Version May 2024
INTRODUCTION — Anti-GBM disease is a small vessel vasculitis in which circulating antibodies are directed against an antigen intrinsic to the glomerular basement membrane (GBM) and alveolar basement membrane (ABM), resulting in rapidly progressive glomerulonephritis and/or alveolar hemorrhage [1]. Goodpasture syndrome and Goodpasture disease are older terms often used synonymously to refer to anti-GBM antibody-mediated disease but also to the clinical constellation of glomerulonephritis and pulmonary hemorrhage, regardless of the underlying pathogenesis.
The pathogenesis, clinical manifestations, and diagnosis of anti-GBM disease will be reviewed here. The treatment of this disorder is discussed separately. (See "Anti-GBM (Goodpasture) disease: Treatment and prognosis".)
The differential diagnosis of glomerular disease and the approach to the patient with suspected kidney disease are discussed in detail elsewhere:
●(See "Glomerular disease: Evaluation and differential diagnosis in adults".)
●(See "Diagnostic approach to adult patients with subacute kidney injury in an outpatient setting".)
EPIDEMIOLOGY — Anti-GBM disease is rare, estimated to occur in fewer than two cases per million population [1]. A study from Ireland reported a national incidence of 1.64 per million population per year and identified both temporal and spatial clusters of cases, suggesting environmental triggers for disease onset [2]; similar incidence estimates have been reported from New Zealand and the Netherlands [3,4]. Anti-GBM disease has been recognized in other White individuals and Asian individuals [3,5,6] but is thought to be rarer in African individuals [1].
Anti-GBM disease accounts for approximately 15 percent of all cases of crescentic glomerulonephritis in large biopsy series [7]. However, it is a rare cause of end-stage kidney disease (ESKD), accounting for 0.8 percent of all ESKD patients in one study [8].
Larger series of anti-GBM disease patients have shown a bimodal age distribution, with peak incidences in the third decade and in the sixth to seventh decades [9-12]. The disease also occurs among children [13]. Younger patients (<30 years) are more likely to present with pulmonary hemorrhage, and older patients (>50 years) are more likely to present with isolated glomerulonephritis [10,14]. There appears to be a slight male predominance in the younger age group and a female predominance in the older age group.
PATHOGENESIS
Antibody formation and specificity — Anti-GBM disease is caused by circulating antibodies directed against an antigen intrinsic to the glomerular basement membrane (GBM). These antibodies have the following properties:
●Specificity – The principal target for the anti-GBM antibodies is the NC1 domain of the alpha-3 chain of type IV collagen (alpha-3(IV) chain), one of six genetically distinct gene products found in basement membrane collagen [15,16]. Further evidence for the importance of the alpha-3(IV) chain comes from a report of a COL4A3 variant in familial anti-GBM disease [17]. There are two principal conformational epitopes localized to the globular NC1 domain of the alpha-3(IV) chain [18-20]. Anti-GBM antibodies constitute up to 1 percent of the circulating immunoglobulin G (IgG) in these patients.
The general limitation of injury to the glomeruli and alveoli parallels the tissue distribution of the alpha-3(IV) chain. In comparison to the more widespread distribution of the alpha-1 and alpha-2 chains of type IV collagen, expression of the alpha-3 chain is highest in the glomerular and alveolar basement membranes (ABMs); lower in the renal tubular basement membranes (TBMs); detectable in the choroid plexus, testis, cochlea, and retina; and virtually absent in many other tissues, such as the small intestine, skin, and placenta [21].
Anti-GBM antibodies may also be directed against other alpha chains [22]. Antibodies eluted from the kidneys of patients with Goodpasture disease were shown to bind most strongly to alpha-3(IV) NC, but the majority also recognized alpha-5(IV) and, to a lesser extent, alpha-4(IV). The kidney-bound antibodies recognized the EA and EB epitopes in alpha-3(IV) and the EA epitope in alpha-5(IV). They did not bind native cross-linked alpha-3, 4, 5 hexamers until they were dissociated [23]. Exposure of cryptic epitopes occurs through disruption of sulfilimine cross-links in the NC1 domain, and this may be caused by autoantibodies directed against peroxidasin [24]. Rarely, anti-GBM antibodies are directed exclusively against the alpha-4(IV) chain, and such antibodies will not be detected by assays that detect the alpha-3(IV) recombinant antigen.
