Anti-Glomerular Basement Membrane Disease

Anti-glomerular basement membrane disease (anti-GBM) is a rare but well-characterized cause of glomerulonephritis. It is defined by the presence of autoantibodies directed at specific antigenic targets within the glomerular and/or pulmonary basement membrane. These antibodies bind to the α3 chain of type IV collagen found in these specialized basement membranes. Its importance for the nephrologist lies in that it is a rare yet highly treatable cause of glomerulonephritis, but one in which delay in institution of the correct therapy can be fatal. This pattern of rapidly progressive glomerulonephritis and lung hemorrhage is often referred to as Goodpasture's syndrome and can be caused by a number of pathologies (Table 1). Ernest Goodpasture originally described autopsy findings in an 18 yr old with massive hemoptysis and acute renal failure during the influenza epidemic of 1918 (1). Thus, anti-GBM disease is a clearly defined cause of Goodpasture's syndrome; however, both pulmonary and renal disease can occur in isolation at least at presentation. A more extensive review of the condition has been published elsewhere (2).

Epidemiology

Anti-GBM disease has an estimated incidence of one case per 2 million per year in European Caucasoid populations (2). It is responsible for 1 to 5% of all types of glomerulonephritis (3) and is the cause in 10 to 20% of patients with crescentic glomerulonephritis (4,5). The disease occurs across all racial groups but is most common in European Caucasoids. All age groups are affected but the peak incidence is in the third decade in young men with a second peak in the sixth and seventh decades affecting men and women equally (2,6,7). Lung hemorrhage is more common in younger men, while isolated renal disease is more frequent in the elderly with near equal gender distribution.

Environmental factors are thought to play a role in triggering the disease. There are a number of case reports of clusters of patients with anti-GBM disease (8,9), which may implicate an infective agent; however, no clear viral association has been identified. Several anecdotal reports have linked anti-GBM disease to hydrocarbon exposure, with review of all cases suggesting a causal link (10,11). There have been case reports of anti-GBM disease following lithotripsy (12,13,14) and ureteric obstruction (15), suggesting that antigen released from a mechanically damaged kidney may initiate disease in susceptible individuals. Regardless of the role of environmental factors in initiating the autoimmune attack, the environment plays a critical role in determining whether anti-GBM antibodies cause lung injury. Pulmonary hemorrhage occurs in nearly all current cigarette smokers, while it is very rare in nonsmokers (16).

Genetic Susceptibility

Anti-GBM disease provides insight into the mechanisms of autoimmunity, in particular the role of human leukocyte antigens (HLA) in disease predisposition. HLA class II molecules, including DR, DP, and DQ, present antigen-derived peptides to T cells, thus initiating immune responses, including antibody production. Anti-GBM disease is associated with DR alleles (as opposed to DQ and DP) with strong positive associations with HLA-DR15 and HLA-DR4 alleles and negative associations with HLA DR-7 and HLA DR-1, both of which are dominantly protective (reviewed in reference 26). There are at least 18 DRβ alleles, and HLA DR15 has been split into the alleles DRB1^*1501-1505. Analysis of these subsets in anti-GBM disease has shown that the disease is associated with DRB1^*1501 and 1502, but the other DR15 alleles are too rare in Caucasian populations to assess. Exactly how these DR subgroups predispose to development of disease remains uncertain. Clearly, other factors are involved in disease initiation as DR 15 is relatively common in the general population, whereas anti-GBM disease is rare. Nevertheless, the dominant naturally processed Goodpasture antigen-derived peptides have been identified, and shown to bind to DR15 alleles with lower affinity than to the “protective” DR7 and DR1 alleles. This raises the question whether protective alleles “steal” the pathogenic peptides from DR15 (27,28).

Pathogenesis

Clinical Features

General malaise, weight loss, fever, or arthralgia may be the initial features of anti-GBM disease in a way similar to but much less prominent than in systemic vasculitis. Symptoms relating to anemia may also occur even in the absence of significant hemoptysis. The principal clinical features relate to development of renal failure due to rapidly progressive glomerulonephritis or pulmonary hemorrhage.

Diagnosis

Differential Diagnosis

The presentation with hemoptysis, lung hemorrhage, and rapidly progressive glomerulonephritis with anti-GBM antibodies makes Goodpasture's disease highly likely, with the main differential diagnosis being from vasculitis. There are a number of reports of patients with vasculitis having anti-GBM antibodies, and with the development of ANCA assays this most commonly occurs in association with myeloperoxidase antibodies (22). In general, they tend to have lower anti-GBM titers that are more readily suppressed by treatment (23,25,45) and can restore renal function even when presenting with severe renal failure unlike Goodpasture's disease. The other causes of pulmonary hemorrhage and renal disease are listed in Table 1 and can usually be distinguished by both clinical context and investigation.

Treatment

Without treatment, the prognosis for patients with anti-GBM disease is dismal. For example, 25 of 53 patients in Wilson and Dixon's series (3) died and only seven retained independent renal function. It appeared that neither steroids nor immunosuppressive drugs had an influence on the renal outcome. Certainly they have none on circulating anti-GBM antibody titers in the short term. The demonstration that anti-GBM antibodies were pathogenic provided a rationale for the current approach to treatment by therapeutic plasma exchange combined with immunosuppressive drugs. The regimen needs to be used intensively to be certain that circulating anti-GBM antibody concentrations will be reduced. Thus, daily whole volume exchanges have been advocated (Table 3). The effectiveness of this approach on improving renal function has been reported from a number of different centers (Table 4). Overall, renal function improves coincident with the introduction of plasma exchange in about 80% of patients with a serum creatinine <600 μmol/L, but in far fewer of those with higher levels or those who require dialysis. Improvement is usually evident within days of starting plasma exchange, which argues in favor of a direct effect. However, it should be emphasized that the regimen has never been properly assessed by a prospective randomized controlled trial because of the rarity and acuteness of the condition. The only reported randomized controlled trial was very small and used lower doses of both plasma exchange and cyclophosphamide than those used generally (46). Overall, plasma exchange is a relatively safe treatment and aids in a rapid reduction in anti-GBM antibodies before the longer-term immunosuppression reduces further antibody synthesis.

