties, respiratory and critical care medicine in particular. Such care is typically provided in specialist centres able to offer plasma exchange and experience in the use of immunosuppressants. We review clinical features, advances in therapy and understanding of pathophysiology.

Introduction

The term pulmonary renal vasculitis syndrome describes diffuse alveolar haemorrhage (DAH) complicating acute glomerulonephritis that often results in severe, life-threatening systemic disease requiring urgent, aggressive therapy. A number of pathologies are implicated, and as such, whilst these patients often present directly to rheumatologists and nephrologists – many require the expertise of a number of specialties – particularly respiratory and critical care medicine. We review clinical features and advances in therapy and understanding of pathophysiology.

Section snippets

Aetiology

Sometimes referred to as “Goodpasture's disease”, since initially attributed to a syndrome recognised by Goodpasture, this eponym is now used exclusively for glomerulonephritis and DAH with glomerular basement membrane (GBM) antibodies. Pulmonary renal “vasculitis”, in fact is more commonly described in the context of anti-neutrophil cytoplasmic antibody (“ANCA”) associated vasculitis (AAV), namely, microscopic polyangitis and Wegener's granulomatosis. DAH is seen in 10–40% of “pauci-immune”

Histopathological findings and pathophysiology

DAH is usually evidenced by pulmonary capillaritis whereby inflammation and fibrinoid necrosis lead to capillary thrombosis and loss of integrity of arterioles, venules, capillaries and lung architecture. Neutrophils infiltrate alveolar septae, spreading into adjacent alveoli accompanied by proteinacous exudates and red cells, which may completely replace the inter-alveolar septae. Diffuse alveolar damage (DAD) without overt vessel wall inflammation and “bland” DAH, without significant alveolar

Diagnosis and investigation

Haemoptysis in DAH can be severe, although is often absent [10]. Cough and dyspnoea are particularly suspicious in the context of a sudden drop in haemoglobin. A history suggestive of connective tissue disease, bleeding diathesis or drug use (including recreational substances) may be useful, although DAH may be the first presentation of such conditions. Careful examination including joints, skin, eyes and oro/nasopharynx may support such diagnoses whilst invasive arterial blood gas monitoring

Treatment

Mortality in DAH is high, particularly where admission to critical care (e.g. for mechanical ventilation is necessary [5], [27], [28]. Expedient, aggressive immunosuppression is essential and many patients require renal replacement therapy or transplantation [29].

Conclusion

Pulmonary renal vasculitis usually results from AAV or Goodpasture's disease but also other connective tissue disorders including SLE. Correct diagnosis is vital, mainly by rapidly excluding other conditions and attributing haemoptysis, fever or anaemia to DAH, detecting renal involvement early. Bronchoscopy, imaging, spirometry, serology and histology may all be appropriate. Despite advances in treatment, DAH usually heralds severe vasculitis and mortality remains high. Optimal treatment is

Take-home messages

•
Pulmonary renal vasculitis is a clinical syndrome of diffuse alveolar haemorrhage and acute glomerulonephritis.
•
ANCA associated vasculitis and Goodpasture's (anti-glomerular basement membrane) disease are the commonest causes.
•
Diagnosis is readily confused with other pathologies such as pneumonia and requires appropriate suspicion supported by bronchoscopic alveolar lavage, lung function testing, lung imaging, haemoglobin or serology.
•
Acute alveolar haemorrhage usually heralds severe vasculitis

References (40)

