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Pulmonary-renal syndrome is diffuse alveolar hemorrhage
and glomerulonephritis occurring simultaneously. Cause is almost
always an autoimmune disorder. Diagnosis is by serologic tests and
sometimes lung and renal biopsy. Treatment typically includes immunosuppression
with corticosteroids and cytotoxic drugs.
Pulmonary-renal syndrome is not a specific entity but is a syndrome that suggests a differential diagnosis and a specific sequence of testing.
The pulmonary pathology is small-vessel vasculitis involving arterioles, venules, and, frequently, alveolar capillaries. The renal pathology is small-vessel vasculitis resulting in a form of focal proliferative glomerulonephritis.
Etiology
Pulmonary-renal syndrome (PRS) is almost always a manifestation of an underlying autoimmune disorder. Goodpasture's syndrome is the prototype cause, but PRS can also be caused by SLE, Wegener's granulomatosis, microscopic polyangiitis, and, less commonly, by other vasculitides and connective tissue disorders (see Table 1: Diffuse Alveolar Hemorrhage and Pulmonary-Renal Syndrome: Causes of Pulmonary-Renal Syndrome ).
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Table 1
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Causes of Pulmonary-Renal
Syndrome
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Disorder
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Examples
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Connective tissue disorders
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Polymyositis or dermatomyositis Progressive systemic sclerosisRA SLE
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Goodpasture's syndrome
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Renal disorders
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Idiopathic immune complex glomerulonephritis
IgA nephropathy
Rapidly progressive glomerulonephritis with heart failure
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Systemic vasculitis
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Behçet's syndrome
Churg-Strauss syndrome
Cryoglobulinemia
Henoch-Schönlein purpura
Microscopic polyarteritis
Wegener's granulomatosis
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Drugs (eg, penicillamine )
Heart failure
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PRS is less commonly a manifestation of IgA-mediated disorders, such as IgA nephropathy or Henoch-Schönlein purpura, and of immune complex–mediated renal disease, such as essential mixed cryoglobulinemia. Rarely, rapidly progressive glomerulonephritis alone can cause PRS through a mechanism of renal failure, volume overload, and pulmonary edema with hemoptysis.
PRS is less commonly a manifestation of IgA-mediated disease, such as IgA nephropathy and Henoch-Schönlein purpura, and of immune complex–mediated renal disease, such as essential mixed cryoglobulinemia. Rarely, rapidly progressive glomerulonephritis alone can cause PRS through a mechanism of renal failure, volume overload, and pulmonary edema with hemoptysis.
Symptoms and Signs
Symptoms and signs typically include dyspnea, cough, fever, and hemoptysis in combination with peripheral edema and hematuria or other signs of glomerulonephritis.
Diagnosis
PRS is suspected in patients with hemoptysis not obviously attributable to other causes (eg, pneumonia, carcinoma, bronchiectasis), particularly when hemoptysis is accompanied by diffuse parenchymal infiltrates and findings suggestive of renal disease.
Initial testing includes urinalysis for evidence of hematuria and red cell casts (suggesting glomerulonephritis), serum creatinine for renal function assessment, and CBC for evidence of anemia. Chest x-ray is done if not yet obtained.
Serum antibody testing may help distinguish some causes, such as
Definitive diagnosis requires lung biopsy with findings of small-vessel vasculitis and renal biopsy with findings of glomerulonephritis with or without antibody deposition.
Pulmonary function tests and bronchoalveolar lavage are not diagnostic of PRS but can be used to help confirm diffuse alveolar hemorrhage in patients with glomerulonephritis and pulmonary infiltrates but without hemoptysis. Lavage fluid that remains hemorrhagic after sequential sampling establishes diffuse alveolar hemorrhage, especially in the context of falling Hct.
Treatment
Immunosuppression is the cornerstone of treatment. Standard induction-remission regimens include pulse IV methylprednisolone (500 to 1000 mg IV once/day for 3 to 5 days). As life-threatening features subside, the dose can then be reduced to 1 mg/kg prednisone (or equivalent) po once/day for the first month, tapered over the next 3 to 4 mo. Cyclophosphamide should be added to corticosteroid therapy in critically ill patients with generalized disease, at a dose of 0.5 to 1 g/m2 IV administered as a pulse once/mo or orally (1 to 2 mg/kg once/day).
Transition to maintenance therapy may occur 6 to 12 mo after the initiation of induction therapy or after clinical remission. Maintenance therapy includes low-dose corticosteroids coupled with cytotoxic agents. However, relapse may occur despite ongoing therapy.
