Anti-Glomerular Basement Membrane Disease

Complex MONDO:0009303 Pathograph 21 Show in embeddings browser Autoimmune disease

Anti-glomerular basement membrane (anti-GBM) disease, historically called Goodpasture syndrome or Goodpasture disease, is a rare organ-specific autoimmune small-vessel vasculitis caused by circulating autoantibodies (predominantly IgG) directed against the noncollagenous-1 (NC1) domain of the alpha-3 chain of type IV collagen, the "Goodpasture antigen." This autoantigen is expressed in the specialized basement membranes of the renal glomerulus and the pulmonary alveolus, so the disease classically presents as a pulmonary-renal syndrome of rapidly progressive (crescentic) glomerulonephritis with diffuse alveolar hemorrhage. It is not a Mendelian disease: susceptibility is strongly linked to HLA-DRB1*15:01 (DR15). Environmental factors, including infection, may trigger disease in susceptible people, but the initiating event is not established for an individual patient.

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6
Pathophys.
1
Histopath.
7
Phenotypes
1
Hypotheses
2
Gaps
21
Pathograph
2
Genes
5
Medical Actions
2
Subtypes
1
Differentials
3
Datasets
1
Trials
2
Models
3
References
1
Deep Research
◆

Subtypes

2
Atypical seronegative anti-GBM disease
A heterogeneous biopsy-defined presentation with linear GBM IgG but absent circulating anti-GBM antibodies. In a 60-patient cohort, kidney injury was generally milder than classic disease, but hematuria, proteinuria, complement deposition, crescent formation, kidney failure, and death still occurred.
Show evidence (2 references)
PMID:33013861 SUPPORT Human Clinical
"Atypical cases of anti-glomerular basement membrane (GBM) disease had absent circulating antibodies but linear IgG deposits along GBM in the kidneys."
Defines the seronegative, biopsy-positive atypical subtype.
PMID:33013861 SUPPORT Human Clinical
"Though heterogeneous, a substantial number of the patients had complement activation and crescent formation. Patients having crescents presented with more severe clinical course and worse outcomes."
Supports heterogeneity and clinically important crescentic disease within the atypical cohort.
Double-positive anti-GBM and ANCA disease
Anti-GBM disease with concurrent ANCA has the severe early presentation of anti-GBM disease but a longer-term relapse risk resembling ANCA-associated vasculitis, so maintenance immunosuppression differs from classic disease.
Show evidence (1 reference)
PMID:28506760 SUPPORT Human Clinical
"No single-positive anti-GBM patients experienced disease relapse, whereas approximately half of surviving patients with AAV and double-positive patients had recurrent disease"
Supports the relapse-prone double-positive trajectory.
◈

Mechanistic Hypotheses

1
Conformeropathy / cryptic-neoepitope model
conformeropathy CANONICAL
Evidence balance 1 support
The dominant mechanistic model holds that anti-GBM disease is an autoimmune "conformeropathy": the immunodominant epitopes are normally sequestered within the cross-linked alpha345NC1 hexamer (immune privilege), and disease requires an environmental insult that dissociates the hexamer to expose cryptic neoepitopes on alpha3/alpha5(IV)NC1 in an HLA-DR15-susceptible host.
Pathograph links
Conformational exposure of cryptic alpha3/alpha5(IV)NC1 epitopes -> HLA-restricted loss of tolerance and anti-GBM IgG production Exposure of normally cryptic NC1 epitopes provides antigenic substrate for the autoreactive response in the conformeropathy model.
Show evidence (1 reference)
PMID:20660402 SUPPORT In Vitro
"The antibodies bound to distinct epitopes encompassing region E(A) in the alpha5NC1 monomer and regions E(A) and E(B) in the alpha3NC1 monomer, but they did not bind to the native cross-linked alpha345NC1 hexamer"
Supports the cryptic-epitope component of the conformeropathy model.
?

Discussions and Knowledge Gaps

2
What diagnostic and treatment approach best identifies and manages atypical seronegative anti-GBM disease?
KNOWLEDGE GAP OPEN gap_atypical_seronegative_management
Attached to
diagnosis#Recognition of atypical seronegative anti-GBM disease
Biopsy-positive, seronegative cases are heterogeneous, and evidence does not justify assuming the natural history or treatment response of classic circulating-antibody-positive disease.
Show evidence (1 reference)
PMID:40973182 SUPPORT Other
"Atypical anti-GBM presentations, including seronegative cases, are now better recognized but their optimal management remains unclear."
The current treatment standard explicitly identifies management as unresolved.
Which induction regimen and emerging adjuncts improve patient and kidney outcomes in prespecified anti-GBM subgroups?
KNOWLEDGE GAP OPEN gap_treatment_comparative_evidence
Attached to
treatments#Cyclophosphamide treatments#Rituximab treatments#Imlifidase (investigational IgG-cleaving enzyme)
Standard treatment is supported largely by observational experience, while rituximab evidence is selected and nonrandomized and the confirmatory imlifidase trial was terminated without posted results.
Show evidence (1 reference)
PMID:40973182 SUPPORT Other
"Future research should define the use of oral versus intravenous cyclophosphamide in anti-GBM disease, clarify the role of rituximab and determine the place of emerging therapies such as imlifidase."
Directly identifies unresolved regimen and adjunctive-treatment questions.
⚙

Pathophysiology

6
Conformational exposure of cryptic alpha3/alpha5(IV)NC1 epitopes
The immunodominant E_A and E_B epitopes are sequestered within the native, cross-linked alpha345NC1 hexamer. Dissociation or conformational alteration exposes epitopes on alpha3 and alpha5 NC1 monomers that patient antibodies can bind. This molecular architecture supports a cryptic-epitope model, but does not by itself establish which exposure initiates disease in humans.
Conformeropathy / cryptic-neoepitope model
COL4A3 hgnc:2204 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COL4A3 (hgnc:2204). hgnc:2204 is a gene from the HUGO Gene Nomenclature Committee.
extracellular matrix organization GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
HLA-restricted loss of tolerance and anti-GBM IgG production Exposure of normally cryptic NC1 epitopes provides antigenic substrate for the autoreactive response in the conformeropathy model. Conformeropathy / cryptic-neoepitope model
Show evidence (2 references)
PMID:20660402 SUPPORT In Vitro
"The antibodies bound to distinct epitopes encompassing region E(A) in the alpha5NC1 monomer and regions E(A) and E(B) in the alpha3NC1 monomer, but they did not bind to the native cross-linked alpha345NC1 hexamer"
Shows the autoantibodies bind cryptic E_A/E_B neoepitopes exposed on dissociated alpha3/alpha5 NC1 monomers but not the intact native hexamer, supporting the conformeropathy model.
PMID:19729652 SUPPORT In Vitro
"the cross-link also confers immune privilege to the collagen IV antigen of Goodpasture autoimmune disease"
Identifies the sulfilimine (S=N) cross-link that stabilizes the NC1 hexamer and confers immune privilege by sequestering the cryptic Goodpasture epitopes.
HLA-restricted loss of tolerance and anti-GBM IgG production
In susceptible hosts, alpha3(IV)NC1-reactive CD4+ T cells and B cells form an autoimmune response that produces directly pathogenic anti-GBM IgG. The strong HLA-DR15 association supports HLA-restricted antigen presentation; HLA susceptibility is not a causal germline mutation.
alpha3(IV)NC1-reactive CD4+ T-helper cell CL:0000084 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves alpha3(IV)NC1-reactive CD4+ T-helper cell, annotated with T cell (CL:0000084). CL:0000084 is a cell type from the Cell Ontology. autoantibody-producing B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves autoantibody-producing B cell, annotated with B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology.
HLA-DRB1 hgnc:4948 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves HLA-DRB1 (hgnc:4948). hgnc:4948 is a gene from the HUGO Gene Nomenclature Committee.
antigen processing and presentation GO:0019882 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves antigen processing and presentation (GO:0019882). GO:0019882 is a biological process from the Gene Ontology. humoral immune response mediated by circulating immunoglobulin GO:0002455 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased humoral immune response mediated by circulating immunoglobulin (GO:0002455). GO:0002455 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Linear anti-GBM IgG deposition Circulating autoantibody binds its basement-membrane target.
Show evidence (2 references)
PMID:8589284 SUPPORT Human Clinical
"reactivity to alpha 3(IV) NC1 domains is both sufficient and necessary for the expression of autoimmune disease directed to the NC1 domain of Type IV collagen"
Supports alpha3(IV)NC1 as the disease-defining autoantigen.
PMID:14569090 SUPPORT Human Clinical
"Goodpasture's disease is a severe nephritis characterized by autoantibodies to the alpha3 chain of type IV collagen, alpha3(IV)NC1, in the glomerular basement membrane. The disease is very strongly associated with HLA-DR15"
Supports the autoantibody target and strong HLA-DR15 association.
Linear anti-GBM IgG deposition
Circulating anti-GBM IgG deposits linearly along glomerular and alveolar basement membranes, positioning pathogenic antibody at both capillary beds.
renal glomerulus UBERON:0000074 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in renal glomerulus (UBERON:0000074). UBERON:0000074 is an anatomical location from the Uberon multi-species anatomy ontology. alveolus of lung UBERON:0002299 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in alveolus of lung (UBERON:0002299). UBERON:0002299 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Complement-dependent capillaritis Tissue-bound antibody initiates complement-dependent inflammation.
Show evidence (1 reference)
PMID:28515156 SUPPORT Other
"It is an archetypic autoimmune disease, caused by the development of directly pathogenic autoantibodies targeting a well characterized autoantigen expressed in the basement membranes of these organs"
Supports pathogenic antibody targeting of organ basement membranes.
Complement-dependent capillaritis
Tissue-bound anti-GBM IgG activates complement and recruits inflammatory leukocytes, producing local capillaritis and capillary-wall injury.
neutrophil CL:0000775 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neutrophil (CL:0000775). CL:0000775 is a cell type from the Cell Ontology. macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
complement activation, classical pathway GO:0006958 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased complement activation, classical pathway (GO:0006958). GO:0006958 is a biological process from the Gene Ontology. ↑ INCREASED leukocyte migration GO:0050900 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased leukocyte migration (GO:0050900). GO:0050900 is a biological process from the Gene Ontology. ↑ INCREASED inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED
renal glomerulus UBERON:0000074 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in renal glomerulus (UBERON:0000074). UBERON:0000074 is an anatomical location from the Uberon multi-species anatomy ontology. alveolus of lung UBERON:0002299 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in alveolus of lung (UBERON:0002299). UBERON:0002299 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Necrotizing crescentic glomerular injury Glomerular capillary-wall injury drives necrosis and crescent formation.
Alveolar capillary-wall disruption Alveolar capillary-wall disruption permits blood to enter alveolar spaces.
Show evidence (1 reference)
PMID:9409643 SUPPORT Model Organism
"These studies support a critical role for complement in the development of anti-GBM disease."
Complement-deficient mouse experiments support a causal effector role for complement; this heterologous model does not reproduce loss of tolerance.
Necrotizing crescentic glomerular injury
Glomerular basement membrane rupture permits fibrin and inflammatory cells into Bowman's space, triggering parietal epithelial and podocyte proliferation, cellular crescents, and rapidly progressive glomerulonephritis.
glomerular parietal/visceral epithelial cell CL:1000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves glomerular parietal/visceral epithelial cell, annotated with glomerular cell (CL:1000746). CL:1000746 is a cell type from the Cell Ontology.
renal glomerulus UBERON:0000074 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in renal glomerulus (UBERON:0000074). UBERON:0000074 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Rapidly progressive glomerulonephritis
Hematuria
Proteinuria
Acute kidney injury
Show evidence (1 reference)
PMID:30404116 SUPPORT Other
"Once deposited in tissue, these autoantibodies incite a local capillaritis which manifests as rapidly progressive glomerulonephritis (GN) in 80 to 90% of patients, and with concurrent alveolar hemorrhage in ∼50%."
Links tissue-deposited autoantibody and capillaritis to rapidly progressive glomerulonephritis.
Alveolar capillary-wall disruption
Injury to the alveolar capillary basement membrane permits blood to enter alveolar spaces, producing diffuse alveolar hemorrhage and consequent blood loss.
alveolus of lung UBERON:0002299 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in alveolus of lung (UBERON:0002299). UBERON:0002299 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Diffuse alveolar hemorrhage
Hemoptysis
Anemia
Show evidence (1 reference)
PMID:30404116 SUPPORT Other
"Once deposited in tissue, these autoantibodies incite a local capillaritis which manifests as rapidly progressive glomerulonephritis (GN) in 80 to 90% of patients, and with concurrent alveolar hemorrhage in ∼50%."
Links local capillaritis to alveolar hemorrhage in approximately half of patients.
✶

