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Pulmonary-renal syndrome (PRS) is diffuse alveolar hemorrhage and glomerulonephritis occurring simultaneously. PRS is always a manifestation of underlying autoimmune disease but is gaining recognition as a diagnostic entity because it suggests a differential diagnosis and a specific sequence of tests and treatments. 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 disease (see Table 1: Diffuse Alveolar Hemorrhage and Pulmonary-Renal Syndromes: Differential Diagnosis of Pulmonary-Renal Syndrome). The number of cases of PRS caused by these latter diseases is probably greater than those caused by Goodpasture's syndrome, but patients with those diseases more commonly present in other ways; only a few present with PRS.

Table 1
Differential Diagnosis of Pulmonary-Renal Syndrome Connective tissue disease Polymyositis or dermatomyositis Progressive systemic sclerosis RA SLE Goodpasture's syndrome Renal disease Idiopathic immune complex glomerulonephritis IgA nephropathy Rapidly progressive glomerulonephritis with heart failure Systemic vasculitis Behçet's syndrome Churg-Strauss syndrome Cryoglobulinemia Henoch-Schönlein purpura Microscopic polyarteritis Wegener's granulomatosis Other Drugs ( penicillamine Some Trade Names CUPRIMINE Click for Drug Monograph ) Heart failure

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.

PRS is suspected in patients with hemoptysis not obviously attributable to other causes (such as pneumonia, carcinoma, or bronchiectasis), particularly when hemoptysis is accompanied by diffuse parenchymal infiltrates. Initial testing includes urinalysis for evidence of hematuria, serum creatinine for renal function assessment, and CBC for evidence of anemia. Pulmonary function tests are not diagnostic, but the finding of an increased diffusing capacity for carbon monoxide (DLco) suggests pulmonary hemorrhage and is due to the increased uptake of carbon monoxide by intra-alveolar Hb.

Serum antibody testing may help distinguish some causes. Antiglomerular basement membrane (anti-GBM) antibodies are pathognomonic for Goodpasture's syndrome, although they also occur in patients with Alport's syndrome after kidney transplantation. Antibodies to double-stranded DNA and reduced serum complements are typical of SLE. Antineutrophil cytoplasmic antibodies (ANCA) directed against proteinase-3 (PR3-ANCA or cytoplasmic ANCA [c-ANCA]) are present in Wegener's granulomatosis. Antineutrophil cytoplasmic antibodies directed against myeloperoxidase (MPO-ANCA, or perinuclear ANCA [p-ANCA]) suggest microscopic polyangiitis.

Goodpasture's Syndrome

(Anti-GBM Antibody Disease)

Goodpasture's syndrome is an autoimmune syndrome of alveolar hemorrhage and glomerulonephritis caused by circulating 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/or 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. Treatment includes plasmapheresis, corticosteroids, and immunosuppressants, such as cyclophosphamide. Prognosis is good when treatment is begun before onset of respiratory or renal failure.

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 and/or pulmonary capillaritis.

Symptoms and Signs

Hemoptysis is the most prominent symptom; however, hemoptysis may be absent in the presence of hemorrhage, and the patient may present with only chest x-ray infiltrates or infiltrates and respiratory distress and/or failure. 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.

Alveolar Hemorrhage (Goodpasture's Syndrome)

Signs vary over time and range from clear lungs on auscultation to crackles and rhonchi. Some patients have peripheral edema and pallor from anemia.

Diagnosis

If initial testing supports the diagnosis of PRS, additional tests are required. 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. Other serologic tests are obtained, such as an antinuclear antibody (ANA) to detect SLE and antistreptolysin-O titer to detect poststreptococcal glomerulonephritis, which may be associated with many of the causes of PRS. ANCA testing is positive (in peripheral pattern) in 25% of Goodpasture's cases. In the presence of glomerulonephritis (hematuria, proteinuria, red cell casts on urinalysis, and/or renal insufficiency), renal biopsy may be indicated. A rapidly progressive focal segmental necrotizing glomerulonephritis with crescent formation is found on biopsy in 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. This also occurs in the diabetic kidney and in fibrillary glomerulonephritis, a rare disorder causing PRS, but GBM binding of antibodies in these disorders is nonspecific.

Pulmonary function tests and bronchoalveolar lavage are not diagnostic of Goodpasture's syndrome 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.

Prognosis and Treatment

Goodpasture's syndrome is often rapidly progressive and can be fatal if prompt recognition and treatment are delayed; prognosis is good when treatment is begun before onset of respiratory or renal failure.

Immediate survival in the face of 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.

Treatment is daily or every-other-day plasmapheresis for 2 to 3 wk using 4-L exchanges to remove anti-GBM antibodies, combined with an IV corticosteroid (usually methylprednisolone Some Trade Names
MEDROL
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1 g over 20 min every other day for 3 doses followed by 1 mg/kg prednisone Some Trade Names
DELTASONE
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once/day) and cyclophosphamide Some Trade Names
CYTOXAN
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(2 mg/kg once/day) for 6 to 12 mo to prevent formation of new antibodies. Therapy can be tapered when pulmonary and renal function stop improving. Long-term morbidity is related to the degree of renal impairment at presentation; patients requiring dialysis at presentation and those with > 50% crescents on biopsy have < 2-yr survival and often require dialysis unless kidney transplantation is performed. Hemoptysis may be a good prognostic sign because it leads to earlier detection of disease; 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.

Last full review/revision November 2005

Content last modified November 2005