Goodpasture's
Syndrome
(Anti-GBM Antibody Disease)
Goodpasture's
syndrome is a subtype of PRS (autoimmune syndrome of alveolar hemorrhage and
glomerulonephritis) caused by circulating anti-glomerular basement
membrane (anti-GBM) antibodies. Goodpasture's syndrome most often
develops in genetically susceptible people who smoke cigarettes,
but hydrocarbon exposure and viral respiratory infections are additional
possible triggers. Symptoms are dyspnea, cough, fatigue, hemoptysis,
and hematuria. Goodpasture's syndrome is suspected in patients with
hemoptysis or hematuria and is confirmed by the presence of anti-GBM
antibodies in the blood or in a renal biopsy specimen. Prognosis
is good when treatment is begun before onset of respiratory or renal
failure. Treatment includes plasmapheresis, corticosteroids, and
immunosuppressants, such as cyclophosphamide.
Pathophysiology
Goodpasture's syndrome is the combination of glomerulonephritis with alveolar hemorrhage in the presence of anti-GBM antibodies. Goodpasture's syndrome most often manifests as diffuse alveolar hemorrhage and glomerulonephritis together but can occasionally cause glomerulonephritis (10 to 20%) or pulmonary disease (10%) alone. Men are affected more often than women.
Anti-GBM antibodies are directed against the noncollagenous (NC-1) domain of the α3 chain of type IV collagen, which is found in highest concentration in the basement membranes of renal and pulmonary capillaries. Environmental exposures—cigarette smoking, viral URI, and hydrocarbon solvent inhalation most commonly and pneumonia less commonly—expose alveolar capillary antigens to circulating antibody in genetically susceptible people, most notably those with HLA-DRw15, -DR4, and -DRB1 alleles. Circulating anti-GBM antibodies bind to basement membranes, fix complement, and trigger a cell-mediated inflammatory response, causing glomerulonephritis, pulmonary capillaritis, or both.
Symptoms and Signs
Hemoptysis is the most prominent symptom; however, hemoptysis may not occur in patients with hemorrhage, and patients may present with only chest x-ray infiltrates or infiltrates and respiratory distress, respiratory failure, or both. Dyspnea, cough, fatigue, fever, and weight loss are common. Up to 40% of patients have gross hematuria, although pulmonary hemorrhage may precede renal manifestations by weeks to years.
Signs vary over time and range from clear lungs on auscultation to crackles and rhonchi. Some patients have peripheral edema due to renal failure and pallor due to anemia.
Diagnosis
Definitive diagnosis of Goodpasture's syndrome requires demonstration of serum anti-GBM antibodies by indirect immunofluorescence testing or, when available, direct enzyme-linked immunosorbent assay (ELISA) testing with recombinant or human NC-1 α3. However, ANCA testing is positive (in peripheral pattern) in only 25% of patients with Goodpasture's syndrome.
Renal biopsy is indicated in patients with glomerulonephritis (hematuria, proteinuria, red cell casts detected with urinalysis, renal insufficiency, or a combination of these findings). A rapidly progressive focal segmental necrotizing glomerulonephritis with crescent formation is found in biopsy specimens in patients with Goodpasture's syndrome and all other causes of PRS. Immunofluorescence staining of renal or lung tissue classically demonstrates linear IgG deposition along the glomerular or alveolar capillaries. IgG deposition also occurs in the kidneys of patients with diabetes and in patients with fibrillary glomerulonephritis, a rare disorder causing PRS, but GBM binding of antibodies in these disorders is nonspecific and does not occur in linear patterns.
Prognosis
Goodpasture's syndrome is often rapidly progressive and can be fatal if prompt recognition and treatment are delayed; prognosis is good when treatment begins before onset of respiratory or renal failure. Long-term morbidity is related to the degree of renal impairment at presentation; patients requiring dialysis at presentation and those with > 50% crescents in the biopsy specimen (who often will require dialysis) usually survive for < 2 yr unless kidney transplantation is done. Hemoptysis may be a good prognostic sign because it leads to earlier detection; the minority of patients who are ANCA-positive respond better to treatment. Relapse occurs in a small number and is linked to continued tobacco use and respiratory infection. In patients with end-stage renal disease who receive kidney transplantation, disease can recur in the graft.
Treatment
Immediate survival in patients with pulmonary hemorrhage and respiratory failure is linked to airway control; endotracheal intubation and mechanical ventilation are recommended for patients with borderline ABGs and impending respiratory failure. Patients with significant renal impairment may require dialysis or kidney transplantation.
Treatment is daily or every-other-day plasmapheresis for 2 to 3 wk using 4-L exchanges to remove anti-GBM antibodies, combined with a corticosteroid (usually methylprednisolone 1 g IV over 20 min once/day or every other day for 3 doses followed by prednisone (1 mg/kg po once/day for 3 wk, then titrated down to 20 mg po once/day for 6 to 12 mo) and cyclophosphamide (2 mg/kg po or IV once/day for 6 to 12 mo) to prevent formation of new antibodies. Therapy can be tapered when pulmonary and renal function stop improving.
Last full review/revision July 2009 by Marvin I. Schwarz, MD
Content last modified July 2009
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