Histopathology

1
Linear IgG deposition along the glomerular basement membrane
Direct immunofluorescence shows pathognomonic linear (ribbon-like) IgG deposition along the GBM, distinguishing anti-GBM disease from pauci-immune (ANCA) and granular (immune-complex) glomerulonephritides.
Show evidence (1 reference)
PMID:40973182 SUPPORT Other
"Diagnosis relies on clinical features, kidney biopsy showing linear IgG deposition along the GBM, and/or detection of circulating anti-GBM antibodies."
Identifies linear GBM IgG deposition as the characteristic diagnostic biopsy finding.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Anti-Glomerular Basement Membrane Disease Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

7
Blood 2
Diffuse alveolar hemorrhage FREQUENT Pulmonary hemorrhage HP:0040223 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary hemorrhage (HP:0040223). HP:0040223 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38493958 SUPPORT Human Clinical
"The pooled prevalence rates of anti-GBM antibodies, antineutrophil cytoplasmic antibodies (ANCA), and lung hemorrhage were 88.8%, 27.4%, and 32.6%, respectively."
Pooled meta-analysis quantifies lung hemorrhage at 32.6% of patients, supporting the FREQUENT frequency band for this phenotype.
PMID:28515156 SUPPORT Other
"40%-60% will have concurrent alveolar hemorrhage"
The McAdoo & Pusey review reports 40-60% of patients have concurrent alveolar hemorrhage, corroborating the FREQUENT frequency band.
Anemia HP:0001903 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:8532389 SUPPORT Human Clinical
"hemoptysis, severe iron deficiency anemia and microscopic hematuria and proteinuria"
A Goodpasture's-disease case report documenting severe iron-deficiency anemia (from pulmonary hemorrhage) at presentation. PARTIAL because this is a single case report.
Genitourinary 3
Hematuria HP:0000790 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hematuria (HP:0000790). HP:0000790 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33013861 SUPPORT Human Clinical
"Thirty eight (63.3%) patients exhibited hematuria and 4 of them had macroscopic hematuria."
Directly documents hematuria in a 60-patient atypical cohort; PARTIAL because the percentage must not be generalized to classic disease.
Proteinuria HP:0000093 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Proteinuria (HP:0000093). HP:0000093 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33013861 SUPPORT Human Clinical
"Proteinuria existed in 56 (93.3%) patients and 26 of them reached nephrotic level."
Directly documents proteinuria in a 60-patient atypical cohort; PARTIAL because its high percentage and severity must not be generalized to classic disease.
Acute kidney injury HP:0001919 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Acute kidney injury (HP:0001919), qualified as temporality acute. HP:0001919 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE
Show evidence (1 reference)
PMID:28515156 SUPPORT Other
"presentation with oligoanuria, a high proportion of glomerular crescents, or kidney failure requiring dialysis augur badly for renal prognosis"
Supports acute kidney injury (oligoanuria, dialysis-requiring kidney failure) as a severe, prognostically important renal phenotype.
Respiratory 1
Hemoptysis HP:0002105 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemoptysis (HP:0002105). HP:0002105 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:8532389 SUPPORT Human Clinical
"hemoptysis, severe iron deficiency anemia and microscopic hematuria and proteinuria"
Directly documents hemoptysis in an anti-GBM case; PARTIAL because this is a single case report and no population frequency is inferred.
Other 1
Rapidly progressive glomerulonephritis HP:0000099 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Glomerulonephritis (HP:0000099), qualified as temporality acute; course progressive. HP:0000099 is a phenotype from the Human Phenotype Ontology.
Temporal: ACUTE Course: PROGRESSIVE
Show evidence (1 reference)
PMID:28515156 SUPPORT Other
"The majority of patients develop widespread glomerular crescent formation, presenting with features of rapidly progressive GN"
Supports rapidly progressive crescentic glomerulonephritis as the cardinal renal phenotype.
🧬

Genetic Associations

2
HLA-DRB1 (DR15 / DRB1*15:01) susceptibility (Susceptibility)
Gene: HLA-DRB1 hgnc:4948 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is HLA-DRB1 (hgnc:4948). hgnc:4948 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: RISK_FACTOR
Show evidence (1 reference)
PMID:14569090 SUPPORT Human Clinical
"The disease is very strongly associated with HLA-DR15"
Directly supports the dominant HLA-DR15 (DRB1*15:01) susceptibility association.
COL4A3 (alpha-3 type IV collagen) autoantigen target gene (Autoantigen target (not a causal germline mutation))
Gene: COL4A3 hgnc:2204 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is COL4A3 (hgnc:2204). hgnc:2204 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:8589284 SUPPORT Human Clinical
"the anti-GBM antibodies from all patients reacted with the alpha 3(IV) NC1 (85% exclusively)"
Supports the alpha-3 chain of type IV collagen (COL4A3 product) as the autoantibody target in anti-GBM/Goodpasture disease.
💊

Medical Actions

5
Plasma exchange (plasmapheresis)
Action: PlasmapheresisNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Plasmapheresis (NCIT:C15304). NCIT:C15304 is a clinical intervention from the NCI Thesaurus. NCIT:C15304
Therapeutic plasma exchange rapidly removes circulating pathogenic anti-GBM IgG and is a cornerstone of induction therapy with glucocorticoids and cyclophosphamide.
Mechanism Target:
INHIBITS Linear anti-GBM IgG deposition — Plasma exchange removes circulating pathogenic anti-GBM IgG, interrupting antibody binding and the downstream complement/neutrophil-mediated injury.
Show evidence (1 reference)
PMID:28515156 SUPPORT Other
"Treatment aims to rapidly remove pathogenic autoantibody, typically with the use of plasma exchange, along with steroids and cytotoxic therapy"
Directly supports antibody removal as the mechanism of plasma exchange.
Target Phenotypes: Glomerulonephritis HP:0000099 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Glomerulonephritis (HP:0000099). HP:0000099 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:40973182 SUPPORT Other
"Historically, untreated disease was rapidly fatal, but the introduction of plasma exchange combined with cyclophosphamide and glucocorticoids has significantly improved outcomes, particularly in patients who are not dialysis-dependent at presentation."
Supports plasma exchange as one component of current combination induction therapy.
PMID:41629746 SUPPORT Human Clinical
"Two patients (22.2%) achieved dialysis independence at 10 and 11 months. Both patients had relatively preserved normal glomeruli (15.8%-37.2%) and achieved early remission."
A 2026 nine-patient dialysis-dependent case series documents selected late recovery; PARTIAL reflects its size, selection, and lack of a control group.
PMID:28515156 SUPPORT Other
"Treatment aims to rapidly remove pathogenic autoantibody, typically with the use of plasma exchange, along with steroids and cytotoxic therapy"
Directly supports plasma exchange as the antibody-removal cornerstone of induction.
High-dose glucocorticoids
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: glucocorticoid CHEBI:24261 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses glucocorticoid (CHEBI:24261). CHEBI:24261 is a therapeutic agent from Chemical Entities of Biological Interest.
Glucocorticoids suppress inflammation and are given with plasma exchange and cyclophosphamide in standard induction therapy.
Show evidence (1 reference)
PMID:28515156 SUPPORT Other
"along with steroids and cytotoxic therapy to prevent ongoing autoantibody production and tissue inflammation"
Supports steroids (with cytotoxic therapy) to control inflammation and autoantibody production.
Cyclophosphamide
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: cyclophosphamide CHEBI:4027 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses cyclophosphamide (CHEBI:4027). CHEBI:4027 is a therapeutic agent from Chemical Entities of Biological Interest.
The cytotoxic agent cyclophosphamide suppresses new autoantibody production and, with plasma exchange and steroids, completes standard induction therapy.
Mechanism Target:
INHIBITS HLA-restricted loss of tolerance and anti-GBM IgG production — Cyclophosphamide suppresses the lymphocyte-driven production of new anti-GBM autoantibody, acting at the autoantibody-formation node.
Show evidence (1 reference)
PMID:28515156 SUPPORT Other
"along with steroids and cytotoxic therapy to prevent ongoing autoantibody production and tissue inflammation"
Directly supports suppression of ongoing autoantibody production by cytotoxic therapy.
Show evidence (1 reference)
PMID:28515156 SUPPORT Other
"along with steroids and cytotoxic therapy to prevent ongoing autoantibody production and tissue inflammation"
Supports cytotoxic therapy (cyclophosphamide is the standard cytotoxic agent) to prevent ongoing autoantibody production.
Rituximab
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: rituximab NCIT:C1702 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses rituximab (NCIT:C1702). NCIT:C1702 is a therapeutic agent from the NCI Thesaurus.
Anti-CD20 B-cell depletion may be considered as second-line treatment when cyclophosphamide is contraindicated. Available outcome estimates are derived mainly from selected case reports and series, not randomized comparison. A 2026 retrospective cohort found faster dialysis independence but no statistically significant difference in absolute dialysis independence or three-year kidney failure.
Mechanism Target:
INHIBITS HLA-restricted loss of tolerance and anti-GBM IgG production — Rituximab depletes CD20+ B cells upstream of new anti-GBM antibody production; it does not directly eliminate mature plasma cells.
Show evidence (1 reference)
PMID:40225363 SUPPORT Human Clinical
"The results indicate that rituximab can be considered as a second-line therapy in anti-GBM disease when cyclophosphamide is contraindicated."
Supports clinical use of the B-cell-depleting agent; PARTIAL because the cited synthesis does not experimentally isolate this mechanistic edge.
Show evidence (2 references)
PMID:40225363 SUPPORT Human Clinical
"Acknowledging the limitations of our study, including publication and selection bias, rituximab had a favorable toxicity and efficacy profile. The results indicate that rituximab can be considered as a second-line therapy in anti-GBM disease when cyclophosphamide is contraindicated."
An individual-patient synthesis of 67 selected published cases supports a second-line role while explicitly identifying publication and selection bias; PARTIAL reflects the nonrandomized evidence base.
DOI:10.3389/fimmu.2026.1835889 SUPPORT Human Clinical
"Although the RTX group demonstrated only numerical advantages in the absolute rate of dialysis independence (50.0% vs. 21.05%, p=0.107) and the 3-year ESRD incidence (42.86% vs. 63.46%, p=0.223), the median time to dialysis independence was significantly shorter in the RTX group compared to the..."
Directly distinguishes a statistically significant time-to-recovery result from nonsignificant absolute kidney outcomes in a retrospective cohort.
Imlifidase (investigational IgG-cleaving enzyme)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Imlifidase (IdeS), an IgG-degrading enzyme of Streptococcus pyogenes, cleaves circulating IgG. A 15-patient open-label Phase 2a study reported antibody levels below the assay reference range at six hours and a kidney-survival signal against historical controls, but required randomized confirmation. The subsequent GOOD-IDES-02 Phase 3 trial was terminated by sponsor decision and has no posted results.
Show evidence (3 references)
PMID:35260419 SUPPORT Human Clinical
"Then 6 hours after imlifidase infusion, all patients had anti-GBM antibodies levels below the reference range of a prespecified assay."
Directly supports rapid anti-GBM antibody cleavage in the 15-patient Phase 2a study.
PMID:35260419 SUPPORT Human Clinical
"In this pilot study, the use of imlifidase was associated with a better outcome compared with earlier publications, without major safety issues, but the findings need to be confirmed in a randomized controlled trial."
Supports an early efficacy signal while directly preserving the authors' requirement for randomized confirmation.
clinicaltrials:NCT05679401 SUPPORT Human Clinical
"An open-label, controlled, randomised, multi-centre Phase 3 trial evaluating renal function in patients with severe anti-GBM disease comparing imlifidase and standard of care (SoC) with SoC alone."
Supports imlifidase as an investigational Phase 3 therapy for severe anti-GBM disease aimed at rapid IgG clearance.
🌍