However, the poor outcome of those patients presenting with a creatinine >600 μmol/L may suggest that in the absence of pulmonary hemorrhage, the benefits of treatment are outweighed by the risks (47). There are a number of anecdotal reports of recovery in such patients (16,48,49,50) who usually have a short history with rapidly declining renal function and a renal biopsy revealing the recent onset of disease with possibly extensive crescent formation without evidence of scarring. Thus, even in the presence of severe renal failure, aggressive treatment may sometimes be justified in particular cases. Pulmonary hemorrhage is usually responsive to treatment with this regimen and may even respond to injection of methylprednisolone (51). Despite aggressive therapy, pulmonary hemorrhage is still the most common cause of death, especially in patients with infections.

Careful monitoring of the full blood count is essential. Cyclophosphamide should be stopped if the white cell count falls below 3.5 × 10⁹/L, while sudden drops in the hemoglobin may reflect recurrent lung hemorrhage. The prednisolone is reduced at weekly intervals to 45 mg, 30 mg, 25 mg, then 20 mg with a slower reduction in dose after this point. Recommendations for monitoring progress after initial treatment are outlined in Table 5. If the disease is under control with no evidence of relapse, then normally all treatment can be stopped within 3 to 4 mo. The disease can relapse after initial symptoms have been controlled but before the antibody titer has been fully suppressed. This usually occurs with a rebound of anti-GBM antibody titers after stopping plasma exchange or more commonly due to superadded infection or fluid overload. Regular surveillance for infections and reducing potential sources of sepsis such as intravascular lines or urinary catheters is essential.

Disease Recurrence

Recurrence of disease with antibody production has been reported but is quite rare. Recurrences may occur many years after the initial presentation with or without evidence of either renal or pulmonary disease (52,53,54,55). These episodes may occur spontaneously or be precipitated by infection or exposure to a toxic agent. Because the diagnosis in recurrent disease can be made more rapidly, outcome is usually better than with the original presentation. Renal transplantation is well known to initiate antibody production with or without renal disease (2). This should not preclude renal transplantation in patients with Goodpasture's disease but careful assessment is required. Our own practice is to delay engraftment for 6 mo after the antibody has become undetectable, and this approach is borne out by the experience of others (56). All patients will need careful monitoring for disease recurrence (presence of microscopic hematuria, rising anti-GBM titers, rising serum creatinine) after transplant; however, the incidence or recurrence is low, occurring in 1 to 12% of transplant recipients (56).

Anti-GBM Disease after Transplantation in Patients with Alport's Disease

Alport's syndrome is an inherited form of glomerulonephritis that usually progresses to end-stage renal failure. The primary abnormality is in the GBM, and it has been appreciated for many years that autoantibodies from patients with Goodpasture's disease did not bind to the GBM of these patients. In fact, the GBM in patients with Alport's lacks the α3, α4, and α5 chains. In the more common X-linked form of the disease, this is due to mutations in COL4A5, which encodes the α5 chain, whereas in the rare autosomal recessive form the defect is in the COL4A3 gene. Thus, there is absence of either α3, α4, or α5 chains in the GBM. It follows that after renal transplantation, patients with these diseases are at risk of developing anti-GBM antibodies directed at the normal α chains in the transplanted kidney. The transient appearance of low titers of these antibodies is not uncommon (57,58), but the risk of developing severe nephritis is small and the overall outcome for renal transplantation in patients with Alport's is good (59).

Nevertheless, there are at least 29 cases of anti-GBM disease after transplantation in Alport's syndrome (53). The onset occurs at a variable time after a first transplant and causes crescentic nephritis indistinguishable from Goodpasture's syndrome. The disease recurs in subsequent grafts, where it usually appears in the immediate post-graft period, coincident with the reappearance of anti-GBM antibodies and linear binding of IgG to the GBM. Treatment should be the same as for Goodpasture's syndrome, but the outlook is very poor with rapid development of severe crescentic nephritis (Figure 1).

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Figure 1.

Progression of anti-glomerular basement membrane (anti-GBM) disease in an Alport's syndrome patient renal transplant. (A) Day 2 after renal transplant with normal histologic appearance in the glomerulus. (B) At day 7 after transplant, there is marked focal proliferation within the glomeruli, which progresses to destruction of the glomeruli and loss of architecture by day 12, as shown in Panel C.

An important practical point is that anti-GBM antibody titers may be low or even negative in conventional immunoassays that have been optimized to detect the α3(IV)NCI. This is because anti-GBM antibodies in this situation are directed primarily against the α5 chain, except in the rare patients with autosomal recessive disease (60). In some published cases, the target for alloantibodies appeared to be the α3 chain (61,62); however, reagents for specific detection of antibodies to the α5 chain of type IV collagen have only become available recently (60).

Conclusion

Anti-GBM disease is a rare cause of renal failure and lung hemorrhage, but a disease in which prompt diagnosis and initiation of correct therapy can produce a cure. It has also provided valuable insight into the mechanisms of human autoimmune disease, including an understanding of the presentation of autoantigens and the precise specificity of pathogenic antibodies. These approaches are being applied to other autoimmune diseases in an attempt to develop disease-specific therapies.