●Isotype – Anti-GBM antibodies are usually IgG, with IgG1 and IgG3 subclasses predominant [25,26]. Rare cases involving immunoglobulin A (IgA) and IgG4 antibodies have also been reported [27-29].
●Clonality – Anti-GBM antibodies are typically polyclonal (derived from multiple independent lymphocytes; having multiple epitope specificities), although rare cases of anti-GBM disease caused by monoclonal antibodies (derived from a single clone of lymphocytes; having a single, uniform epitope specificity) have been reported [30,31].
The production of these autoantibodies is short-lived and thought to be in response to an unknown inciting stimulus [1]. The development of anti-GBM antibodies may precede the onset of clinical signs and symptoms by many months [32].
The pathogenicity of anti-GBM antibodies has been demonstrated by passive transfer experiments in which antibodies obtained from the plasma or eluted from the glomeruli of patients with this disorder produced glomerulonephritis when infused into animals. The ability of these antibodies to bind rapidly and tightly to the GBM may underlie the typically fulminant nature of this disease [33].
The variable pathogenicity of different anti-GBM antibodies is consistent with a report that antibodies against the alpha-3(IV) chain exist in normal individuals without evidence of kidney disease [34]. In this report, the anti-GBM titers and avidity were substantially lower and of a different IgG subclass distribution than seen in patients with anti-GBM disease. As these autoantibodies could be found in all studied sera, they may represent natural autoantibodies, found without immunization in all mammals and important for opsonizing debris.
Patients with and without alveolar hemorrhage appear to have similar autoantibodies against the alpha-3(IV) chain [15]. The variable presence of pulmonary disease appears to reflect a general lack of access of the circulating anti-GBM antibodies to the ABM or to the cryptic nature of the antigen. Thus, patients with pulmonary involvement often have underlying pulmonary injury due to smoking or, less frequently, infection, cocaine inhalation, or hydrocarbon exposure [35-37]. One report, however, described antibodies binding to laminin-521 in approximately one-third of patients with anti-GBM disease, particularly in those with pulmonary hemorrhage [38]. (See 'Environmental triggers' below.)
Activation of complement — Autoantibodies binding to the GBM cause damage by activating the complement system, leading to neutrophil recruitment by C5a and cellular injury by the terminal membrane attack complex [39]. Animal experiments indicate that both the classical and alternative pathways are involved, while evidence for the lectin pathway was not evident [40]. An important role of complement factor C3 was also suggested by two clinical studies showing that intensive C3 staining and slightly reduced C3 levels in serum were associated with a worse prognosis [41,42]. Similar results have been reported earlier using an assay for the circulating terminal membrane attack complex [43].
Autoreactive T cells — Experimental models and clinical studies suggest that autoreactive T cells may contribute to the development of anti-GBM disease [19,44-48]:
●T cells isolated from patients with this disorder, but not from controls, react against the alpha-3 chain of type IV collagen, the same molecule against which the anti-GBM antibodies are directed [19,49]. Regulatory T cells (CD4+ CD25+) appear to play a role in regulation of the autoimmune response [45].
●In experimental autoimmune glomerulonephritis, both Th1 and Th17 cells play a role in crescent formation [50]. The administration of an anti-CD8 monoclonal antibody or an anti-CD154 antibody could prevent and/or treat experimental crescentic glomerulonephritis [44,46]. Similarly, regulatory T cells (CD4+ CD25+), which counter the effects of autoreactive T cells, reduce the severity of glomerular lesions in murine anti-GBM glomerulonephritis [48].
●A T cell epitope-inducing anti-GBM disease in experimental models has been characterized [51,52]. Mucosal tolerance and protection from disease could be induced by nasal administration of a dominant epitope [53]. Certain microbial peptides have similarities to this T cell epitope and elicit production of anti-GBM antibody and severe glomerulonephritis [54,55]. Peptides complementary to the dominant peptide in alpha-3(IV) can also induce experimental glomerulonephritis via the idiotype/anti-idiotype network [56]. Epitope spreading may explain immune responses to other regions of the alpha-3 chain and the alpha-4 chain [57].
These observations suggest that autoreactive T cells, in addition to enhancing B cell function and antibody production, may have a direct causative role in glomerular and alveolar injury. The presence of potentially autoreactive T cells in normal individuals has been demonstrated by a study showing primary T cell responses to peptides derived from the alpha-3(IV) chain [58].
