Goodpasture Syndrome

Omar H. Mohamedaly

Goodpasture syndrome refers to the pulmonary–renal syndrome of diffuse alveolar hemorrhage (DAH) and glomerulonephritis. The term often is used interchangeably with Goodpasture disease, although, strictly speaking, the term disease should be restricted to the presence of circulating or tissue-bound antiglomerular basement membrane antibody (AGBMA), while the term syndrome may be applied to any pathogenesis. The term AGBMA disease may be more appropriate and, to avoid confusion, will be used in this chapter.

Interestingly, the original description of the eponymous syndrome by American pathologist Ernest Goodpasture at Vanderbilt University in 1919 was likely referring to a vasculitis rather than what we now refer to as AGBMA disease. It was the case of an 18-year-old man who died 6 weeks after influenza infection and was found to have DAH, glomerulonephritis, splenic infarcts, and vasculitis of the small bowel. This case report does highlight salient features that have been shown to be important in AGBMA disease.

As the term AGBMA disease implies, it is an autoimmune disorder resembling a type II hypersensitivity reaction. The AGBMA itself, first identified in 1965, is now known to target the noncollagenous-1 (NC1) domain of the α3 chain of type IV collagen. Expression of the α3 chain is highest in glomerular and alveolar basement membranes, which explains the clinical syndrome of DAH and glomerulonephritis in AGBMA disease. α3 Chain expression is also found, though at much lower levels, in renal tubular basement membranes, choroid plexus, cochlea, and retina.

AGBMA disease is a rare disease with a reported incidence of about one patient per million population. It may, however, be responsible for up to 20% of all cases of rapidly progressive glomerulonephritis. Prevalence data are difficult to assess. A bimodal distribution has been described with slight male predominance in younger patients in the third decade and equal sex distribution to a slight female predominance in older patients in the sixth and seventh decades. The younger group is more likely to present with the full pulmonary–renal syndrome, while older patients tend to have disease limited to the kidneys.

In about 60% to 80% of cases, pulmonary and renal diseases present simultaneously; however, pulmonary disease may appear up to 12 months prior to renal disease. In about 5% to 10% of cases, lung involvement occurs alone. It is worth noting, though, that even in the absence of overt renal disease, AGBMA deposits are often found in the glomeruli if kidney biopsy is performed.

Pulmonary symptoms are most common on presentation, including hemoptysis, cough, and/or dyspnea. The degree of hemoptysis varies considerably; it can be minimal or life-threatening. Glomerulonephritis rarely manifests with hypertension and gross hematuria. Fatigue related to renal failure is more common. Fever may be present, especially in the context of antecedent flu-like symptoms or upper respiratory tract infection. However, other systemic symptoms such as malaise, weight loss, arthralgia, and myalgia should raise suspicion for vasculitis.

Laboratory evaluation may reveal iron-deficiency anemia related to alveolar hemorrhage. Urinary sediment is active with microscopic hematuria, nonnephrotic range proteinuria, and, occasionally, erythrocyte casts or dysmorphic erythrocytes. Serum creatinine is often elevated. Complement levels are normal; reduced C3 and/or C4 should point to vasculitis or alternative diagnoses as the cause of the pulmonary–renal syndrome. Circulating AGBMA can be detected in greater than 90% of patients presenting with AGBMA disease. Positive antineutrophil cytoplasmic antibody (ANCA) titers may be found in up to 30% of cases.

Imaging tends to be nonspecific. Chest radiographs often show diffuse symmetric airspace opacities and, less commonly, asymmetric, focal, or interstitial opacities. Pleural effusions are rare in the absence of concomitant volume overload or infection. Pulmonary infiltrates usually resolve over days. Occasionally, the chest radiograph can be normal despite a history of hemoptysis. Chest computed tomography is reportedly more sensitive for DAH than plain radiography and can demonstrate ground-glass opacities and consolidation, though such findings are hardly specific for DAH.

During active alveolar hemorrhage, pulmonary function tests reveal an increase in the diffusing capacity of the lung for carbon monoxide (DLCO), reflecting the presence of abundant erythrocytes in the alveolar space creating a large diffusion sink for CO to which hemoglobin has a high affinity. An increase in DLCO above 30% of predicted normal has been suggested as an indicator of widespread intra-alveolar hemorrhage. Such an increase may precede clinical and radiographic changes and can, therefore, be used in monitoring for recurrence of DAH.

