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).Table 1: Cause of rapidly progressive glomerulonephritis/renal failure and lung hemorrhageaEpidemiology 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). Disease Associations A large number of diseases have been associated with Goodpasture's syndrome on the basis of individual cases; however, the most consistently reported associations are with membranous nephropathy (16,17,18,19,20) and anti-neutrophil cytoplasmic (ANCA)-associated vasculitis (17,18,19,20). Approximately 10% of patients with ANCA-positive vasculitis have anti-GBM antibodies, most of whom exhibit a perinuclear pattern of ANCA and antibodies against myeloperoxidase (21,22,23,24). Double-positive patients are notable because the disease behaves more like vasculitis than anti-GBM disease with a better response to therapy (23,25). It is reasonable to speculate that for both membranous and ANCA-positive vasculitis, damage to the kidney elicits an immune response against the GBM leading to the production of antibodies, which may or may not contribute to disease progression. 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 The Goodpasture Antigen The GBM is a specialized basement membrane separating the glomerular endothelial cells from visceral epithelial cells. It has contact with blood due to the presence of fenestrae in the endothelium, which allows antibodies direct access to the GBM for binding. Type IV collagens are found only in basement membranes and there are six types: α1 through α6. The major type IV collagens in most basement membranes are α1 and α2, whereas α3, α4, and α5 predominate in the GBM. Each chain of type IV collagen consists of a central long collagenous domain, a collagenous N-terminus (called the 7S domain), and the noncollagenous C-terminal (NC1 domain). Three α-chains self-assemble to form a monomer, and these monomers are linked at their NC1 domains by disulfide bridges producing a fixed hexamer. The monomers are also linked at the 7S domains, thus stabilizing this complex meshwork. The autoantibodies in anti-GBM disease are directed at the NC1 domain of the α3 chain of type IV collagen. Recent work has shown that the antibodies bind principally to the amino-terminal region of the NC1 domain (29,30,31). Although antibodies from patients may bind to other regions of the NC1 domain, only binding to the amino terminal region correlated with prognosis as assessed by dialysis dependency at 6 mo after antibody measurement (31). This antigen, as well as being located in the lung, is also found in a number of other specialized basement membranes, including Bruch's membrane in the eye and the retinal capillaries, cochlear, neuromuscular junction, and choroid plexus in the brain. Anti-GBM Antibodies Experiments by Lerner et al. (32) established that anti-GBM antibodies are pathogenic (33). They showed that antibodies eluted from kidneys of patients with Goodpasture's disease could bind to the GBM of squirrel monkeys when injected in vivo and elicit a pattern of disease similar to anti-GBM disease. Anti-GBM antibodies in kidney and blood have identical specificities (34), and further evidence for the pathogenicity of anti-GBM antibodies comes from the close correlation between disease activity and antibody level (35), and more recently by association between antibody binding to specific regions of the NC1 domain and renal prognosis (31). It should be emphasized, however, that the relationship between anti-GBM antibody level and glomerular injury is not straightforward: For example, intercurrent infection greatly increases the severity of glomerular injury independent of the anti-GBM antibody concentration. Cell-mediated mechanisms are important in generating the antibody with patients' T cells proliferating in response to exposure to Goodpasture antigen and are required to provide signals to enable B cell proliferation and antibody production. T cells have been isolated from patients with anti-GBM disease, which are reactive with autoantigens recognized by anti-GBM antibodies (36,37). In addition, there is evidence of T cells infiltrating the renal cortex in anti-GBM disease (38), and macrophages and neutrophils are a prominent feature within inflamed glomeruli, highlighting the importance of cell-mediated mechanisms in the effector phase of disease. 