Environmental triggers — Anti-GBM disease is most often of unknown etiology, although it can occasionally be found with a temporal association with prior pulmonary and kidney injury (table 1). The association with infections may lead to clustering of cases, as was observed in North West London, United Kingdom, during the coronavirus disease 2019 (COVID-19) pandemic [59,60] (see 'Epidemiology' above). Immune dysregulation, either inborn or acquired, also appears to predispose to anti-GBM antibody generation and anti-GBM disease. It seems logical that glomerular and alveolar damage causes the release of increased amounts of autoantigen. If natural antibodies normally are involved in the clearance of such debris, an increased release would trigger an increased production, which in cases of immune dysregulation could become uncontrolled.
It is also possible that the associated injury results in ensuing damage and reveals an epitope that is normally hidden from the immune system [59]. Another possibility of the pulmonary association is that damage to alveolar capillaries that occurs in these settings allows access of existing circulating anti-GBM antibodies to antigen in the ABM.
Anti-GBM disease has been reported following treatment with the lymphocyte-depleting agent alemtuzumab [61]. The loss of regulatory T cell subsets or abnormal immune cell reconstitution after lymphocyte depletion may contribute to the development of anti-GBM disease and other autoimmune disorders after exposure to this agent.
Immune checkpoint inhibitor therapy has also been associated with rare cases of anti-GBM disease, including one case without detectable circulating anti-GBM antibodies [62-65]. The mechanisms underlying this association remain unclear.
Genetic susceptibility — Rare cases of familial anti-GBM disease have been reported [17,66-68], and there is increasing evidence that genetic factors affect the susceptibility to anti-GBM disease. Patients with HLA-DR15 and -DR4 appear to be at increased risk, while those with DR1 and DR7 are at lesser risk [69], and the association with DR15 has been confirmed in Chinese [70] and Japanese patients [71].
The importance of genetic factors in determining the development of anti-GBM disease is supported by findings in rodent models. In mice immunized with alpha-3(IV) NC1, the emergence of crescentic glomerulonephritis and lung hemorrhage was restricted to mice with major histocompatability complex (MHC) haplotypes H-2s, b, or d [72]. The nephritogenic response in H-2s maps more specifically to the Ab/Aa region. Organ inflammation was also associated with the emergence of an IL-12/Th1-like T cell phenotype, a finding consistent with a role for T cells as mentioned above. In rats with experimental anti-GBM glomerulonephritis, susceptibility was determined by copy number variation in the Fcgr3 gene [73] and by expression of the AP-1 transcription factor JunD [74]. Studies in congenic rats showed that both of these genetic loci have effects on susceptibility by modulating macrophage activity [75].
More specific molecular analysis of DR beta chains has found that a particular six-amino-acid motif common to DRw15 and DR4 may confer disease susceptibility [76]. This motif interacts with a short nephritogenic sequence of the alpha-3(IV) chain, which is in close vicinity of the EA epitope recognized by the anti-GBM autoantibodies [77]. One experimental study suggests that when this epitope is presented by DR1 instead of DR15 the peptide exposes a different set of amino acid residue side-chains, and this promotes the development of tolerogenic CD4+ T regulatory cells specific for the alpha-3(IV) chain [78]. The tolerogenic response promoted by DR1 seems to be dominant over the nephritogenic response induced by DR15. Using the same model, investigators were able to prevent and treat experimental anti-GBM disease by blocking the DR15 molecule with a peptide [79].
CLINICAL MANIFESTATIONS
Overview of typical findings — Most (approximately 90 percent) patients with anti-GBM disease present with clinical features of rapidly progressive glomerulonephritis. Between 25 and 60 percent present with concomitant alveolar hemorrhage, and a small proportion of patients present with isolated pulmonary findings. (See "Overview of the classification and treatment of rapidly progressive (crescentic) glomerulonephritis", section on 'Clinical presentation'.)
Systemic complaints and signs, such as malaise, weight loss, fever, or arthralgia, are usually experienced only for a few weeks. The presence of such signs for a longer period suggests that the patient is double positive for anti-GBM and anti-myeloperoxidase (MPO-ANCA) and has features of concurrent vasculitis [80].
Serum complement levels are typically within the normal range in patients with anti-GBM disease.
Other variants of atypical anti-GBM disease have been reported. (See 'Other variants' below.)