R. Cervera et al.
Catastrophic antiphospholipid syndrome (CAPS): descriptive analysis of a series of 280 patients from the “CAPS registry”
J Autoimmun
(May–Jun 2009)
J.W. Leatherman
Immune alveolar hemorrhage
Chest
(Jun 1987)
M. Chen et al.
Severe pulmonary hemorrhage in patients with end-stage renal disease in antineutrophil cytoplasmic autoantibody-associated vasculitis
Am J Med Sci
(Jun 2009)
C.B. Wilson et al.
Anti-glomerular basement membrane antibody-induced glomerulonephritis
Kidney Int
(Feb 1973)
S Yung et al.
Anti-DNA antibodies in the pathogenesis of lupus nephritis—the emerging mechanisms
Autoimmun Rev
(Feb 2008)
H. Xiao et al.
The role of neutrophils in the induction of glomerulonephritis by anti-myeloperoxidase antibodies
Am J Pathol
(Jul 2005)
M.P. Kuligowski et al.
Anti-myeloperoxidase antibodies rapidly induce {alpha}4 integrin-dependent glomerular neutrophil adhesion
Blood
(June 18 2009)
J.D. Ooi et al.
Advances in the pathogenesis of goodpasture's disease: From epitopes to autoantibodies to effector T cells
J Autoimmun
(Nov 2008)
A.D. Salama et al.
Shining a LAMP on pauci-immune focal segmental glomerulonephritis
Kidney Int
(Jul 2009)
H. Gallagher et al.
Pulmonary renal syndrome: A 4-year, single-center experience
Am J Kidney Dis
(Jan 2002)

F. Holguin et al.

Prognostic factors for hospital mortality and ICU admission in patients with ANCA-related pulmonary vasculitis

Am J Med Sci

(Oct 2008)

H. Badsha et al.

Pulmonary hemorrhage in systemic lupus erythematosus

Semin Arthritis Rheum

(Jun 2004)

R.W. Erickson et al.

Treatment of hemorrhagic lupus pneumonitis with plasmapheresis

Semin Arthritis Rheum

(Oct 1994)

L. Guillevin et al.

Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients

Arthritis Rheum

(Mar 1999)

S.J. Haworth et al.

Pulmonary haemorrhage complicating wegener's granulomatosis and microscopic polyarteritis

Br Med J (Clin Res Ed)

(Jun 1985)

R. Saxena et al.

Circulating autoantibodies as serological markers in the differential diagnosis of pulmonary renal syndrome

J Intern Med

(Aug 1995)

J.L. Niles et al.

The syndrome of lung hemorrhage and nephritis is usually an ANCA-associated condition

Arch Intern Med

(Feb 26 1996)

M.R. Zamora et al.

Diffuse alveolar hemorrhage and systemic lupus erythematosus clinical presentation, histology, survival, and outcome

Medicine (Baltimore)

(May 1997)

E.J. Mark et al.

Pulmonary capillaritis and hemorrhage in patients with systemic vasculitis

Arch Pathol Lab Med

(May 1985)

M.I. Schwarz et al.

Small vessel vasculitis of the lung

Thorax

(2000)

Cited by (36)