Environmental Factors

2
Cigarette smoking as a pulmonary-disease modifier
exposure to cigarette smoking ECTO:0100003 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to cigarette smoking (ECTO:0100003). ECTO:0100003 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Current smoking is associated with pulmonary involvement in anti-GBM disease. This observational association supports smoking as a harmful modifier of the pulmonary phenotype, not as a necessary cause of autoimmunity.
Show evidence (1 reference)
PMID:8281713 SUPPORT Human Clinical
"Pulmonary disease was significantly associated with current smoking (p < 0.01)."
Directly reports the association in a 29-patient retrospective cohort.
Mechanism Target:
EXACERBATES Alveolar capillary-wall disruption — Exacerbating rather than triggering, because this exposure does not cause the disease: the antibody is already made, and smoking decides whether the lung is involved. The classic 1983 series settles both halves of that sentence. All 37 cigarette smokers in it had lung haemorrhage against 2 of 10 non-smokers, and crucially the anti-GBM antibody titres did not differ between the two groups, so smoking is not acting by making more antibody. That null result is what places this edge on the alveolar capillary wall rather than on the loss-of-tolerance node, and it is a stronger argument for the target than the association alone would be. One patient in that series resumed smoking and the lung haemorrhage returned, which is a within-patient rechallenge and the strongest causal design available anywhere in this entry.
Show evidence (4 references)
PMID:6140495 SUPPORT Human Clinical
"Of these, all 37 cigarette smokers suffered lung haemorrhage, compared with only 2 of 10 non-smokers"
A near-complete separation between smokers and non-smokers for lung involvement in a series of patients who all had the same autoantibody disease. It is the size of this contrast, not a mechanism, that carries the edge.
PMID:6140495 SUPPORT Human Clinical
"There was no significant difference between the titres of circulating anti-GBM antibodies in smokers and non-smokers"
The item that decides the target. Smokers and non-smokers had the same antibody titres, so smoking is not acting on the autoantibody arm at all, which is why this link points at the alveolar capillary wall and not at the loss-of-tolerance node upstream.
PMID:6140495 SUPPORT Human Clinical
"In 1 patient resumption of smoking was closely followed by recrudescence of lung haemorrhage"
A within-patient rechallenge: the exposure stopped, resumed, and the bleeding returned with it. One patient only, but it is the strongest causal design in this entry and it is carried for that reason.
+ 1 more reference
Infection as a possible environmental trigger
Spatial and temporal clustering supports an environmental contribution, and infection is one proposed trigger in genetically susceptible people. The evidence does not identify a necessary or sufficient exposure.
Show evidence (1 reference)
PMID:28515156 SUPPORT Other
"The recent confirmation of spatial and temporal clustering of cases suggests that environmental factors, including infection, may trigger disease in genetically susceptible individuals."
Directly supports infection as an environmental trigger in HLA-susceptible hosts.
Mechanism Target:
PREDISPOSES HLA-restricted loss of tolerance and anti-GBM IgG production — Pointed at the loss-of-tolerance node because the cited sentence conditions its claim on genetic susceptibility and that node is the one carrying the HLA restriction. Graded predisposing rather than triggering despite the sentence using the word trigger, because the sentence hedges it twice, saying clustering suggests environmental factors may trigger disease, and the exposure's own name calls infection possible. The intermediates are unknown in the strict sense: no organism is named and no route from infection to autoantibody production is given.
Show evidence (1 reference)
PMID:28515156 SUPPORT Other
"The recent confirmation of spatial and temporal clustering of cases suggests that environmental factors, including infection, may trigger disease in genetically susceptible individuals."
States that confirmed spatial and temporal clustering of cases suggests environmental factors including infection may trigger disease in genetically susceptible individuals. Clustering is an argument that something environmental is at work rather than evidence that infection is the thing.
🔬

Biochemical Markers

2
Circulating anti-GBM antibodies (Positive)
Context: Serum anti-GBM antibodies (anti-alpha3(IV)NC1) detected by ELISA are the principal serologic marker, although atypical seronegative disease occurs.
Pathograph Readouts
Readout Of HLA-restricted loss of tolerance and anti-GBM IgG production Positive Diagnostic
Detectable circulating anti-GBM antibody reports the autoantibody-production mechanism.
Show evidence (1 reference)
PMID:38493958 SUPPORT Human Clinical
"The pooled prevalence rates of anti-GBM antibodies, antineutrophil cytoplasmic antibodies (ANCA), and lung hemorrhage were 88.8%, 27.4%, and 32.6%, respectively."
Supports circulating anti-GBM positivity as a diagnostic readout in most patients.
Show evidence (1 reference)
PMID:38493958 SUPPORT Human Clinical
"The pooled prevalence rates of anti-GBM antibodies, antineutrophil cytoplasmic antibodies (ANCA), and lung hemorrhage were 88.8%, 27.4%, and 32.6%, respectively."
Anti-GBM antibody positivity is detected in 88.8% of patients, supporting it as the defining biochemical marker.
Circulating ANCA (double-positive disease) (Positive)
Context: ANCA co-positivity defines a clinically important overlap group with relapse behavior more similar to ANCA-associated vasculitis than classic anti-GBM disease.
Show evidence (2 references)
PMID:38493958 SUPPORT Human Clinical
"The pooled prevalence rates of anti-GBM antibodies, antineutrophil cytoplasmic antibodies (ANCA), and lung hemorrhage were 88.8%, 27.4%, and 32.6%, respectively."
Quantifies ANCA co-positivity at 27.4% in the meta-analysis.
PMID:28506760 SUPPORT Human Clinical
"No single-positive anti-GBM patients experienced disease relapse, whereas approximately half of surviving patients with AAV and double-positive patients had recurrent disease"
Supports ANCA co-positivity as a clinically meaningful biochemical stratifier that predicts relapse, unlike monophasic single-positive disease.
🔬

Diagnosis

2
Anti-GBM serology plus renal biopsy
Diagnosis integrates the clinical presentation with serum anti-GBM antibody testing and kidney biopsy showing linear IgG deposition along the GBM. Either circulating antibody or characteristic biopsy evidence may establish antibody involvement; ANCA testing identifies double-positive disease.
Results: Positive circulating anti-GBM antibodies with linear GBM IgG on biopsy confirm the diagnosis; concurrent ANCA positivity defines double-positive disease.
Show evidence (1 reference)
PMID:40973182 SUPPORT Other
"Diagnosis relies on clinical features, kidney biopsy showing linear IgG deposition along the GBM, and/or detection of circulating anti-GBM antibodies."
Directly states the clinical, biopsy, and circulating-antibody diagnostic criteria without requiring every modality to be positive.
Recognition of atypical seronegative anti-GBM disease
Absence of detectable circulating anti-GBM antibodies does not exclude an atypical presentation when kidney biopsy shows linear GBM IgG. This category is heterogeneous and should not be assumed to follow classic disease.
Results: Linear GBM IgG with absent circulating anti-GBM antibodies.
Show evidence (1 reference)
PMID:33013861 SUPPORT Human Clinical
"Atypical cases of anti-glomerular basement membrane (GBM) disease had absent circulating antibodies but linear IgG deposits along GBM in the kidneys."
Directly defines the seronegative, biopsy-positive atypical presentation in a 60-patient cohort.
📈

Progression

2
Acute organ-threatening presentation
Classic disease generally presents as rapidly progressive glomerulonephritis, with pulmonary hemorrhage in about half of cases. Dialysis dependence at presentation is associated with a lower likelihood of kidney recovery.
Show evidence (2 references)
PMID:40973182 SUPPORT Other
"It is caused by autoantibodies directed against the α3 chain of type IV collagen, leading to rapidly progressive glomerulonephritis with pulmonary haemorrhage in ∼50% of cases."
Supports the characteristic acute renal presentation and approximate pulmonary-hemorrhage proportion.
PMID:40973182 SUPPORT Other
"Dialysis-dependent patients have a lower likelihood of renal recovery, and treatment decisions must consider biopsy findings, clinical severity and potential contraindications to standard immunosuppression."
Supports the prognostic importance of dialysis dependence at presentation.
Relapse after remission
Relapse is rare in classic single-positive disease, so routine long-term maintenance immunosuppression is generally unnecessary. Double-positive anti-GBM/ANCA disease has higher relapse risk and requires an AAV-like maintenance strategy.
Show evidence (1 reference)
PMID:40973182 SUPPORT Other
"Unlike anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis, relapses are rare in classic anti-GBM disease, and long-term maintenance immunosuppression is not routinely required. However, 'double positive' patients (anti-GBM and ANCA) have a higher relapse risk and require maintenance..."
Directly distinguishes classic monophasic disease from the relapse-prone double-positive subgroup.
📊

Prevalence

1
General population across included epidemiologic studies
Annual Incidence 0.06–0.179 per 100,000 1–9 per 1,000,000
The systematic review reported 0.60-1.79 new cases per million population per year (0.06-0.179 per 100,000 per year). The range straddles the lower boundary of the coarse 1-9-per-million class.
Show evidence (1 reference)
PMID:38493958 SUPPORT Human Clinical
"The overall incidence of anti-GBM disease ranged from 0.60 to 1.79 per million population per annum."
Supports the annual incidence range and its normalized rate conversion.
🌍

Epidemiology

1
One-year patient and kidney outcomes
Pooled one-year patient and kidney survival were 76.2% and 30.2%, respectively. Kidney function at diagnosis and the proportion of normal glomeruli were strong prognostic factors; these pooled outcomes should not be treated as an individual prognosis.
Show evidence (1 reference)
PMID:38493958 SUPPORT Human Clinical
"The pooled one-year patient and kidney survival rates were 76.2% and 30.2%, respectively. Kidney function on diagnosis and normal glomeruli percentage were identified as strong prognostic factors."
Supports the one-year survival figures and the prognostic importance of baseline kidney function.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Anti-Glomerular Basement Membrane Disease:

ANCA-associated vasculitis
Overlapping Features ANCA-associated vasculitis (granulomatosis with polyangiitis, microscopic polyangiitis) is the principal differential for a pulmonary-renal syndrome; it shows pauci-immune (not linear) staining, and may co-occur as double-positive disease.
Show evidence (1 reference)
PMID:28506760 SUPPORT Human Clinical
"Double-positive patients shared characteristics of ANCA-associated vasculitis (AAV), such as older age distribution and longer symptom duration before diagnosis, and features of anti-GBM disease"
Supports ANCA-associated vasculitis as the key differential/overlap entity, including the double-positive presentation.
📊

Related Datasets

3
Spatio-temporal interaction of immune and renal cells determines glomerular crescent formation in autoimmune kidney disease geo:GSE303481
Rapidly progressive glomerulonephritis (RPGN) is the most aggressive group of autoimmune kidney disease with the worst prognosis. Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis, anti-glomerular basement membrane (anti-GBM) and lupus nephritis are the most common causes of RPGN and are characterized by the formation of glomerular crescents and infiltration of leukocytes that eventually lead to glomerulosclerosis and kidney failure.
human BULK RNA SEQ n=15
PMID:41028563
Identified by GEO DataSets index search for Anti-Glomerular Basement Membrane Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
Spatio-temporal interaction of immune and renal cells determines glomerular crescent formation in autoimmune kidney disease geo:GSE294965
Rapidly progressive glomerulonephritis (RPGN) is the most aggressive group of autoimmune kidney disease with the worst prognosis. Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis, anti-glomerular basement membrane (anti-GBM) and lupus nephritis are the most common causes of RPGN and are characterized by the formation of glomerular crescents and infiltration of leukocytes that eventually lead to glomerulosclerosis and kidney failure.
human n=9
PMID:40393992
Identified by GEO DataSets index search for Anti-Glomerular Basement Membrane Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
Effects of a Tricaprylin Emulsion on Anti-glomerular Basement Membrane Glomerulonephritis in Rats geo:GSE46295
Expression data from rat with anti-glomerular basement membrane nephritis (anti-GBM). We used microarrays to analyze the transcriptome of kidney from anti-GBM model rat with or without drug treatment
rat MICROARRAY n=12
PMID:26235580
Identified by GEO DataSets index search for Anti-Glomerular Basement Membrane Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
🔬

Clinical Trials

1
NCT05679401 PHASE_III TERMINATED
GOOD-IDES-02: Phase 3 open-label, randomised, controlled, multi-centre trial comparing imlifidase plus standard-of-care versus standard-of-care alone in severe anti-GBM disease. The registry reports termination by sponsor decision (not for a safety reason), actual enrollment of 50, and no posted results as of 2026-08-05.
Target Phenotypes: Glomerulonephritis HP:0000099 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Glomerulonephritis (HP:0000099). HP:0000099 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT05679401 SUPPORT Human Clinical
"An open-label, controlled, randomised, multi-centre Phase 3 trial evaluating renal function in patients with severe anti-GBM disease comparing imlifidase and standard of care (SoC) with SoC alone."
Defines the GOOD-IDES-02 Phase 3 trial of imlifidase in severe anti-GBM disease.
🐁

Animal Models

2
Complement C3-deficient, C4-deficient, and wild-type mice in a heterologous anti-GBM nephritis model Mus musculus
C3 or C4 deficiency reduced neutrophil infiltration, proteinuria, and capillary thrombosis after nephritogenic antibody exposure, supporting a causal complement role. The heterologous antibody-transfer model bypasses human loss of tolerance, and protection was overcome at higher antibody dose.
Proteinuria Glomerular capillary thrombosis
Species
Mus musculus
Genotype
Complement C3-deficient, C4-deficient, and wild-type mice in a heterologous anti-GBM nephritis model
Show evidence (1 reference)
PMID:9409643 SUPPORT Model Organism
"These studies support a critical role for complement in the development of anti-GBM disease. However, the protective effect of complement deficiency can be broken if the dose of nephritogenic antibody is increased."
Supports complement dependence and states the antibody-dose limitation of the model.
alpha3(IV)NC1 127-148-immunized Wistar Kyoto rats Rattus norvegicus
Antigen-immunized rats model autoreactive anti-GBM nephritis. In this 2026 study, butyrate-modified m-P14 peptide reduced renal injury and inflammatory readouts. This induced rodent model is preclinical and does not establish efficacy or safety in people.
Proteinuria Glomerular crescent formation
Species
Rattus norvegicus
Genotype
alpha3(IV)NC1 127-148-immunized Wistar Kyoto rats
Show evidence (1 reference)
PMID:42278340 SUPPORT Model Organism
"M-P14-BA reduced proteinuria, crescent formation, glomerular IgG deposition, complement activation, and inflammatory cell infiltration, with overall efficacy comparable to m-P14 in early treatment settings."
Directly reports the treatment effects in antigen-immunized rats.
{ }