Kidney manifestations — The presentation of anti-GBM disease is similar to that of other forms of rapidly progressive glomerulonephritis: relatively acute kidney injury with a urinalysis showing proteinuria (which is usually not in the nephrotic range) and a nephritic sediment characterized by dysmorphic red cells (including acanthocytes), white cells, and red cell and granular casts. Macroscopic hematuria is more common in anti-GBM disease compared with other forms of rapidly progressive glomerulonephritis.
A relatively mild degree of kidney involvement may be more common than previously appreciated in patients with anti-GBM disease. A retrospective review from one center in Australia found that 5 of 14 patients (36 percent) with this disorder had hematuria and/or proteinuria but a normal creatinine clearance or serum concentration of creatinine [81].
Pulmonary manifestations — Pulmonary involvement, generally consisting of alveolar hemorrhage, affects 25 to 60 percent of patients. In rare cases, pulmonary disease predominates [28,82]. Pulmonary manifestations include shortness of breath, cough, sometimes overt hemoptysis, pulmonary infiltrates on chest radiograph, and an increased carbon monoxide diffusing capacity (DLCO) due to the presence of hemoglobin in the alveoli. Iron deficiency anemia, possibly due to prolonged pulmonary bleeding, may be seen. (See "The diffuse alveolar hemorrhage syndromes".)
Other variants
Double-positive anti-GBM and ANCA-associated disease — Patients with acute glomerulonephritis with or without pulmonary hemorrhage also may have granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Thus, the serum should be tested for antineutrophil cytoplasmic antibodies (ANCA), as well as anti-glomerular basement membrane (GBM) antibodies. Anti-GBM disease and systemic vasculitis not only have similar clinical manifestations, but between 10 and 50 percent of patients with anti-GBM disease also test positively for ANCA (usually anti-myeloperoxidase [MPO-ANCA]) at the time of diagnosis and may have signs of a systemic vasculitis or a marked systemic inflammatory response [12,83-85]. (See 'Serological testing' below.)
Low levels of ANCA may be detectable years before the production of anti-GBM antibodies and the onset of clinical symptoms. This was shown by an analysis of stored serum samples that had been obtained at the time of enlistment and every other year thereafter from 30 United States military personnel who subsequently developed anti-GBM disease [32]. Patients who were diagnosed with anti-GBM disease and healthy controls were identified from the military database, and serum samples were obtained from the Department of Defense Serum Repository. Compared with matching controls, a greater number of patients with anti-GBM disease had anti-proteinase 3 (PR3-ANCA) and anti-myeloperoxidase (MPO-ANCA) levels detected in multiple serum samples that had been obtained in the years preceding the onset of disease (82 versus 14 percent in controls for PR3-ANCA, and 73 versus 27 percent in controls for MPO-ANCA). In all cases, ANCA were detected in earlier samples than anti-GBM antibodies, which were detected months, but not years, prior to the onset of clinical symptoms.
The anti-GBM antibodies in patients who also have ANCA (double positive) have the same antigen specificity as those in patients with anti-GBM disease alone [86]. However, a nation-wide Swedish and single-center Chinese study found that double-positive patients may have lower levels but a broader spectrum of anti-GBM antibodies compared with those with anti-GBM antibodies alone [12,87]. In addition, ANCA-positive patients may develop a relapse of systemic vasculitis (see 'Antibody formation and specificity' above). Even if the patient was negative for ANCA on initial testing, ANCA serology should be repeated if there are signs of recurrent disease. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies".)
The detection of ANCA is clinically relevant as these patients may be more likely to have treatable disease than those who have only anti-GBM antibodies. However, larger series suggest that the initial outcome is similar to those with anti-GBM disease alone [4,84,85,88]. Longer-term management should be tailored to the vasculitis. (See "Anti-GBM (Goodpasture) disease: Treatment and prognosis", section on 'Whom to treat'.)
Anti-GBM disease associated with membranous nephropathy — Several cases of anti-GBM disease associated with membranous nephropathy (MN) have been described [89-94]. The onset of anti-GBM disease may precede, coincide with, or follow the diagnosis of MN. In one series, patients with combined anti-GBM disease and MN (n = 8) had a lower serum creatinine level at diagnosis (524 versus 916 micromol/L [5.9 versus 10.4 mg/dL]), lower proportion with oliguria/anuria (0 versus 50 percent), and better kidney survival at one year (62 versus 13 percent) compared with patients with anti-GBM disease without MN (n = 30) [91]. Although overall anti-GBM antibody levels were similar between the two groups, patients with combined anti-GBM disease and MN had lower antibody levels against the EB conformational epitope of alpha-3(IV) NC1. Serum antibodies against the phospholipase A2 receptor (PLA2R) were undetectable in patients with combined anti-GBM disease with MN.