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. Pulmonary Hemorrhage Historically, hemoptysis has been the most common presenting feature, occurring in approximately 70% of reported cases and often preceding the onset of renal disease by months or years (3,39,40,41). The frequency of pulmonary hemorrhage is probably much less now because of the lower prevalence of cigarette smoking. The patients are frequently dyspneic with a cough; however, the degree of hemoptysis bears no correlation to the quantity of pulmonary hemorrhage, and the bleeding that occurs can lead to anemia. As mentioned earlier, pulmonary hemorrhage occurs almost exclusively in current smokers. In addition, it is known to be precipitated by intercurrent infections and fluid overload. It can be episodic and in many patients resolves spontaneously; in others, however, it can progress from minor hemoptysis to profound hemorrhage leading to respiratory failure in a matter of hours. Indeed, pulmonary hemorrhage is the primary cause of early death in anti-GBM disease, making prompt diagnosis imperative. Clinical signs in lung hemorrhage are variable, often with signs on physical examination. Inspiratory crackles and occasionally bronchial breathing may be heard. Diagnosis may be made by noting a sudden fall in the hemoglobin in someone with hemoptysis, which is usually accompanied by radiologic changes on chest x-ray. The classical appearance of pulmonary hemorrhage includes alveolar-type shadowing with sparing of the upper lung fields. Unlike infection, shadowing tends not to be limited by fissures, and can resolve over 48 h. However, the picture is often complicated by coexistent fluid overload or infection. The KCO, a measure of the diffusion capability of the lung corrected for lung volume, is a sensitive indicator of lung hemorrhage. Because hemoglobin avidly binds carbon monoxide, the KCO is markedly elevated in lung hemorrhage (42,43). In addition to its diagnostic value, it also can provide a serial assessment to follow resolution of disease. Despite the potential seriousness of lung hemorrhage, when patients recover there is virtually no residual pulmonary deficit or fibrosis. We and others have reported minor reductions in KCO at long-term follow-up (28). Renal Manifestations in Anti-GBM Disease Renal disease can occur in isolation or in association with pulmonary hemorrhage. In general, renal disease progresses rapidly once significant injury has occurred and rarely resolves spontaneously. The urine sediment shows microscopic hematuria with red cell cast formation as disease progresses, and in severe disease macroscopic hematuria may occur often with associated loin pain. Proteinuria is modest (<3 g/24 h), but can be heavier when the disease has a more subacute course. Progressive renal failure usually develops leading to oliguria, which is a poor prognostic sign, and under these conditions fluid overload, super-added infection, and lung hemorrhage with hypoxia all contribute to renal failure. Diagnosis Anti-GBM Antibodies The diagnosis of Goodpasture's disease is dependent on the detection of anti-GBM antibodies either in the circulation or in kidney tissue. These antibodies are normally detected using an enzyme-linked immunosorbent assay method, although where doubt exists a Western blot in a specialized center will be required. The antibodies have not been reported to occur in the absence of disease, and false negatives are rare when appropriate checks are performed. The antibodies can also be detected on renal biopsy specimens with characteristic linear staining for IgG and frequently C3 detected along the GBM; however, this pattern of staining has been reported in a number of other circumstances (Table 2) giving false positive results. The anti-GBM antibodies are nearly always IgG, however, there are case reports of both IgA and IgM antibodies causing disease (44).Table 2: Causes of linear staining on direct immunofluorescence microscopy of kidney tissueRenal Biopsy A renal biopsy is essential in suspected anti-GBM disease, with renal involvement allowing diagnostic confirmation and assessing renal prognosis. The histologic pattern of disease starts with mesangial expansion and hypercellularity and progresses to focal and segmental glomerulonephritis with infiltration by leukocytes accompanied by segmental necrosis with prominent breaks in the GBM. Later, glomeruli develop extensive crescent formation composed of parietal epithelial cells and macrophages in association with destruction of the GBM. Of particular note (and in contrast to other forms of crescentic nephritis), the crescents are usually at the same stage of evolution—again emphasizing the explosive nature of the disease. Interstitial inflammation is usually present and may relate to the binding of antibody to basement membrane of distal convoluted tubules. As the disease progresses, the glomeruli show diffuse inflammation with segmental or total necrosis and extensive crescent formation, which eventually leads to scarring and the appearance of an end-stage kidney. Linear binding of IgG is universally detected by direct immunofluorescence. Linear C3 is found in 60 to 70% of kidney biopsies but does not influence the severity of the renal lesion. 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.Table 3: Treatment of anti-GBM diseaseaTable 4: Results of studies assessing the effect of treatment on mortality and renal survivalaHowever, 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.Table 5: Monitoring treatment of anti-GBM diseaseaDisease 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).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.