Source YAML

click to show 
name: Anti-Glomerular Basement Membrane Disease
creation_date: "2026-06-29T00:00:00Z"
description: >-
  Anti-glomerular basement membrane (anti-GBM) disease, historically called
  Goodpasture syndrome or Goodpasture disease, is a rare organ-specific
  autoimmune small-vessel vasculitis caused by circulating autoantibodies
  (predominantly IgG) directed against the noncollagenous-1 (NC1) domain of the
  alpha-3 chain of type IV collagen, the "Goodpasture antigen." This autoantigen
  is expressed in the specialized basement membranes of the renal glomerulus and
  the pulmonary alveolus, so the disease classically presents as a
  pulmonary-renal syndrome of rapidly progressive (crescentic) glomerulonephritis
  with diffuse alveolar hemorrhage. It is not a Mendelian disease: susceptibility
  is strongly linked to HLA-DRB1*15:01 (DR15). Environmental factors, including
  infection, may trigger disease in susceptible people, but the initiating event
  is not established for an individual patient.
category: Complex
disease_term:
  preferred_term: anti-glomerular basement membrane disease
  term:
    id: MONDO:0009303
    label: anti-glomerular basement membrane disease
parents:
- Autoimmune disease
synonyms:
- Goodpasture syndrome
- Goodpasture disease
- anti-GBM antibody disease
- anti-basement membrane antibody disease
- pulmonary-renal syndrome
references:
- reference: PMID:28515156
  title: Anti-Glomerular Basement Membrane Disease.
- reference: PMID:40973182
  title: Anti-glomerular basement membrane disease-treatment standard.
- reference: PMID:38493958
  title: "Epidemiology, clinical features, risk factors, and outcomes in anti-glomerular basement membrane disease: A systematic review and meta-analysis."
has_subtypes:
- name: Atypical seronegative anti-GBM disease
  display_name: Atypical seronegative anti-GBM disease
  description: >-
    A heterogeneous biopsy-defined presentation with linear GBM IgG but absent
    circulating anti-GBM antibodies. In a 60-patient cohort, kidney injury was
    generally milder than classic disease, but hematuria, proteinuria, complement
    deposition, crescent formation, kidney failure, and death still occurred.
  evidence:
  - reference: PMID:33013861
    reference_title: "Clinical-Pathological Features and Outcome of Atypical Anti-glomerular Basement Membrane Disease in a Large Single Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Atypical cases of anti-glomerular basement membrane (GBM) disease had absent
      circulating antibodies but linear IgG deposits along GBM in the kidneys.
    explanation: Defines the seronegative, biopsy-positive atypical subtype.
  - reference: PMID:33013861
    reference_title: "Clinical-Pathological Features and Outcome of Atypical Anti-glomerular Basement Membrane Disease in a Large Single Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Though heterogeneous, a substantial number of the patients had complement
      activation and crescent formation. Patients having crescents presented with
      more severe clinical course and worse outcomes.
    explanation: Supports heterogeneity and clinically important crescentic disease within the atypical cohort.
- name: Double-positive anti-GBM and ANCA disease
  display_name: Double-positive anti-GBM and ANCA disease
  description: >-
    Anti-GBM disease with concurrent ANCA has the severe early presentation of
    anti-GBM disease but a longer-term relapse risk resembling ANCA-associated
    vasculitis, so maintenance immunosuppression differs from classic disease.
  evidence:
  - reference: PMID:28506760
    reference_title: Patients double-seropositive for ANCA and anti-GBM antibodies have varied renal survival, frequency of relapse, and outcomes compared to single-seropositive patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No single-positive anti-GBM patients experienced disease relapse, whereas
      approximately half of surviving patients with AAV and double-positive
      patients had recurrent disease
    explanation: Supports the relapse-prone double-positive trajectory.
pathophysiology:
- name: Conformational exposure of cryptic alpha3/alpha5(IV)NC1 epitopes
  role: trigger
  description: >-
    The immunodominant E_A and E_B epitopes are sequestered within the native,
    cross-linked alpha345NC1 hexamer. Dissociation or conformational alteration
    exposes epitopes on alpha3 and alpha5 NC1 monomers that patient antibodies
    can bind. This molecular architecture supports a cryptic-epitope model, but
    does not by itself establish which exposure initiates disease in humans.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: COL4A3
    term:
      id: hgnc:2204
      label: COL4A3
  biological_processes:
  - preferred_term: extracellular matrix organization
    modifier: ABNORMAL
    term:
      id: GO:0030198
      label: extracellular matrix organization
  downstream:
  - target: HLA-restricted loss of tolerance and anti-GBM IgG production
    description: >-
      Exposure of normally cryptic NC1 epitopes provides antigenic substrate for
      the autoreactive response in the conformeropathy model.
    hypothesis_groups:
    - conformeropathy
    evidence:
    - reference: PMID:20660402
      reference_title: Molecular architecture of the Goodpasture autoantigen in anti-GBM nephritis.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: >-
        The antibodies bound to distinct epitopes encompassing region E(A) in the
        alpha5NC1 monomer and regions E(A) and E(B) in the alpha3NC1 monomer, but
        they did not bind to the native cross-linked alpha345NC1 hexamer
      explanation: >-
        Supports cryptic-epitope exposure; INDIRECT because the human study does
        not establish that exposure temporally initiates loss of tolerance.
  evidence:
  - reference: PMID:20660402
    reference_title: Molecular architecture of the Goodpasture autoantigen in anti-GBM nephritis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The antibodies bound to distinct epitopes encompassing region E(A) in the
      alpha5NC1 monomer and regions E(A) and E(B) in the alpha3NC1 monomer, but
      they did not bind to the native cross-linked alpha345NC1 hexamer
    explanation: >-
      Shows the autoantibodies bind cryptic E_A/E_B neoepitopes exposed on
      dissociated alpha3/alpha5 NC1 monomers but not the intact native hexamer,
      supporting the conformeropathy model.
  - reference: PMID:19729652
    reference_title: A sulfilimine bond identified in collagen IV.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the cross-link also confers immune privilege to the collagen IV antigen of
      Goodpasture autoimmune disease
    explanation: >-
      Identifies the sulfilimine (S=N) cross-link that stabilizes the NC1 hexamer
      and confers immune privilege by sequestering the cryptic Goodpasture
      epitopes.
- name: HLA-restricted loss of tolerance and anti-GBM IgG production
  description: >-
    In susceptible hosts, alpha3(IV)NC1-reactive CD4+ T cells and B cells form an
    autoimmune response that produces directly pathogenic anti-GBM IgG. The
    strong HLA-DR15 association supports HLA-restricted antigen presentation;
    HLA susceptibility is not a causal germline mutation.
  biological_scale: CELLULAR
  genes:
  - preferred_term: HLA-DRB1
    term:
      id: hgnc:4948
      label: HLA-DRB1
  cell_types:
  - preferred_term: alpha3(IV)NC1-reactive CD4+ T-helper cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: autoantibody-producing B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: antigen processing and presentation
    term:
      id: GO:0019882
      label: antigen processing and presentation
  - preferred_term: humoral immune response mediated by circulating immunoglobulin
    modifier: INCREASED
    term:
      id: GO:0002455
      label: humoral immune response mediated by circulating immunoglobulin
  downstream:
  - target: Linear anti-GBM IgG deposition
    description: Circulating autoantibody binds its basement-membrane target.
    evidence:
    - reference: PMID:28515156
      reference_title: Anti-Glomerular Basement Membrane Disease.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        It is an archetypic autoimmune disease, caused by the development of
        directly pathogenic autoantibodies targeting a well characterized
        autoantigen expressed in the basement membranes of these organs
      explanation: Directly links pathogenic autoantibody production to basement-membrane targeting.
  evidence:
  - reference: PMID:8589284
    reference_title: Identification of the alpha 3 chain of type IV collagen as the common autoantigen in antibasement membrane disease and Goodpasture syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      reactivity to alpha 3(IV) NC1 domains is both sufficient and necessary for
      the expression of autoimmune disease directed to the NC1 domain of Type IV
      collagen
    explanation: Supports alpha3(IV)NC1 as the disease-defining autoantigen.
  - reference: PMID:14569090
    reference_title: The fine specificity and cytokine profile of T-helper cells responsive to the alpha3 chain of type IV collagen in Goodpasture's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Goodpasture's disease is a severe nephritis characterized by autoantibodies
      to the alpha3 chain of type IV collagen, alpha3(IV)NC1, in the glomerular
      basement membrane. The disease is very strongly associated with HLA-DR15
    explanation: Supports the autoantibody target and strong HLA-DR15 association.
- name: Linear anti-GBM IgG deposition
  description: >-
    Circulating anti-GBM IgG deposits linearly along glomerular and alveolar
    basement membranes, positioning pathogenic antibody at both capillary beds.
  biological_scale: TISSUE
  locations:
  - preferred_term: renal glomerulus
    term:
      id: UBERON:0000074
      label: renal glomerulus
  - preferred_term: alveolus of lung
    term:
      id: UBERON:0002299
      label: alveolus of lung
  downstream:
  - target: Complement-dependent capillaritis
    description: Tissue-bound antibody initiates complement-dependent inflammation.
    evidence:
    - reference: PMID:9409643
      reference_title: Protection against anti-glomerular basement membrane (GBM)-mediated nephritis in C3- and C4-deficient mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        These studies support a critical role for complement in the development of
        anti-GBM disease.
      explanation: Supports complement as a causal effector after anti-GBM antibody deposition in mice.
  evidence:
  - reference: PMID:28515156
    reference_title: Anti-Glomerular Basement Membrane Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      It is an archetypic autoimmune disease, caused by the development of
      directly pathogenic autoantibodies targeting a well characterized
      autoantigen expressed in the basement membranes of these organs
    explanation: Supports pathogenic antibody targeting of organ basement membranes.
- name: Complement-dependent capillaritis
  description: >-
    Tissue-bound anti-GBM IgG activates complement and recruits inflammatory
    leukocytes, producing local capillaritis and capillary-wall injury.
  biological_scale: TISSUE
  locations:
  - preferred_term: renal glomerulus
    term:
      id: UBERON:0000074
      label: renal glomerulus
  - preferred_term: alveolus of lung
    term:
      id: UBERON:0002299
      label: alveolus of lung
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: complement activation, classical pathway
    modifier: INCREASED
    term:
      id: GO:0006958
      label: complement activation, classical pathway
  - preferred_term: leukocyte migration
    modifier: INCREASED
    term:
      id: GO:0050900
      label: leukocyte migration
  - preferred_term: inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  downstream:
  - target: Necrotizing crescentic glomerular injury
    description: Glomerular capillary-wall injury drives necrosis and crescent formation.
    evidence:
    - reference: PMID:30404116
      reference_title: Antiglomerular Basement Membrane Disease.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Once deposited in tissue, these autoantibodies incite a local capillaritis
        which manifests as rapidly progressive glomerulonephritis (GN) in 80 to 90%
        of patients, and with concurrent alveolar hemorrhage in ∼50%.
      explanation: Directly links deposited autoantibody and capillaritis to renal injury.
  - target: Alveolar capillary-wall disruption
    description: Alveolar capillary-wall disruption permits blood to enter alveolar spaces.
    evidence:
    - reference: PMID:30404116
      reference_title: Antiglomerular Basement Membrane Disease.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Once deposited in tissue, these autoantibodies incite a local capillaritis
        which manifests as rapidly progressive glomerulonephritis (GN) in 80 to 90%
        of patients, and with concurrent alveolar hemorrhage in ∼50%.
      explanation: Directly links local capillaritis to alveolar hemorrhage.
  evidence:
  - reference: PMID:9409643
    reference_title: Protection against anti-glomerular basement membrane (GBM)-mediated nephritis in C3- and C4-deficient mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These studies support a critical role for complement in the development of
      anti-GBM disease.
    explanation: >-
      Complement-deficient mouse experiments support a causal effector role for
      complement; this heterologous model does not reproduce loss of tolerance.
- name: Necrotizing crescentic glomerular injury
  role: outcome
  description: >-
    Glomerular basement membrane rupture permits fibrin and inflammatory cells
    into Bowman's space, triggering parietal epithelial and podocyte
    proliferation, cellular crescents, and rapidly progressive glomerulonephritis.
  biological_scale: TISSUE
  locations:
  - preferred_term: renal glomerulus
    term:
      id: UBERON:0000074
      label: renal glomerulus
  cell_types:
  - preferred_term: glomerular parietal/visceral epithelial cell
    term:
      id: CL:1000746
      label: glomerular cell
  downstream:
  - target: Rapidly progressive glomerulonephritis
    evidence:
    - reference: PMID:28515156
      reference_title: Anti-Glomerular Basement Membrane Disease.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The majority of patients develop widespread glomerular crescent formation,
        presenting with features of rapidly progressive GN
      explanation: Directly links crescent formation to the clinical renal phenotype.
  - target: Hematuria
    evidence:
    - reference: PMID:33013861
      reference_title: "Clinical-Pathological Features and Outcome of Atypical Anti-glomerular Basement Membrane Disease in a Large Single Cohort."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Thirty eight (63.3%) patients exhibited hematuria and 4 of them had
        macroscopic hematuria.
      explanation: >-
        Documents hematuria in a 60-patient atypical anti-GBM cohort; PARTIAL
        because this observational result does not isolate the causal edge and
        must not be generalized as a classic-disease frequency.
  - target: Proteinuria
    evidence:
    - reference: PMID:33013861
      reference_title: "Clinical-Pathological Features and Outcome of Atypical Anti-glomerular Basement Membrane Disease in a Large Single Cohort."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Proteinuria existed in 56 (93.3%) patients and 26 of them reached
        nephrotic level.
      explanation: >-
        Documents proteinuria in a 60-patient atypical anti-GBM cohort; PARTIAL