MN has also been associated with crescentic glomerulonephritis in patients with positive testing for ANCA [92]. (See "Membranous nephropathy: Treatment and prognosis", section on 'Patients with crescentic GN'.)
Anti-GBM disease without detectable circulating anti-GBM antibodies — A rare variant of anti-GBM disease, described as "atypical anti-GBM nephritis", has been reported in a series of 20 patients who presented with hematuria, proteinuria, and mild kidney function impairment, without pulmonary hemorrhage [95]. Kidney biopsy in these patients demonstrated bright, linear IgG deposition along the GBM but without features of crescentic glomerulonephritis. The evolution of the disorder was indolent and not rapidly progressive. Monoclonality was commonly observed. Anti-GBM antibodies were not detected with conventional assays or Western blot methods. One-year patient and kidney survival were 93 and 85 percent, respectively. These atypical cases accounted for approximately 12 percent of anti-GBM patients at the center.
Similar clinical features were observed in another series of 60 patients from China [96]. In this study, 5 percent had alveolar hemorrhage. All patients had linear IgG deposits on kidney biopsy; 42 percent showed crescent formation, and 8 percent had crescentic glomerulonephritis (crescents occupying >50 percent of glomeruli). Over a mean of 36 months, 23 percent progressed to ESKD; deposition of C3 was associated with a worse kidney outcome.
Several possible reasons may explain the discrepancy between positive linear staining for IgG in the kidney biopsy and negative commercial testing for circulating anti-GBM antibodies. First, circulating antibodies have a much shorter half-life than kidney-bound antibodies, and when antibody production ceases, there is a time interval during which antibodies are detectable in the kidney but not in the plasma. Secondly, commercial immunoassays for anti-GBM antibodies are based upon purified bovine or recombinant human alpha(IV) chains that contain the most common epitopes, but some patients react to other epitopes and even to other molecules. As an example, a case of anti-GBM disease has been described with circulating anti-laminin 521 antibodies but no circulating antibodies against alpha-3(IV) NC1 [97]. There are reports of patients with negative testing by immunoassay who test positive for anti-GBM antibodies in other assays, such as indirect immunofluorescence using primate kidney sections, Western blot, and a biosensor system [98,99]. Thirdly, some patients have anti-GBM antibodies with IgG4 subclass restriction, which may be less readily detected by some commercial assays. Interestingly, such patients with anti-GBM antibodies that are predominantly subclass IgG4 are frequently young female smokers with severe lung involvement [28,100,101].
Anti-GBM disease after transplantation — One interesting setting in which this disorder can occur is 5 to 10 percent of kidney transplants in patients with underlying Alport syndrome (hereditary nephritis) [102]. These patients most commonly have an abnormality in the alpha-5 chain of type IV collagen, although alpha-3 and alpha-4 chain abnormalities may occur. This leads to defective organization of the alpha-5, -4 and -3 collagen chains in the basement membrane and altered Goodpasture antigen in the alpha-3 chain, so it is not recognized by anti-GBM antibodies. By comparison, the Goodpasture antigen is normal in the donor kidney, potentially initiating an immune response against this previously "unseen" antigen in the transplanted kidney [102]. The alloantibody produced in X-linked Alport posttransplantation nephritis, however, recognizes a different epitope than the autoantibody in Goodpasture disease [23]. (See "Genetics, pathogenesis, and pathology of Alport syndrome (hereditary nephritis)".)
EVALUATION AND DIAGNOSIS
When to suspect anti-GBM disease — The diagnosis of anti-GBM disease should be suspected in any patient presenting with clinical symptoms and/or signs concerning for acute or subacute nephritic syndrome (eg, hematuria, proteinuria, cellular casts, kidney function impairment), particularly if accompanied by rapid progression and/or pulmonary (alveolar) hemorrhage. Anti-GBM disease should also be suspected in patients presenting with alveolar hemorrhage alone since pulmonary disease may be the predominant presenting feature in rare cases. (See "Glomerular disease: Evaluation and differential diagnosis in adults", section on 'Glomerulonephritis (hematuria with proteinuria, kidney function impairment, or other manifestations)'.)