Clinical associations of renal involvement in ANCA-associated vasculitis
2020, Autoimmunity Reviews
Citation Excerpt :
The observed differences in our cohort might add to the idea of distinct presentation forms in PR3-ANCA vasculitis. Severe pulmonary haemorrhage has previously been closely linked to renal manifestations [25,26]. While the current study observed a strong association between pulmonary haemorrhage and renal involvement, respiratory distress/pulmonary fibrosis or asthma and wheeze or evidence of obstructive airway disease showed a negative association with renal involvement.
Renal involvement in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis is associated with significant morbidity and higher mortality rates. This study examined clinical manifestations associated with renal involvement in ANCA-associated vasculitis within a large, international cross-sectional cohort.
Univariate and multivariate analyses were performed to identify clinical factors associated with renal disease, which was defined as i) a serum-creatinine >30% above normal and a fall in creatinine-clearance >25%; or ii) haematuria attributable to active vasculitis.
The study cohort include 1230 patients from 31 countries; 723 (58.8%) presented with renal involvement: microscopic polyangiitis (82.2%), granulomatosis with polyangiitis (58.6%), and eosinophilic granulomatosis with polyangiitis (26.4%). The following clinical and laboratory factors were more common among patients with renal disease: age (OR 1.01, 95% CI 1.01–1.02), fever (OR 1.97, 95% CI 1.35–2.88), fatigue (OR 1.55, 95% CI 1.14–2.10), weight loss (OR 1.62, 95% CI 1.23–2.12), polyarthritis (OR 1.39, 95% CI 1.02–1.89), petechiae/purpura (OR 1.47, 95% CI 1.06–2.05), pulmonary haemorrhage (OR 5.23, 95% CI 1.39–19.63), gastrointestinal symptoms (OR 2.19, 95% CI 1.34–3.58), seizures (OR 3.42, 95% CI 1.26–9.30), lower serum albumin (OR 2.42, 95% CI 1.64–3.57), higher CRP (OR 2.06, 95% CI 1.04–4.06), low serum C3 at baseline (OR 3.86, 95% CI 1.30–11.53), myeloperoxidase- (OR 7.97, 95% CI 2.74–23.20) and proteinase 3-ANCA (OR 3.40, 95% CI 1.22–9.50). The following clinical factors were less common among patients with renal disease: mononeuritis multiplex (OR 0.63, 95% CI 0.41–0.98), proptosis/exophthalmos (OR 0.19, 95% CI 0.06–0.59), nasal polyps (OR 0.32, 95% CI 0.19–0.55), septal defect/perforation (OR 0.29, 95% CI 0.14–0.60), respiratory distress/pulmonary fibrosis/asthma (OR 0.08, 95% CI 0.04–0.19), and wheeze/obstructive airway disease (OR 0.29, 95% CI 0.16–0.52).
In this large international study, several clinical and laboratory factors were identified as associated with renal involvement in ANCA-associated vasculitis.
Multiple organ dysfunction secondary to Churg-Strauss syndrome: A case report and review of the literature
2015, Acta Colombiana de Cuidado Intensivo
Presentamos el caso de un hombre de 58 años con síndrome febril prolongado asociado a dificultad respiratoria, episodios de broncoespasmo, deterioro de la función renal y mononeuropatía múltiple que evoluciona a disfunción orgánica múltiple. Después de un amplio estudio microbiológico, imagenológico, broncoscópico y citológico se diagnosticó vasculitis ANCA positivo compatible con síndrome de Churg-Strauss. Tras el inicio de terapia inmunosupresora y ciclo de plasmaféresis el paciente evoluciona satisfactoriamente, se retira el soporte ventilatorio, inicia rehabilitación y finalmente egresa.
We report the case of a 58 year old man with persistent fever and respiratory distress associated with episodes of bronchospasm, renal function impairment and multiple mononeuropathy with development of multiple organic dysfunction. After extensive microbiological study, imaging, bronchoscopic and cytological he was diagnosed with positive ANCA vasculitis compatible with Churg-Strauss syndrome. Following the initiation of immunosuppressive therapy and plasmapheresis cycle the patient evolved satisfactorily, ventilatory support is removed the rehabilitation starts and finally he is discharged.
Rapidly progressive crescentic glomerulonephritis: Early treatment is a must
2014, Autoimmunity Reviews
Citation Excerpt :
Patients with Goodpasture syndrome respond well to corticosteroids and cyclophosphamide if treatment is initiated early. Plasma exchange is indicated in patients with massive alveolar hemorrhage [77]. Plasmapheresis may also offer some other advantages over immunosuppression alone, including an earlier disappearance of circulating anti-GBM antibodies and better serum creatinine levels at recovery.