        because this observational result does not isolate the causal edge and
        must not be generalized as a classic-disease frequency.
  - target: Acute kidney injury
    evidence:
    - reference: PMID:28515156
      reference_title: Anti-Glomerular Basement Membrane Disease.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        presentation with oligoanuria, a high proportion of glomerular crescents,
        or kidney failure requiring dialysis augur badly for renal prognosis
      explanation: Links severe crescentic injury with acute oligoanuric kidney failure.
  evidence:
  - reference: PMID:30404116
    reference_title: Antiglomerular Basement Membrane Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Once deposited in tissue, these autoantibodies incite a local capillaritis
      which manifests as rapidly progressive glomerulonephritis (GN) in 80 to 90%
      of patients, and with concurrent alveolar hemorrhage in ∼50%.
    explanation: >-
      Links tissue-deposited autoantibody and capillaritis to rapidly progressive
      glomerulonephritis.
- name: Alveolar capillary-wall disruption
  role: outcome
  description: >-
    Injury to the alveolar capillary basement membrane permits blood to enter
    alveolar spaces, producing diffuse alveolar hemorrhage and consequent blood
    loss.
  biological_scale: TISSUE
  locations:
  - preferred_term: alveolus of lung
    term:
      id: UBERON:0002299
      label: alveolus of lung
  downstream:
  - target: Diffuse alveolar hemorrhage
    evidence:
    - reference: PMID:30404116
      reference_title: Antiglomerular Basement Membrane Disease.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Once deposited in tissue, these autoantibodies incite a local capillaritis
        which manifests as rapidly progressive glomerulonephritis (GN) in 80 to 90%
        of patients, and with concurrent alveolar hemorrhage in ∼50%.
      explanation: Directly links capillaritis to the hemorrhage phenotype.
  - target: Hemoptysis
    evidence:
    - reference: PMID:8532389
      reference_title: Progression from Goodpasture's disease to membranous glomerulonephritis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        hemoptysis, severe iron deficiency anemia and microscopic hematuria and
        proteinuria
      explanation: Documents hemoptysis in anti-GBM disease; PARTIAL because it is a single case.
  - target: Anemia
    evidence:
    - reference: PMID:8532389
      reference_title: Progression from Goodpasture's disease to membranous glomerulonephritis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        hemoptysis, severe iron deficiency anemia and microscopic hematuria and
        proteinuria
      explanation: Documents hemorrhage-associated iron-deficiency anemia; PARTIAL because it is a single case.
  evidence:
  - reference: PMID:30404116
    reference_title: Antiglomerular Basement Membrane Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Once deposited in tissue, these autoantibodies incite a local capillaritis
      which manifests as rapidly progressive glomerulonephritis (GN) in 80 to 90%
      of patients, and with concurrent alveolar hemorrhage in ∼50%.
    explanation: Links local capillaritis to alveolar hemorrhage in approximately half of patients.
mechanistic_hypotheses:
- hypothesis_group_id: conformeropathy
  hypothesis_label: Conformeropathy / cryptic-neoepitope model
  status: CANONICAL
  description: >-
    The dominant mechanistic model holds that anti-GBM disease is an autoimmune
    "conformeropathy": the immunodominant epitopes are normally sequestered
    within the cross-linked alpha345NC1 hexamer (immune privilege), and disease
    requires an environmental insult that dissociates the hexamer to expose
    cryptic neoepitopes on alpha3/alpha5(IV)NC1 in an HLA-DR15-susceptible host.
  evidence:
  - reference: PMID:20660402
    reference_title: Molecular architecture of the Goodpasture autoantigen in anti-GBM nephritis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The antibodies bound to distinct epitopes encompassing region E(A) in the
      alpha5NC1 monomer and regions E(A) and E(B) in the alpha3NC1 monomer, but
      they did not bind to the native cross-linked alpha345NC1 hexamer
    explanation: Supports the cryptic-epitope component of the conformeropathy model.
phenotypes:
- category: Renal
  name: Rapidly progressive glomerulonephritis
  description: >-
    Crescentic glomerulonephritis with rapid (days-to-weeks) loss of kidney
    function, often progressing to dialysis dependence.
  phenotype_term:
    preferred_term: Glomerulonephritis
    term:
      id: HP:0000099
      label: Glomerulonephritis
    temporality: ACUTE
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:28515156
    reference_title: Anti-Glomerular Basement Membrane Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The majority of patients develop widespread glomerular crescent formation,
      presenting with features of rapidly progressive GN
    explanation: Supports rapidly progressive crescentic glomerulonephritis as the cardinal renal phenotype.
- category: Respiratory
  name: Diffuse alveolar hemorrhage
  description: >-
    Bleeding into the alveolar spaces from alveolar capillary basement-membrane
    injury; hemoptysis may occur but is not required for recognition.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Pulmonary hemorrhage
    term:
      id: HP:0040223
      label: Pulmonary hemorrhage
  evidence:
  - reference: PMID:38493958
    reference_title: "Epidemiology, clinical features, risk factors, and outcomes in anti-glomerular basement membrane disease: A systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The pooled prevalence rates of anti-GBM antibodies, antineutrophil
      cytoplasmic antibodies (ANCA), and lung hemorrhage were 88.8%, 27.4%, and
      32.6%, respectively.
    explanation: >-
      Pooled meta-analysis quantifies lung hemorrhage at 32.6% of patients,
      supporting the FREQUENT frequency band for this phenotype.
  - reference: PMID:28515156
    reference_title: Anti-Glomerular Basement Membrane Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      40%-60% will have concurrent alveolar hemorrhage
    explanation: >-
      The McAdoo & Pusey review reports 40-60% of patients have concurrent
      alveolar hemorrhage, corroborating the FREQUENT frequency band.
- category: Respiratory
  name: Hemoptysis
  description: Coughing up blood arising from pulmonary hemorrhage.
  phenotype_term:
    preferred_term: Hemoptysis
    term:
      id: HP:0002105
      label: Hemoptysis
  evidence:
  - reference: PMID:8532389
    reference_title: Progression from Goodpasture's disease to membranous glomerulonephritis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hemoptysis, severe iron deficiency anemia and microscopic hematuria and
      proteinuria
    explanation: >-
      Directly documents hemoptysis in an anti-GBM case; PARTIAL because this is
      a single case report and no population frequency is inferred.
- category: Renal
  name: Hematuria
  description: Blood in the urine accompanying glomerular injury.
  phenotype_term:
    preferred_term: Hematuria
    term:
      id: HP:0000790
      label: Hematuria
  evidence:
  - reference: PMID:33013861
    reference_title: "Clinical-Pathological Features and Outcome of Atypical Anti-glomerular Basement Membrane Disease in a Large Single Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thirty eight (63.3%) patients exhibited hematuria and 4 of them had
      macroscopic hematuria.
    explanation: >-
      Directly documents hematuria in a 60-patient atypical cohort; PARTIAL
      because the percentage must not be generalized to classic disease.
- category: Renal
  name: Proteinuria
  description: Glomerular protein loss accompanying kidney involvement; severity varies by presentation.
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: PMID:33013861
    reference_title: "Clinical-Pathological Features and Outcome of Atypical Anti-glomerular Basement Membrane Disease in a Large Single Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Proteinuria existed in 56 (93.3%) patients and 26 of them reached
      nephrotic level.
    explanation: >-
      Directly documents proteinuria in a 60-patient atypical cohort; PARTIAL
      because its high percentage and severity must not be generalized to classic disease.
- category: Renal
  name: Acute kidney injury
  description: Acute decline in glomerular filtration, often with oliguria, a key prognostic feature.
  phenotype_term:
    preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
    temporality: ACUTE
  evidence:
  - reference: PMID:28515156
    reference_title: Anti-Glomerular Basement Membrane Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      presentation with oligoanuria, a high proportion of glomerular crescents,
      or kidney failure requiring dialysis augur badly for renal prognosis
    explanation: >-
      Supports acute kidney injury (oligoanuria, dialysis-requiring kidney
      failure) as a severe, prognostically important renal phenotype.
- category: Hematologic
  name: Anemia
  description: Anemia from pulmonary blood loss and/or kidney disease.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:8532389
    reference_title: Progression from Goodpasture's disease to membranous glomerulonephritis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hemoptysis, severe iron deficiency anemia and microscopic hematuria and
      proteinuria
    explanation: >-
      A Goodpasture's-disease case report documenting severe iron-deficiency
      anemia (from pulmonary hemorrhage) at presentation. PARTIAL because this is
      a single case report.
genetic:
- name: HLA-DRB1 (DR15 / DRB1*15:01) susceptibility
  gene_term:
    preferred_term: HLA-DRB1
    term:
      id: hgnc:4948
      label: HLA-DRB1
  association: Susceptibility
  relationship_type: RISK_FACTOR
  notes: >-
    Anti-GBM disease is strongly HLA-restricted: the HLA-DRB1*15:01 (DR15)
    allele dominates susceptibility and provides the restricting element for
    presentation of alpha3(IV)NC1 peptides to autoreactive CD4+ T-helper cells.
    This is a risk allele, not a causal germline mutation; inheritance of the
    disease itself is multifactorial.
  evidence:
  - reference: PMID:14569090
    reference_title: The fine specificity and cytokine profile of T-helper cells responsive to the alpha3 chain of type IV collagen in Goodpasture's disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disease is very strongly associated with HLA-DR15
    explanation: Directly supports the dominant HLA-DR15 (DRB1*15:01) susceptibility association.
- name: COL4A3 (alpha-3 type IV collagen) autoantigen target gene
  gene_term:
    preferred_term: COL4A3
    term:
      id: hgnc:2204
      label: COL4A3
  association: Autoantigen target (not a causal germline mutation)
  notes: >-
    COL4A3 encodes the alpha-3 chain of type IV collagen; its C-terminal NC1
    domain (alpha3(IV)NC1) is the Goodpasture autoantigen. COL4A3 is the target
    of the autoimmune response, NOT a site of disease-causing germline variants
    in anti-GBM disease. (By contrast, loss-of-function variants in COL4A3/4/5
    cause the hereditary structural disease Alport syndrome — a mechanistically
    distinct condition.)
  evidence:
  - reference: PMID:8589284
    reference_title: Identification of the alpha 3 chain of type IV collagen as the common autoantigen in antibasement membrane disease and Goodpasture syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the anti-GBM antibodies from all patients reacted with the alpha 3(IV) NC1
      (85% exclusively)
    explanation: >-
      Supports the alpha-3 chain of type IV collagen (COL4A3 product) as the
      autoantibody target in anti-GBM/Goodpasture disease.
biochemical:
- name: Circulating anti-GBM antibodies
  presence: Positive
  context: >-
    Serum anti-GBM antibodies (anti-alpha3(IV)NC1) detected by ELISA are the
    principal serologic marker, although atypical seronegative disease occurs.
  readouts:
  - target: HLA-restricted loss of tolerance and anti-GBM IgG production
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Detectable circulating anti-GBM antibody reports the autoantibody-production mechanism.
    evidence:
    - reference: PMID:38493958
      reference_title: "Epidemiology, clinical features, risk factors, and outcomes in anti-glomerular basement membrane disease: A systematic review and meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The pooled prevalence rates of anti-GBM antibodies, antineutrophil
        cytoplasmic antibodies (ANCA), and lung hemorrhage were 88.8%, 27.4%, and
        32.6%, respectively.
      explanation: Supports circulating anti-GBM positivity as a diagnostic readout in most patients.
  evidence:
  - reference: PMID:38493958
    reference_title: "Epidemiology, clinical features, risk factors, and outcomes in anti-glomerular basement membrane disease: A systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The pooled prevalence rates of anti-GBM antibodies, antineutrophil
      cytoplasmic antibodies (ANCA), and lung hemorrhage were 88.8%, 27.4%, and
      32.6%, respectively.
    explanation: >-
      Anti-GBM antibody positivity is detected in 88.8% of patients, supporting
      it as the defining biochemical marker.
- name: Circulating ANCA (double-positive disease)
  presence: Positive
  context: >-
    ANCA co-positivity defines a clinically important overlap group with relapse
    behavior more similar to ANCA-associated vasculitis than classic anti-GBM
    disease.
  evidence:
  - reference: PMID:38493958
    reference_title: "Epidemiology, clinical features, risk factors, and outcomes in anti-glomerular basement membrane disease: A systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The pooled prevalence rates of anti-GBM antibodies, antineutrophil
      cytoplasmic antibodies (ANCA), and lung hemorrhage were 88.8%, 27.4%, and
      32.6%, respectively.
    explanation: Quantifies ANCA co-positivity at 27.4% in the meta-analysis.
  - reference: PMID:28506760
    reference_title: Patients double-seropositive for ANCA and anti-GBM antibodies have varied renal survival, frequency of relapse, and outcomes compared to single-seropositive patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No single-positive anti-GBM patients experienced disease relapse, whereas
      approximately half of surviving patients with AAV and double-positive
      patients had recurrent disease
    explanation: >-
      Supports ANCA co-positivity as a clinically meaningful biochemical stratifier
      that predicts relapse, unlike monophasic single-positive disease.
environmental:
- name: Cigarette smoking as a pulmonary-disease modifier
  exposure_term:
    preferred_term: exposure to cigarette smoking
    term:
      id: ECTO:0100003
      label: exposure to cigarette smoking
  influences_mechanisms:
  - target: Alveolar capillary-wall disruption
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Exacerbating rather than triggering, because this exposure does not
      cause the disease: the antibody is already made, and smoking decides
      whether the lung is involved. The classic 1983 series settles both
      halves of that sentence. All 37 cigarette smokers in it had lung
      haemorrhage against 2 of 10 non-smokers, and crucially the anti-GBM
      antibody titres did not differ between the two groups, so smoking is
      not acting by making more antibody. That null result is what places
      this edge on the alveolar capillary wall rather than on the
      loss-of-tolerance node, and it is a stronger argument for the target