In addition, the following clinical scenarios should raise suspicion for a less common variant of anti-GBM disease:
●Patients with features of systemic disease, such as malaise, weight loss, fever, or arthralgia, which suggest a concurrent vasculitis (see 'Double-positive anti-GBM and ANCA-associated disease' above)
●Patients with the nephrotic syndrome who develop a rapid decline in kidney function (see 'Anti-GBM disease associated with membranous nephropathy' above)
●Patients with proteinuria, hematuria, or mild kidney function impairment who have linear IgG staining of the glomerular basement membrane (GBM) on kidney biopsy (see 'Anti-GBM disease without detectable circulating anti-GBM antibodies' above)
●Kidney transplant recipients with underlying Alport syndrome (hereditary nephritis) who present with acute glomerulonephritis or graft failure (see 'Anti-GBM disease after transplantation' above)
Establishing the diagnosis — Patients suspected of having anti-GBM disease should undergo a diagnostic evaluation for possible causes of acute glomerulonephritis. In general, this evaluation consists of laboratory testing and, in many patients, a kidney biopsy to obtain a definitive diagnosis. (See "Glomerular disease: Evaluation and differential diagnosis in adults", section on 'Evaluation of glomerulonephritis'.)
The diagnosis of anti-GBM disease requires demonstration of anti-GBM antibodies either in the serum or the kidney. Kidney biopsy should be performed, unless there is a contraindication, because the accuracy of serologic assays is variable. In addition, kidney biopsy provides important information regarding the activity and chronicity of kidney involvement that may help guide therapy and excludes other possible causes of glomerulonephritis. (See 'Kidney biopsy' below and 'Serological testing' below.)
Testing for antineutrophil cytoplasmic antibodies (ANCA), if not already performed as part of the initial evaluation of suspected glomerulonephritis, should be performed in all patients who are diagnosed with anti-GBM disease. The presence of both anti-GBM antibodies and ANCA supports a diagnosis of double-positive anti-GBM and ANCA-associated disease. (See 'Serological testing' below and 'Double-positive anti-GBM and ANCA-associated disease' above.)
Kidney biopsy — A kidney biopsy should be performed without delay in all patients suspected of having anti-GBM disease, unless contraindicated. However, a kidney biopsy may be delayed in patients who require urgent treatment for alveolar hemorrhage. (See "The kidney biopsy", section on 'Contraindications'.)
Light microscopy usually shows crescentic glomerulonephritis (although milder cases do occur), whereas immunofluorescence microscopy demonstrates the virtually pathognomonic finding of linear deposition of IgG along the glomerular capillaries and occasionally the distal tubules (picture 1A-E). In rare cases, the antibody may be IgA or immunoglobulin M (IgM) [30].
In some cases, the tubular staining reflects distinct circulating anti-tubular basement membrane (TBM) antibodies. The observation that the associated tubulointerstitial disease (interstitial infiltrate and fibrosis, tubular atrophy) is more severe in patients with anti-TBM antibodies is consistent with these antibodies being pathogenetically important [103]. However, alpha-3(IV) NC1 is present in a proportion of tubules (distal), so tubular deposits may reflect increased access of anti-GBM antibody to the TBM.
Serological testing — The diagnosis of anti-GBM disease can usually be established rapidly (particularly when kidney biopsy cannot be performed or will be delayed), either by serum assay for anti-GBM antibodies using a direct enzyme-linked immunoassay (ELISA) with purified or semi-purified antigens or by indirect immunofluorescence. Neither method is completely reliable; thus, a kidney biopsy to confirm the diagnosis is recommended unless contraindicated. (See 'Kidney biopsy' above.)
As stated above, patients with suspected anti-GBM disease should also be tested for ANCA. (See 'Double-positive anti-GBM and ANCA-associated disease' above and 'Establishing the diagnosis' above.)
The more common approach is the detection of anti-GBM antibodies in serum using a direct ELISA; the specificity of the antibody can be confirmed by Western blot [104]. High antibody titers are usually found in those with rapidly progressive disease [98,105]. The sensitivity varies depending upon the commercial kit used, ranging from 63 to nearly 100 percent [105,106]. False-negative results may occur in those with low antibody titers [98] and in some patients with Alport syndrome who develop posttransplant anti-GBM disease, with antibodies directed against the alpha-5(IV) chain [107]. (See "Genetics, pathogenesis, and pathology of Alport syndrome (hereditary nephritis)" and 'Anti-GBM disease without detectable circulating anti-GBM antibodies' above.)