The term crescentic glomerulonephritis (GN) refers to a pathologic condition characterized by extracapillary proliferation in > 50% of glomeruli. Clinically crescentic GN is characterized by a nephritic syndrome rapidly progressing to end stage renal disease (ESRD). Three types of crescentic GN have been identified. Type 1 includes cases of Goodpasture syndrome characterized by linear deposits of antibodies along the glomerular basement membrane (GBM) at immunofluorescence. Type 2 is a heterogeneous group of primary or secondary glomerular diseases complicated by crescentic GN. In this category there are granular deposits of immunoglobulins and complement fractions on the glomerular tuft. Type 3 includes cases of ANCA-associated small-vessel vasculitis. Immunofluorescence is negative or may show only faint deposits of immunoglobulins. The etiology and the initial pathogenetic factors are different in the three types, but the final mechanisms leading to crescent formation and the renal symptoms and signs are similar. The prognosis depends on the timeline of diagnosis and treatment. Although some patients requiring dialysis may recover a good renal function, usually the higher the serum creatinine at presentation the worse the outcome. When treatment is initiated early, most patients obtain a complete or partial remission. High-dose corticosteroids and cyclophosphamide represent the standard therapy for crescentic GN. The addition of plasma exchange may also be helpful, particularly in patients with massive alveolar hemorrhage. Anti-B monoclonal antibodies have also been used in some patients with crescentic GN, but their role in this particular area is still poorly established.
The pulmonary-renal syndrome: A diagnostic and therapeutic emergency for the internist and the intensivist
2013, Revue de Medecine Interne
Le syndrome pneumo-rénal (SPR) est une urgence rare qui se définit par l’association d’une hémorragie alvéolaire le plus souvent asphyxiante et d’une glomérulonéphrite rapidement progressive. La lésion histologique rénale caractéristique et commune à toutes les étiologies de SPR est la glomérulonéphrite extracapillaire. Le SPR est une urgence diagnostique et thérapeutique, et tout retard est grevé d’un préjudice vital et fonctionnel, de séquelles pulmonaires et rénales. Les étiologies du SPR sont dominées par les vascularites systémiques nécrosantes associées aux ANCA et le syndrome de Goodpasture. Plus rarement, le SPR peut être attribué à un lupus systémique, une cryoglobulinémie, un purpura rhumatoïde ou une endocardite infectieuse subaiguë. Le diagnostic différentiel peut être délicat et rend compte d’une certaine ambiguïté nosologique. Le traitement d’attaque associe habituellement une corticothérapie systémique, du cyclophosphamide et des échanges plasmatiques. La place des biothérapies à la phase initiale reste à définir.
The pulmonary-renal syndrome is a rare and life-threatening condition. It is defined as the association of a diffuse alveolar hemorrhage and a rapidly progressive glomerulonephritis. The characteristic histological lesion common to all underlying diseases is a necrotizing and crescentic glomerulonephritis. The pulmonary-renal syndrome is a diagnostic and therapeutic emergency: any delay in its management will lead to death or serious functional damage as pulmonary and renal impairment. ANCA-associated vasculitis and Goodpasture's disease are the main disorders associated to pulmonary-renal syndrome. More rarely systemic lupus, cryoglobulinaemia, Henoch-Schonlein purpura or subacute endocarditis may induce a pulmonary-renal syndrome. Differential diagnosis can sometimes be difficult, highlighting some ambiguity in the definition of the syndrome. Initial treatment usually associates systemic corticosteroid, cyclophosphamide and plasma exchange. The role of biotherapy as first line therapy remains to be determined.
Plasma exchange in systemic autoimmune diseases
2013, Seminarios de la Fundacion Espanola de Reumatologia
La aféresis terapéutica engloba un gran número de técnicas que tienen como principal fundamento procesar la sangre de un paciente a través de un dispositivo extracorpóreo con el objetivo de eliminar anticuerpos e inmunocomplejos preformados para evitar el daño tisular, eliminar mediadores de la inflamación como complemento y citocinas que podrían contribuir al daño, aportar factores deficitarios y estimular clonas linfocitarias para mejorar la respuesta a la terapia inmunosupresora.
Entre los diferentes tipos de aféresis, los más utilizados para el tratamiento de las enfermedades autoinmunes sistémicas son el recambio plasmático terapéutico y la inmunoadsorción.
Para una correcta utilización de estos procedimientos, la American Society for Apheresis ha establecido más de 65 indicaciones clasificadas en diferentes categorías según el nivel de evidencia. En esta revisión se analizan las indicaciones de estas terapéuticas en las diferentes enfermedades autoinmunes sistémicas.
De esta revisión se puede concluir que los recambios plasmáticos terapéuticos son una posibilidad terapéutica eficaz y segura en el tratamiento de afectaciones graves de las enfermedades autoinmunes y una opción válida en casos de enfermedad refractaria a los tratamientos convencionales.