      than the association alone would be. One patient in that series
      resumed smoking and the lung haemorrhage returned, which is a
      within-patient rechallenge and the strongest causal design available
      anywhere in this entry.
    evidence:
    - reference: PMID:6140495
      reference_title: "Cigarette smoking and lung haemorrhage in glomerulonephritis caused by autoantibodies to glomerular basement membrane."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Of these, all 37 cigarette smokers suffered lung haemorrhage, compared with only 2 of 10 non-smokers"
      explanation: >-
        A near-complete separation between smokers and non-smokers for lung
        involvement in a series of patients who all had the same
        autoantibody disease. It is the size of this contrast, not a
        mechanism, that carries the edge.
    - reference: PMID:6140495
      reference_title: "Cigarette smoking and lung haemorrhage in glomerulonephritis caused by autoantibodies to glomerular basement membrane."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "There was no significant difference between the titres of circulating anti-GBM antibodies in smokers and non-smokers"
      explanation: >-
        The item that decides the target. Smokers and non-smokers had the
        same antibody titres, so smoking is not acting on the autoantibody
        arm at all, which is why this link points at the alveolar capillary
        wall and not at the loss-of-tolerance node upstream.
    - reference: PMID:6140495
      reference_title: "Cigarette smoking and lung haemorrhage in glomerulonephritis caused by autoantibodies to glomerular basement membrane."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In 1 patient resumption of smoking was closely followed by recrudescence of lung haemorrhage"
      explanation: >-
        A within-patient rechallenge: the exposure stopped, resumed, and the
        bleeding returned with it. One patient only, but it is the strongest
        causal design in this entry and it is carried for that reason.
    - reference: PMID:8281713
      reference_title: "Anti-GBM disease: predictive value of clinical, histological and serological data."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Pulmonary disease was significantly associated with current smoking (p < 0.01)."
      explanation: >-
        Reports pulmonary disease significantly associated with current
        smoking. It reaches the clinical expression of this node rather than
        the wall disruption itself, and as an association within a case series
        it cannot separate smoking as cause of lung involvement from smoking
        as a marker of who gets it.
  description: >-
    Current smoking is associated with pulmonary involvement in anti-GBM disease.
    This observational association supports smoking as a harmful modifier of the
    pulmonary phenotype, not as a necessary cause of autoimmunity.
  effect: HARMFUL
  evidence:
  - reference: PMID:8281713
    reference_title: "Anti-GBM disease: predictive value of clinical, histological and serological data."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Pulmonary disease was significantly associated with current smoking (p < 0.01).
    explanation: Directly reports the association in a 29-patient retrospective cohort.
- name: Infection as a possible environmental trigger
  influences_mechanisms:
  - target: HLA-restricted loss of tolerance and anti-GBM IgG production
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Pointed at the loss-of-tolerance node because the cited sentence
      conditions its claim on genetic susceptibility and that node is the one
      carrying the HLA restriction. Graded predisposing rather than triggering
      despite the sentence using the word trigger, because the sentence hedges
      it twice, saying clustering suggests environmental factors may trigger
      disease, and the exposure's own name calls infection possible. The
      intermediates are unknown in the strict sense: no organism is named and
      no route from infection to autoantibody production is given.
    evidence:
    - reference: PMID:28515156
      reference_title: "Anti-Glomerular Basement Membrane Disease."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The recent confirmation of spatial and temporal clustering of cases suggests that environmental factors, including infection, may trigger disease in genetically susceptible individuals."
      explanation: >-
        States that confirmed spatial and temporal clustering of cases
        suggests environmental factors including infection may trigger disease
        in genetically susceptible individuals. Clustering is an argument that
        something environmental is at work rather than evidence that infection
        is the thing.
  description: >-
    Spatial and temporal clustering supports an environmental contribution, and
    infection is one proposed trigger in genetically susceptible people. The
    evidence does not identify a necessary or sufficient exposure.
  effect: HARMFUL
  evidence:
  - reference: PMID:28515156
    reference_title: Anti-Glomerular Basement Membrane Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The recent confirmation of spatial and temporal clustering of cases
      suggests that environmental factors, including infection, may trigger
      disease in genetically susceptible individuals.
    explanation: Directly supports infection as an environmental trigger in HLA-susceptible hosts.
diagnosis:
- name: Anti-GBM serology plus renal biopsy
  description: >-
    Diagnosis integrates the clinical presentation with serum anti-GBM antibody
    testing and kidney biopsy showing linear IgG deposition along the GBM.
    Either circulating antibody or characteristic biopsy evidence may establish
    antibody involvement; ANCA testing identifies double-positive disease.
  results: >-
    Positive circulating anti-GBM antibodies with linear GBM IgG on biopsy
    confirm the diagnosis; concurrent ANCA positivity defines double-positive
    disease.
  evidence:
  - reference: PMID:40973182
    reference_title: Anti-glomerular basement membrane disease-treatment standard.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Diagnosis relies on clinical features, kidney biopsy showing linear IgG
      deposition along the GBM, and/or detection of circulating anti-GBM antibodies.
    explanation: >-
      Directly states the clinical, biopsy, and circulating-antibody diagnostic
      criteria without requiring every modality to be positive.
- name: Recognition of atypical seronegative anti-GBM disease
  description: >-
    Absence of detectable circulating anti-GBM antibodies does not exclude an
    atypical presentation when kidney biopsy shows linear GBM IgG. This category
    is heterogeneous and should not be assumed to follow classic disease.
  results: Linear GBM IgG with absent circulating anti-GBM antibodies.
  evidence:
  - reference: PMID:33013861
    reference_title: "Clinical-Pathological Features and Outcome of Atypical Anti-glomerular Basement Membrane Disease in a Large Single Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Atypical cases of anti-glomerular basement membrane (GBM) disease had
      absent circulating antibodies but linear IgG deposits along GBM in the kidneys.
    explanation: Directly defines the seronegative, biopsy-positive atypical presentation in a 60-patient cohort.
histopathology:
- name: Linear IgG deposition along the glomerular basement membrane
  diagnostic: true
  description: >-
    Direct immunofluorescence shows pathognomonic linear (ribbon-like) IgG
    deposition along the GBM, distinguishing anti-GBM disease from pauci-immune
    (ANCA) and granular (immune-complex) glomerulonephritides.
  finding_term:
    preferred_term: linear glomerular basement membrane IgG deposition
  evidence:
  - reference: PMID:40973182
    reference_title: Anti-glomerular basement membrane disease-treatment standard.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Diagnosis relies on clinical features, kidney biopsy showing linear IgG
      deposition along the GBM, and/or detection of circulating anti-GBM antibodies.
    explanation: >-
      Identifies linear GBM IgG deposition as the characteristic diagnostic
      biopsy finding.
treatments:
- name: Plasma exchange (plasmapheresis)
  description: >-
    Therapeutic plasma exchange rapidly removes circulating pathogenic anti-GBM
    IgG and is a cornerstone of induction therapy with glucocorticoids and
    cyclophosphamide.
  treatment_term:
    preferred_term: Plasmapheresis
    term:
      id: NCIT:C15304
      label: Plasmapheresis
  target_phenotypes:
  - preferred_term: Glomerulonephritis
    term:
      id: HP:0000099
      label: Glomerulonephritis
  target_mechanisms:
  - target: Linear anti-GBM IgG deposition
    treatment_effect: INHIBITS
    description: >-
      Plasma exchange removes circulating pathogenic anti-GBM IgG, interrupting
      antibody binding and the downstream complement/neutrophil-mediated injury.
    evidence:
    - reference: PMID:28515156
      reference_title: Anti-Glomerular Basement Membrane Disease.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Treatment aims to rapidly remove pathogenic autoantibody, typically with
        the use of plasma exchange, along with steroids and cytotoxic therapy
      explanation: Directly supports antibody removal as the mechanism of plasma exchange.
  evidence:
  - reference: PMID:40973182
    reference_title: Anti-glomerular basement membrane disease-treatment standard.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Historically, untreated disease was rapidly fatal, but the introduction of
      plasma exchange combined with cyclophosphamide and glucocorticoids has
      significantly improved outcomes, particularly in patients who are not
      dialysis-dependent at presentation.
    explanation: Supports plasma exchange as one component of current combination induction therapy.
  - reference: PMID:41629746
    reference_title: "Plasma Exchange for Anti-GBM Disease With Dialysis Dependency: A Case Series on Clinical Outcomes and Safety."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two patients (22.2%) achieved dialysis independence at 10 and 11 months.
      Both patients had relatively preserved normal glomeruli (15.8%-37.2%) and
      achieved early remission.
    explanation: >-
      A 2026 nine-patient dialysis-dependent case series documents selected late
      recovery; PARTIAL reflects its size, selection, and lack of a control group.
  - reference: PMID:28515156
    reference_title: Anti-Glomerular Basement Membrane Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Treatment aims to rapidly remove pathogenic autoantibody, typically with
      the use of plasma exchange, along with steroids and cytotoxic therapy
    explanation: Directly supports plasma exchange as the antibody-removal cornerstone of induction.
- name: High-dose glucocorticoids
  description: >-
    Glucocorticoids suppress inflammation and are given with plasma exchange and
    cyclophosphamide in standard induction therapy.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: glucocorticoid
      term:
        id: CHEBI:24261
        label: glucocorticoid
  evidence:
  - reference: PMID:28515156
    reference_title: Anti-Glomerular Basement Membrane Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      along with steroids and cytotoxic therapy to prevent ongoing autoantibody
      production and tissue inflammation
    explanation: Supports steroids (with cytotoxic therapy) to control inflammation and autoantibody production.
- name: Cyclophosphamide
  description: >-
    The cytotoxic agent cyclophosphamide suppresses new autoantibody production
    and, with plasma exchange and steroids, completes standard induction therapy.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cyclophosphamide
      term:
        id: CHEBI:4027
        label: cyclophosphamide
  target_mechanisms:
  - target: HLA-restricted loss of tolerance and anti-GBM IgG production
    treatment_effect: INHIBITS
    description: >-
      Cyclophosphamide suppresses the lymphocyte-driven production of new
      anti-GBM autoantibody, acting at the autoantibody-formation node.
    evidence:
    - reference: PMID:28515156
      reference_title: Anti-Glomerular Basement Membrane Disease.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        along with steroids and cytotoxic therapy to prevent ongoing autoantibody
        production and tissue inflammation
      explanation: Directly supports suppression of ongoing autoantibody production by cytotoxic therapy.
  evidence:
  - reference: PMID:28515156
    reference_title: Anti-Glomerular Basement Membrane Disease.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      along with steroids and cytotoxic therapy to prevent ongoing autoantibody
      production and tissue inflammation
    explanation: >-
      Supports cytotoxic therapy (cyclophosphamide is the standard cytotoxic agent)
      to prevent ongoing autoantibody production.
- name: Rituximab
  description: >-
    Anti-CD20 B-cell depletion may be considered as second-line treatment when
    cyclophosphamide is contraindicated. Available outcome estimates are derived
    mainly from selected case reports and series, not randomized comparison. A
    2026 retrospective cohort found faster dialysis independence but no
    statistically significant difference in absolute dialysis independence or
    three-year kidney failure.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
  target_mechanisms:
  - target: HLA-restricted loss of tolerance and anti-GBM IgG production
    treatment_effect: INHIBITS
    description: >-
      Rituximab depletes CD20+ B cells upstream of new anti-GBM antibody
      production; it does not directly eliminate mature plasma cells.
    evidence:
    - reference: PMID:40225363
      reference_title: Efficacy and Safety of Rituximab in Antiglomerular Basement Membrane Disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The results indicate that rituximab can be considered as a second-line
        therapy in anti-GBM disease when cyclophosphamide is contraindicated.
      explanation: >-
        Supports clinical use of the B-cell-depleting agent; PARTIAL because the
        cited synthesis does not experimentally isolate this mechanistic edge.
  evidence:
  - reference: PMID:40225363
    reference_title: Efficacy and Safety of Rituximab in Antiglomerular Basement Membrane Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acknowledging the limitations of our study, including publication and
      selection bias, rituximab had a favorable toxicity and efficacy profile.
      The results indicate that rituximab can be considered as a second-line
      therapy in anti-GBM disease when cyclophosphamide is contraindicated.
    explanation: >-
      An individual-patient synthesis of 67 selected published cases supports a
      second-line role while explicitly identifying publication and selection
      bias; PARTIAL reflects the nonrandomized evidence base.
  - reference: DOI:10.3389/fimmu.2026.1835889
    reference_title: "Rituximab is associated with accelerated dialysis independence in anti-glomerular basement membrane disease: a retrospective cohort analysis of renal survival"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although the RTX group demonstrated only numerical advantages in the
      absolute rate of dialysis independence (50.0% vs. 21.05%, p=0.107) and the
      3-year ESRD incidence (42.86% vs. 63.46%, p=0.223), the median time to