False-positive results occasionally occur with commercial ELISA assays that do not use purified Goodpasture antigen [104,105,108]. ELISA assays for the detection of anti-GBM antibodies that use native or recombinant human alpha-3(IV) antigen substrates are much more sensitive and specific, with reported sensitivity of 95 to 100 percent and specificity of 91 to 100 percent [106].
Indirect immunofluorescence is rarely performed and requires an experienced kidney pathologist. This test involves incubation of the patient's serum with normal human or primate kidney tissue. Fluorescein-labeled anti-human IgG is then added to see whether IgG deposition has occurred, and the results are compared with those obtained with normal serum. The test has a high false-negative rate, possibly as high as 40 percent. However, if performed appropriately and in the proper clinical setting (eg, severe acute glomerulonephritis), a positive test is probably diagnostic, although rigorous studies have not been performed.
One case report provides an example in which commercial tests inaccurately suggested that a patient had anti-GBM antibodies, which was clarified using recombinant human alpha-3(IV) NC1 proteins [108]. A patient with slowly progressive dyspnea, hematuria, and proteinuria had positive circulating anti-GBM antibodies as detected by standard testing and, on kidney biopsy, trace linear IgG deposits along the GBM. Repeat testing using recombinant human NC1 domains demonstrated that the patient had antibodies against alpha-2(IV) NC1 and not to the Goodpasture antigen alpha-3(IV) NC1. The positive commercial tests were probably detecting nonspecific cross-reactivity to alpha-3(IV) NC1.
Pulmonary studies — Pulmonary studies are not required to establish the diagnosis of anti-GBM disease; however, a chest radiograph is generally performed in patients who present with recent-onset hemoptysis or dyspnea. Findings on plain chest radiographs in patients with anti-GBM disease and alveolar hemorrhage are nonspecific and typically show new patchy or diffuse opacities. Further evaluation with high-resolution thoracic computed tomography (CT) scan, which characteristically shows ground glass or consolidative opacities in a diffuse and bilateral distribution, is necessary before pulmonary involvement can be ruled out (see "The diffuse alveolar hemorrhage syndromes", section on 'Radiographic findings'). The gold standard to diagnose pulmonary hemorrhage when alternative reasons for pulmonary symptoms and signs are present is bronchoalveolar lavage [82]. (See "The diffuse alveolar hemorrhage syndromes", section on 'Bronchoalveolar lavage'.)
Pulmonary function testing is not routinely performed but may show an increased carbon monoxide diffusing capacity (DLCO), which is due to the presence of hemoglobin in the alveoli. However, in acute alveolar hemorrhage, the patient may not be sufficiently stable to perform this test. (See "Overview of pulmonary function testing in adults".)
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of anti-GBM disease includes other causes of acute glomerulonephritis associated with pulmonary hemorrhage (ie, "pulmonary renal syndromes") and other kidney disorders in which linear IgG staining may be seen in the glomeruli on kidney biopsy:
●Acute glomerulonephritis with pulmonary hemorrhage ("pulmonary renal syndrome") – Pulmonary hemorrhage can also be seen with other acute nephritides due to pulmonary edema, or to lung involvement in antineutrophil cytoplasmic antibodies (ANCA)-positive and other forms of systemic vasculitis (such as IgA vasculitis [Henoch-Schönlein purpura] and mixed cryoglobulinemia syndrome) and systemic lupus erythematosus [35]. In one report of 45 such patients, eight had anti-GBM disease, while 25 had a systemic vasculitis [35]. Differentiating between these disorders upon the basis of clinical features alone can be difficult, and serologic testing and kidney biopsy are generally required to establish the diagnosis.
•(See "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis", section on 'Diagnosis'.)
•(See "Lupus nephritis: Diagnosis and classification", section on 'Evaluation and diagnosis'.)
•(See "Clinical manifestations of antiphospholipid syndrome", section on 'Pulmonary involvement'.)
Although they are not forms of acute glomerulonephritis, antiphospholipid antibody syndrome and pulmonary infection with concomitant acute kidney injury may also present in a similar manner to the pulmonary renal syndromes listed above [109]. (See "Diagnosis of antiphospholipid syndrome", section on 'Diagnosis'.)