Therapeutic apheresis encompasses a large number of techniques whose main purpose is to process patients’ blood through an extracorporeal device. The aim is to remove antibodies and preformed immune complex to avoid tissue damage, eliminate inflammatory mediators – such as complement and cytokines, which could contribute to further damage – restore deficiencies, and stimulate lymphocyte clones to improve the response to immunosuppressive therapy.
Among the different types of apheresis, the most commonly used for the treatment of autoimmune diseases are plasma exchange and immunoadsorption.
To aid the correct use of these procedures, the American Society for Apheresis has established more than 65 indications classified into different categories according to the level of evidence. In this review, we analyze the distinct therapeutic indications for the treatment of different autoimmune diseases.
This review indicates that plasma exchange is a safe and effective therapeutic option for treating the serious manifestations of systemic autoimmune diseases and is a valid option for those patients with diseases refractory to conventional treatments.
Renal involvement in anti-neutrophil cytoplasmic autoantibody associated vasculitis
2013, Autoimmunity Reviews
Citation Excerpt :
Renal involvement is of particular importance in AAV because of its frequency and because of its impact on prognosis. With the exception of CSS, where kidney involvement is not a prominent feature [4–6], renal involvement is present in about 70% of patients with Wegener's granulomatosis [7,8], now called granulomatosis with polyangiitis (GPA) [9], and in almost 100% of patients with microscopic polyangiitis [10,11] (Fig. 1). Data from the Italian registry of kidney biopsies have shown that necrotizing vasculitis is the major form of nephropathy in patients presenting with acute renal failure undergoing kidney biopsy [12].
Renal involvement is a common and often severe complication of anti-neutrophil cytoplasmic autoantibody (ANCA) associated vasculitides (AAV).
With the exception of Churg–Strauss syndrome (CSS), where kidney involvement is not a prominent feature, renal disease is present in about 70% of patients with Wegener's granulomatosis, now called granulomatosis with polyangiitis (GPA) and in almost 100% of patients with microscopic polyangiitis (MPA).
Kidney involvement is generally characterized by a pauci-immune necrotizing and crescentic glomerulonephritis with a very rapid decline of renal function (rapidly progressive glomerulonephritis).
Even though there are not qualitative differences in glomerular lesions in patients with GPA or with MPA, chronic damage is significantly higher in MPA (and/or P-ANCA positive patients) than in GPA (and/or C-ANCA positive patients).
If untreated necrotizing and crescentic glomerulonephritis has an unfavorable course leading in a few weeks or months to end stage renal disease.
Serum creatinine at diagnosis, sclerotic lesions and the number of normal glomeruli at kidney biopsy are the best predictors of renal outcome.
Corticosteroids and cyclophosphamide (with the addition of plasma exchange in the most severe cases) are the cornerstone of induction treatment of ANCA-associated renal vasculitis, followed by azathioprine for maintenance.
Rituximab is as effective as cyclophosphamide in inducing remission in AAV and probably superior to cyclophosphamide in patients with severe flare, and could be preferred in younger patients in order to preserve fertility and in patients with serious relapses.

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ReviewPulmonary renal vasculitis syndromes

Abstract

Introduction

Section snippets

Aetiology

Histopathological findings and pathophysiology

Diagnosis and investigation

Treatment

Conclusion

Take-home messages

J Autoimmun

Chest

Am J Med Sci

Kidney Int

Autoimmun Rev

Am J Pathol

Blood

J Autoimmun

Kidney Int

Am J Kidney Dis

Am J Med Sci

Semin Arthritis Rheum

Semin Arthritis Rheum

Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients

Arthritis Rheum

Pulmonary haemorrhage complicating wegener's granulomatosis and microscopic polyarteritis

Br Med J (Clin Res Ed)

Circulating autoantibodies as serological markers in the differential diagnosis of pulmonary renal syndrome

J Intern Med

The syndrome of lung hemorrhage and nephritis is usually an ANCA-associated condition

Arch Intern Med

Diffuse alveolar hemorrhage and systemic lupus erythematosus clinical presentation, histology, survival, and outcome

Medicine (Baltimore)

Pulmonary capillaritis and hemorrhage in patients with systemic vasculitis

Arch Pathol Lab Med

Small vessel vasculitis of the lung

Thorax

Review
Pulmonary renal vasculitis syndromes