AGBMA titers do not always correlate with disease activity, though they are generally useful for monitoring. Higher levels are thought to indicate more severe renal disease. The most commonly used assay is an enzyme-linked immunosorbent antibody (ELISA) assay which has a sensitivity of 70% to 100% depending on the specific antigen used. Assays using native or recombinant human α3 (IV) antigen substrates have a reported sensitivity of 95% to 100% and specificity of 91% to 100%. Confirmatory Western blot is performed at many centers.

The pathogenicity of AGBMA was demonstrated in a classic experiment in which antibodies isolated from serum or renal eluate samples of patients with Goodpasture syndrome induced glomerulonephritis in recipient monkeys. Interestingly, in some animal models AGBMA leads to renal but not pulmonary disease. After identification of the epitope as the α3 (IV) chain with its cDNA mapped to chromosome 2q35-37, it was cloned and shown to induce expression of the protein bound by AGBMA when transfected into cells. These antibodies are typically of the IgG 1 or 3 subclass and less commonly of the IgA or IgM class. They do not bind native cross-linked α-3,4,5 hexamers until they are dissociated. Autoreactive T cells have also been implicated in the pathogenesis of AGBMA disease. T cells specific for the NC1 domain of the α3 (IV) chain have been found at higher frequency in patients with AGBMA disease than in controls. There is also growing evidence that effector T cells may contribute directly to injury and that CD4⁺ CD25⁺regulatory T cells may facilitate the autoimmune response seen in AGBMA disease.

The inciting factor triggering the autoimmune response remains unknown. A combination of environmental and genetic factors is most likely. Temporal association between development of AGBMA disease and various infections and exposures suggests the role for some injurious stimulus that exposes previously concealed basement membrane epitopes that either stimulate an autoimmune response or, more likely, are attacked by already circulating autoreactive antibodies and T cells. The association with influenza infection, first described by Goodpasture himself, has subsequently been reported in larger series. Other upper respiratory tract infections, hydrocarbon exposure, and tobacco use have all been implicated as well. In one study, 100% of smokers with AGBMA disease developed both DAH and glomerulonephritis, whereas only 20% of nonsmokers developed DAH, suggesting that direct pulmonary insult is needed to precipitate DAH in AGBMA disease. Similarly, there are reports of AGBMA disease occurring rarely after lithotripsy or in the presence of urinary tract infection or other glomerulonephritis conditions. Genetic predisposition is suggested by the presence of HLA-DR2 and HLA-B7 in 90% and 60% of AGBMA disease patients, respectively. HLA-DRw15, a subtype of DR2, and DR4 in particular increase the risk of AGBMA disease. Disease susceptibility is most likely conferred by a common 6-amino acid motif found in these antigens, which are uncommon in blacks who have a lower incidence of the disease. DR1 and DR7 portend a lower risk of AGBMA disease.

On histopathological examination, lung biopsy specimens typically demonstrate bland pulmonary hemorrhage with intra-alveolar erythrocytes and hemosiderin-laden macrophages. Much less commonly, pulmonary capillaritis may be seen. Alveolar wall necrosis as seen in pulmonary vasculitis is uncommon. Kidney biopsy reveals focal segmental necrotizing glomerulonephritis with crescent formation. Immunofluorescence reveals the pathognomonic finding of uninterrupted linear deposition of IgG along the glomerular basement membrane. In 60% to 70% of biopsies, linear C3 deposition is also seen. Similar appearance on immunofluorescence can be found in lung biopsies as well, though these are more technically challenging to demonstrate. Typical staining can be found in kidney biopsies even in the absence of overt renal disease.

Treatment strategies are aimed at removing circulating antibodies as well as preventing new antibody formation. Isolated DAH responds to corticosteroids, though glomerulonephritis is typically resistant to corticosteroid monotherapy. The mainstay of therapy is the combination of plasmapheresis, corticosteroids, and immunosuppressives. Plasmapheresis is typically performed daily or every other day for 2 to 3 weeks with volumes of 3 to 6 L per session. The only randomized controlled trial was a small study in which two of eight patients receiving plasmapheresis progressed to dialysis dependence, compared with six of nine patients who were not plasmapheresed. The benefit, however, seemed to correlate with the serum creatinine level and percent of crescents found on renal biopsy. Nevertheless, the biological plausibility of AGBMA removal with plasmapheresis, as well as observations that AGBMA titers, declines more rapidly in patients receiving a plasmapheresis in addition to corticosteroids, and immunosuppressives (compared with those receiving corticosteroids and immunosuppressives alone) led to the recommendation of plasmapheresis for all patients with AGBMA disease.

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