●Linear IgG staining on kidney biopsy – There are two other disorders in which linear IgG staining can be seen in the glomeruli: diabetic nephropathy and fibrillary glomerulonephritis. In the former and perhaps in the latter, the IgG is nonspecifically absorbed onto the highly permeable glomerular capillary wall and onto the fibrils, respectively. Staining is rarely as strong as with anti-GBM disease (see "Glomerular diseases due to nonamyloid fibrillar deposits"). In diabetic nephropathy, there is also linear deposition of albumin and other plasma proteins [110].
Diabetic nephropathy and fibrillary glomerulonephritis can be easily distinguished from anti-GBM disease on both clinical and histopathologic grounds. Circulating anti-GBM antibodies are absent in both disorders, and crescents are not seen in diabetic nephropathy. The history of diabetes, the finding of diabetic glomerulosclerosis on light microscopy, and, in fibrillary glomerulonephritis, the presence of the characteristic fibrils on electron microscopy are also helpful.
SUMMARY AND RECOMMENDATIONS
●Definition – Anti-GBM antibody disease is a disorder in which circulating antibodies are directed against an antigen intrinsic to the glomerular basement membrane (GBM) in the kidney, thereby resulting in acute or rapidly progressive glomerulonephritis that is typically associated with crescent formation. (See 'Introduction' above.)
●Pathogenesis – The principal target for the anti-GBM antibodies is the NC1 domain of the alpha-3 chain of type IV collagen (alpha-3(IV) chain), which is highly expressed in the GBM and alveoli. Anti-GBM disease is most often idiopathic, although it can occasionally follow pulmonary injury or kidney injury, such as infections, inhalation of hydrocarbons, or other forms of glomerulonephritis. (See 'Pathogenesis' above.)
●Clinical manifestations – Most (>90 percent) patients with anti-GBM disease present with clinical features of rapidly progressive glomerulonephritis. Somewhere between 20 to 60 percent present with concomitant alveolar hemorrhage, and a small proportion of patients present with isolated pulmonary findings. Systemic complaints and signs, such as malaise, weight loss, fever, or arthralgia, are usually present only during a short prodromal period. (See 'Clinical manifestations' above.)
●When to suspect anti-GBM disease – The diagnosis of anti-GBM disease should be suspected in any patient presenting with clinical symptoms and/or signs concerning for acute glomerulonephritis (eg, hematuria, proteinuria, cellular casts, kidney function impairment), particularly if accompanied by rapid progression and/or pulmonary (alveolar) hemorrhage. Anti-GBM disease should also be suspected in patients presenting with alveolar hemorrhage alone since pulmonary disease may be the predominant presenting feature in rare cases. (See 'When to suspect anti-GBM disease' above.)
In addition, the following clinical scenarios should raise suspicion for a less common variant of anti-GBM disease:
•Patients with features of systemic disease, such as malaise, weight loss, fever, or arthralgia, which suggest a concurrent vasculitis (see 'Double-positive anti-GBM and ANCA-associated disease' above)
•Patients with a known diagnosis of membranous nephropathy (MN) who develop a rapid decline in kidney function (see 'Anti-GBM disease associated with membranous nephropathy' above)
•Patients with proteinuria, hematuria, or mild kidney function impairment who have linear immunoglobulin G (IgG) staining of the GBM on kidney biopsy (see 'Anti-GBM disease without detectable circulating anti-GBM antibodies' above)
•Kidney transplant recipients with underlying Alport syndrome (hereditary nephritis) who present with acute glomerulonephritis or graft failure (see 'Anti-GBM disease after transplantation' above)
●Establishing the diagnosis – The diagnosis of anti-GBM disease requires demonstration of anti-GBM antibodies either in the serum or the kidney. Kidney biopsy should be performed, unless there is a contraindication, because the accuracy of serologic assays is variable. In addition, kidney biopsy provides important information regarding the activity and chronicity of kidney involvement that may help guide therapy and excludes other possible causes of glomerulonephritis. Testing for antineutrophil cytoplasmic antibodies (ANCA) should be performed in all patients who are diagnosed with anti-GBM disease. The presence of both anti-GBM antibodies and ANCA supports a diagnosis of double-positive anti-GBM and ANCA-associated disease. (See 'Establishing the diagnosis' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Raghu Kalluri, MD, PhD, who contributed to earlier versions of this topic review.
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