      dialysis independence was significantly shorter in the RTX group compared
      to the control group (26 vs. 41 days, p=0.009).
    explanation: >-
      Directly distinguishes a statistically significant time-to-recovery result
      from nonsignificant absolute kidney outcomes in a retrospective cohort.
- name: Imlifidase (investigational IgG-cleaving enzyme)
  description: >-
    Imlifidase (IdeS), an IgG-degrading enzyme of Streptococcus pyogenes, cleaves
    circulating IgG. A 15-patient open-label Phase 2a study reported antibody
    levels below the assay reference range at six hours and a kidney-survival
    signal against historical controls, but required randomized confirmation.
    The subsequent GOOD-IDES-02 Phase 3 trial was terminated by sponsor decision
    and has no posted results.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:35260419
    reference_title: "Endopeptidase Cleavage of Anti-Glomerular Basement Membrane Antibodies in vivo in Severe Kidney Disease: An Open-Label Phase 2a Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Then 6 hours after imlifidase infusion, all patients had anti-GBM
      antibodies levels below the reference range of a prespecified assay.
    explanation: Directly supports rapid anti-GBM antibody cleavage in the 15-patient Phase 2a study.
  - reference: PMID:35260419
    reference_title: "Endopeptidase Cleavage of Anti-Glomerular Basement Membrane Antibodies in vivo in Severe Kidney Disease: An Open-Label Phase 2a Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this pilot study, the use of imlifidase was associated with a better
      outcome compared with earlier publications, without major safety issues,
      but the findings need to be confirmed in a randomized controlled trial.
    explanation: >-
      Supports an early efficacy signal while directly preserving the authors'
      requirement for randomized confirmation.
  - reference: clinicaltrials:NCT05679401
    reference_title: "A Phase 3 Open-label, Controlled, Randomised, Multi-centre Trial Comparing Imlifidase and Standard-of-care With Standard-of-care Alone in the Treatment of Severe Anti-GBM Antibody Disease (Goodpasture Disease)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An open-label, controlled, randomised, multi-centre Phase 3 trial
      evaluating renal function in patients with severe anti-GBM disease
      comparing imlifidase and standard of care (SoC) with SoC alone.
    explanation: >-
      Supports imlifidase as an investigational Phase 3 therapy for severe
      anti-GBM disease aimed at rapid IgG clearance.
clinical_trials:
- name: NCT05679401
  phase: PHASE_III
  status: TERMINATED
  description: >-
    GOOD-IDES-02: Phase 3 open-label, randomised, controlled, multi-centre trial
    comparing imlifidase plus standard-of-care versus standard-of-care alone in
    severe anti-GBM disease. The registry reports termination by sponsor decision
    (not for a safety reason), actual enrollment of 50, and no posted results as
    of 2026-08-05.
  target_phenotypes:
  - preferred_term: Glomerulonephritis
    term:
      id: HP:0000099
      label: Glomerulonephritis
  evidence:
  - reference: clinicaltrials:NCT05679401
    reference_title: "A Phase 3 Open-label, Controlled, Randomised, Multi-centre Trial Comparing Imlifidase and Standard-of-care With Standard-of-care Alone in the Treatment of Severe Anti-GBM Antibody Disease (Goodpasture Disease)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An open-label, controlled, randomised, multi-centre Phase 3 trial
      evaluating renal function in patients with severe anti-GBM disease
      comparing imlifidase and standard of care (SoC) with SoC alone.
    explanation: Defines the GOOD-IDES-02 Phase 3 trial of imlifidase in severe anti-GBM disease.
epidemiology:
- name: One-year patient and kidney outcomes
  description: >-
    Pooled one-year patient and kidney survival were 76.2% and 30.2%, respectively.
    Kidney function at diagnosis and the proportion of normal glomeruli were
    strong prognostic factors; these pooled outcomes should not be treated as an
    individual prognosis.
  evidence:
  - reference: PMID:38493958
    reference_title: "Epidemiology, clinical features, risk factors, and outcomes in anti-glomerular basement membrane disease: A systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The pooled one-year patient and kidney survival rates were 76.2% and 30.2%,
      respectively. Kidney function on diagnosis and normal glomeruli percentage
      were identified as strong prognostic factors.
    explanation: Supports the one-year survival figures and the prognostic importance of baseline kidney function.
prevalence:
- population: General population across included epidemiologic studies
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_low: 0.06
  rate_high: 0.179
  notes: >-
    The systematic review reported 0.60-1.79 new cases per million population
    per year (0.06-0.179 per 100,000 per year). The range straddles the lower
    boundary of the coarse 1-9-per-million class.
  evidence:
  - reference: PMID:38493958
    reference_title: "Epidemiology, clinical features, risk factors, and outcomes in anti-glomerular basement membrane disease: A systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The overall incidence of anti-GBM disease ranged from 0.60 to 1.79 per
      million population per annum.
    explanation: Supports the annual incidence range and its normalized rate conversion.
progression:
- phase: Acute organ-threatening presentation
  notes: >-
    Classic disease generally presents as rapidly progressive glomerulonephritis,
    with pulmonary hemorrhage in about half of cases. Dialysis dependence at
    presentation is associated with a lower likelihood of kidney recovery.
  evidence:
  - reference: PMID:40973182
    reference_title: Anti-glomerular basement membrane disease-treatment standard.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      It is caused by autoantibodies directed against the α3 chain of type IV
      collagen, leading to rapidly progressive glomerulonephritis with pulmonary
      haemorrhage in ∼50% of cases.
    explanation: Supports the characteristic acute renal presentation and approximate pulmonary-hemorrhage proportion.
  - reference: PMID:40973182
    reference_title: Anti-glomerular basement membrane disease-treatment standard.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Dialysis-dependent patients have a lower likelihood of renal recovery, and
      treatment decisions must consider biopsy findings, clinical severity and
      potential contraindications to standard immunosuppression.
    explanation: Supports the prognostic importance of dialysis dependence at presentation.
- phase: Relapse after remission
  notes: >-
    Relapse is rare in classic single-positive disease, so routine long-term
    maintenance immunosuppression is generally unnecessary. Double-positive
    anti-GBM/ANCA disease has higher relapse risk and requires an AAV-like
    maintenance strategy.
  evidence:
  - reference: PMID:40973182
    reference_title: Anti-glomerular basement membrane disease-treatment standard.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Unlike anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis,
      relapses are rare in classic anti-GBM disease, and long-term maintenance
      immunosuppression is not routinely required. However, 'double positive'
      patients (anti-GBM and ANCA) have a higher relapse risk and require
      maintenance immunosuppressive treatment.
    explanation: Directly distinguishes classic monophasic disease from the relapse-prone double-positive subgroup.
differential_diagnoses:
- name: ANCA-associated vasculitis
  description: >-
    ANCA-associated vasculitis (granulomatosis with polyangiitis, microscopic
    polyangiitis) is the principal differential for a pulmonary-renal syndrome;
    it shows pauci-immune (not linear) staining, and may co-occur as
    double-positive disease.
  evidence:
  - reference: PMID:28506760
    reference_title: Patients double-seropositive for ANCA and anti-GBM antibodies have varied renal survival, frequency of relapse, and outcomes compared to single-seropositive patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Double-positive patients shared characteristics of ANCA-associated
      vasculitis (AAV), such as older age distribution and longer symptom
      duration before diagnosis, and features of anti-GBM disease
    explanation: >-
      Supports ANCA-associated vasculitis as the key differential/overlap entity,
      including the double-positive presentation.
animal_models:
- species: Mus musculus
  genotype: Complement C3-deficient, C4-deficient, and wild-type mice in a heterologous anti-GBM nephritis model
  description: >-
    C3 or C4 deficiency reduced neutrophil infiltration, proteinuria, and
    capillary thrombosis after nephritogenic antibody exposure, supporting a
    causal complement role. The heterologous antibody-transfer model bypasses
    human loss of tolerance, and protection was overcome at higher antibody dose.
  associated_phenotypes:
  - Proteinuria
  - Glomerular capillary thrombosis
  evidence:
  - reference: PMID:9409643
    reference_title: Protection against anti-glomerular basement membrane (GBM)-mediated nephritis in C3- and C4-deficient mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These studies support a critical role for complement in the development of
      anti-GBM disease. However, the protective effect of complement deficiency
      can be broken if the dose of nephritogenic antibody is increased.
    explanation: Supports complement dependence and states the antibody-dose limitation of the model.
- species: Rattus norvegicus
  genotype: alpha3(IV)NC1 127-148-immunized Wistar Kyoto rats
  description: >-
    Antigen-immunized rats model autoreactive anti-GBM nephritis. In this 2026
    study, butyrate-modified m-P14 peptide reduced renal injury and inflammatory
    readouts. This induced rodent model is preclinical and does not establish
    efficacy or safety in people.
  associated_phenotypes:
  - Proteinuria
  - Glomerular crescent formation
  evidence:
  - reference: PMID:42278340
    reference_title: Butyric Acid-Modified m-P14 Peptide Ameliorates Anti-Glomerular Basement Membrane Disease.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      M-P14-BA reduced proteinuria, crescent formation, glomerular IgG deposition,
      complement activation, and inflammatory cell infiltration, with overall
      efficacy comparable to m-P14 in early treatment settings.
    explanation: Directly reports the treatment effects in antigen-immunized rats.
discussions:
- discussion_id: gap_atypical_seronegative_management
  prompt: What diagnostic and treatment approach best identifies and manages atypical seronegative anti-GBM disease?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - diagnosis#Recognition of atypical seronegative anti-GBM disease
  rationale: >-
    Biopsy-positive, seronegative cases are heterogeneous, and evidence does not
    justify assuming the natural history or treatment response of classic
    circulating-antibody-positive disease.
  evidence:
  - reference: PMID:40973182
    reference_title: Anti-glomerular basement membrane disease-treatment standard.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Atypical anti-GBM presentations, including seronegative cases, are now
      better recognized but their optimal management remains unclear.
    explanation: The current treatment standard explicitly identifies management as unresolved.
- discussion_id: gap_treatment_comparative_evidence
  prompt: Which induction regimen and emerging adjuncts improve patient and kidney outcomes in prespecified anti-GBM subgroups?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#Cyclophosphamide
  - treatments#Rituximab
  - treatments#Imlifidase (investigational IgG-cleaving enzyme)
  rationale: >-
    Standard treatment is supported largely by observational experience, while
    rituximab evidence is selected and nonrandomized and the confirmatory
    imlifidase trial was terminated without posted results.
  evidence:
  - reference: PMID:40973182
    reference_title: Anti-glomerular basement membrane disease-treatment standard.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Future research should define the use of oral versus intravenous
      cyclophosphamide in anti-GBM disease, clarify the role of rituximab and
      determine the place of emerging therapies such as imlifidase.
    explanation: Directly identifies unresolved regimen and adjunctive-treatment questions.
notes: >-
  Anti-GBM disease is an acquired autoimmune disease with NO GeneReviews chapter
  and no causal germline mutation. The COL4A3/COL4A4/COL4A5 genes encode the
  type IV collagen network that is the AUTOANTIGEN target; loss-of-function
  variants in those same genes cause the hereditary structural disease Alport
  syndrome (GeneReviews PMID:20301386), which is mechanistically distinct and was
  deliberately NOT conflated with anti-GBM disease during curation. The
  molecular_mimicry_autoimmunity module was considered but not declared as a
  conformance target: anti-GBM disease is best modeled as a conformeropathy
  (cryptic-neoepitope unmasking) rather than classic post-infectious molecular
  mimicry, so no false conformance was asserted.
datasets:
- accession: geo:GSE303481
  title: Spatio-temporal interaction of immune and renal cells determines glomerular crescent formation in autoimmune kidney disease
  description: Rapidly progressive glomerulonephritis (RPGN) is the most aggressive group of autoimmune kidney disease with the worst prognosis. Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis, anti-glomerular basement membrane (anti-GBM) and lupus nephritis are the most common causes of RPGN and are characterized by the formation of glomerular crescents and infiltration of leukocytes that eventually lead to glomerulosclerosis and kidney failure.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 15
  publication: PMID:41028563
  notes: Identified by GEO DataSets index search for Anti-Glomerular Basement Membrane Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE294965
  title: Spatio-temporal interaction of immune and renal cells determines glomerular crescent formation in autoimmune kidney disease
  description: Rapidly progressive glomerulonephritis (RPGN) is the most aggressive group of autoimmune kidney disease with the worst prognosis. Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis, anti-glomerular basement membrane (anti-GBM) and lupus nephritis are the most common causes of RPGN and are characterized by the formation of glomerular crescents and infiltration of leukocytes that eventually lead to glomerulosclerosis and kidney failure.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  sample_count: 9
  publication: PMID:40393992
  notes: Identified by GEO DataSets index search for Anti-Glomerular Basement Membrane Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE46295
  title: Effects of a Tricaprylin Emulsion on Anti-glomerular Basement Membrane Glomerulonephritis in Rats
  description: Expression data from rat with anti-glomerular basement membrane nephritis (anti-GBM). We used microarrays to analyze the transcriptome of kidney from anti-GBM model rat with or without drug treatment
  organism:
    preferred_term: rat
    term:
      id: NCBITaxon:10116
      label: Rattus norvegicus
  data_type: MICROARRAY
  sample_count: 12
  publication: PMID:26235580
  notes: Identified by GEO DataSets index search for Anti-Glomerular Basement Membrane Disease (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
📚

References & Deep Research

References

3
PMID:28515156
Anti-Glomerular Basement Membrane Disease.
No top-level findings curated for this source.
PMID:40973182
Anti-glomerular basement membrane disease-treatment standard.
No top-level findings curated for this source.
PMID:38493958
Epidemiology, clinical features, risk factors, and outcomes in anti-glomerular basement membrane disease: A systematic review and meta-analysis.
No top-level findings curated for this source.

Deep Research

1
Claude Code ▸
1. Disease Information
claude-haiku-4-5-20251001, claude-opus-4-8[1m] 16 citations 2026-06-29T11:19:50.469889

1. Disease Information

Overview. Anti-glomerular basement membrane (anti-GBM) disease is a rare, organ-specific autoimmune small-vessel vasculitis caused by circulating autoantibodies (predominantly IgG) directed against the non-collagenous-1 (NC1) domain of the α3 chain of type IV collagen — the "Goodpasture antigen" — which is expressed in the specialized basement membranes of the renal glomerulus and pulmonary alveolus. The classic presentation is a pulmonary–renal syndrome: rapidly progressive (crescentic) glomerulonephritis (RPGN) together with diffuse alveolar hemorrhage (DAH). When both organs are involved the term Goodpasture syndrome/disease is traditionally used; isolated renal-limited or (rarely) lung-limited forms also occur.

Key identifiers. - MONDO: MONDO:0009303 (anti-glomerular basement membrane disease) - OMIM: 233450 (GOODPASTURE SYNDROME) ✔ - Orphanet: ORPHA:375 (Anti-glomerular basement membrane disease / Goodpasture syndrome) - ICD-10: M31.0 (Hypersensitivity angiitis – Goodpasture syndrome); ICD-11: 4A44.A0 / GB61 cross-mapped - MeSH: D019867 "Anti-Glomerular Basement Membrane Disease" - UMLS/SNOMED CT: 236519009 (Anti-glomerular basement membrane disease)

Synonyms / alternative names. Goodpasture syndrome; Goodpasture disease; anti-GBM antibody disease; anti-basement-membrane antibody disease; pulmonary–renal syndrome (descriptive, not specific). The eponym honors Ernest Goodpasture, who described a fatal case during the 1919 influenza pandemic.

Data derivation. This entry is built from aggregated disease-level resources (systematic reviews/meta-analyses, single-center cohort series, mechanistic biochemistry) rather than individual EHR patients — appropriate given the disease's rarity.

2. Etiology

Causal mechanism

Anti-GBM disease is fundamentally an autoantibody-mediated (Type II hypersensitivity) conformeropathy. The proximate cause is the breakdown of immune tolerance to the α3(IV)NC1 domain, generating high-affinity IgG that binds basement-membrane antigen and triggers complement- and neutrophil-mediated necrotizing injury. It is not a Mendelian disease; it arises from a strong genetic susceptibility background acted on by an environmental "second hit."

Genetic risk factors

  • HLA-DRB1*15:01 (DR15 haplotype) is the dominant susceptibility allele. It is "found in more than 80% of patients with anti-GBM antibody disease" (Medscape/Phelps & Rees ⚠ PMID:10231356). DRB1*15:01 and DRB1*04 are positively associated.
  • Susceptibility loci: Phelps & Rees (Kidney Int 1999 ⚠ PMID:10231356) established the HLA-DRB1 dominance hierarchy of risk.

Genetic protective factors

  • HLA-DRB1*07:01 (and DRB1*01) confer dominant protection: "individuals inheriting DRB1*1501 and DRB1*0701 have no higher risk of disease than does the general population" (Medscape synthesis of Phelps & Rees ⚠).

Environmental / acquired risk factors ("second hits" that expose the cryptic antigen)

  • Cigarette smoking — strongly associated, especially with the pulmonary-hemorrhage phenotype.
  • Hydrocarbon / organic-solvent inhalation — classic occupational/inhalational trigger (case literature, e.g., Egyptian J Bronchol 2026).
  • Pulmonary infection (viral respiratory infections, influenza historically).
  • Extracorporeal shock-wave lithotripsy — "can disrupt the glomerular basement membrane and unmask epitopes" (Merck Manual / CJASN review).
  • Alemtuzumab (anti-CD52) — lymphocyte-depleting therapy; "loss of regulatory T cell subsets, or abnormal immune cell repopulation after depletion" (PMC7573726 ⚠).
  • Membranous nephropathy and ANCA-associated vasculitis can precede or co-occur, "unmasking" GBM antigen.
  • Age/sex: bimodal age peaks (young men 20–30; older adults 60–70, more women).

Gene–environment interaction. The canonical model: an HLA-DRB1*15:01–restricted CD4⁺ T-cell response to α3(IV)NC1 epitopes provides help for autoantibody production, but disease only manifests when an environmental insult (smoke, hydrocarbons, infection, lithotripsy) perturbs the GBM and exposes the normally sequestered cryptic epitopes — converting subclinical autoreactivity into overt injury.

3. Phenotypes

Phenotype Type HPO suggestion Frequency Notes
Rapidly progressive (crescentic) glomerulonephritis Lab/clinical sign HP:0000099 Glomerulonephritis; HP:0012622 Chronic kidney disease ~Most renal cases Acute, often dialysis-requiring
Diffuse alveolar / pulmonary hemorrhage Clinical sign HP:0040223 Pulmonary hemorrhage; HP:0002105 Hemoptysis 32.6% (meta-analysis ✔ PMID:38493958) Smoking-associated
Hematuria Lab abnormality HP:0000790 Hematuria Very frequent Glomerular (dysmorphic RBC, casts)
Proteinuria (usually sub-nephrotic) Lab abnormality HP:0000093 Proteinuria Frequent
Acute kidney injury / oliguria Clinical sign HP:0001919 Acute kidney injury; HP:0100518 Dysuria/oliguria (use HP:0100626 Oliguria) Frequent Strong prognostic marker
Elevated serum creatinine / azotemia Lab abnormality HP:0003259 Elevated circulating creatinine Frequent Baseline value is key prognosticator
Dyspnea / respiratory failure Symptom HP:0002094 Dyspnea Common in pulmonary cases
Iron-deficiency / hemorrhagic anemia Lab abnormality HP:0001891 Iron deficiency anemia; HP:0001903 Anemia Common From alveolar bleeding
Hypertension Clinical sign HP:0000822 Hypertension Variable Less prominent than in other GN
Constitutional (malaise, fatigue, weight loss, fever) Symptoms HP:0012378 Fatigue; HP:0001824 Weight loss Common prodrome

Characteristics. Onset is typically acute/subacute in adults; the disease is monophasic in classic single-positive cases (relapse <3%). Severity is severe and often organ-threatening at presentation. Pulmonary hemorrhage can be immediately life-threatening; renal disease frequently progresses to end-stage within days–weeks if untreated.

Quality-of-life impact. Survivors who reach ESRD face lifelong dialysis or transplantation; pulmonary survivors generally recover lung function. No disease-specific QoL instrument exists; generic CKD/dialysis QoL measures (KDQOL, EQ-5D, SF-36) apply.

4. Genetic / Molecular Information

This is NOT a monogenic disease — there are no causal germline mutations. The "molecular genetics" is the genetics of the autoantigen and of HLA susceptibility.

  • Autoantigen gene: COL4A3 (HGNC:2204; chromosome 2q36.3), encoding the α3 chain of type IV collagen. Its C-terminal NC1 domain (α3(IV)NC1) is the Goodpasture antigen. The collateral chains COL4A4 (HGNC:2205) and COL4A5 (HGNC:2207, Xq22.3) form the α3α4α5(IV) network.
  • Susceptibility "gene": HLA class II — HLA-DRB1 (HGNC:4948), allele DRB1*15:01.
  • No pathogenic somatic variants, copy-number, or chromosomal abnormalities are implicated in pathogenesis. (Conversely, loss-of-function mutations in COL4A3/4/5 cause Alport syndrome — and transplanted Alport patients can develop de novo anti-GBM antibodies against the newly encountered α3/α5(IV) antigen, the converse experiment of nature.)
  • Functional consequence: The disease results from a conformational change, not a sequence change — see Mechanism.

Epigenetics / molecular profiling. No established disease-specific methylation/histone signature. Transcriptomic/proteomic profiling is largely confined to research cohorts; no validated multi-omics diagnostic exists.

5. Environmental Information

  • Toxins / inhalational: organic solvents and hydrocarbons (gasoline, paint thinners); cigarette smoke is the best-established lifestyle exposure and disproportionately drives the alveolar-hemorrhage phenotype.
  • Mechanical: extracorporeal shock-wave lithotripsy (GBM disruption).
  • Iatrogenic: alemtuzumab and other lymphocyte-depleting agents.
  • Infectious agents: respiratory viral infections (historically influenza — Goodpasture's index 1919 case); no single pathogen is causal. Infection is regarded as a nonspecific trigger/adjuvant rather than an etiologic organism.

6. Mechanism / Pathophysiology

This is the mechanistic core and the best-characterized aspect of the disease — a model "autoimmune conformeropathy."

Step 1 — The sequestered/cryptic autoantigen and its "immune privilege"

The Goodpasture antigen is the C-terminal NC1 domain of α3(IV) collagen, identified by Saus, Hudson and colleagues as the common target of anti-basement-membrane antibodies (✔ PMID:8589284):

"Reactivity to alpha 3(IV) NC1 domains is both sufficient and necessary for the expression of autoimmune disease directed to the NC1 domain of Type IV collagen."

In the mature GBM, six NC1 domains associate into an α3α4α5 NC1 hexamer (two trimeric "caps" joined head-to-head). The two immunodominant epitopes — E_A and E_B, located on α3(IV)NC1 — are buried by intraprotomer interactions with α4 and α5 NC1 domains and locked by novel sulfilimine (S=N) crosslinks discovered by Vanacore et al. (Science 2009 ⚠ PMID:19729652). These crosslinks "confer immune privilege to the Goodpasture autoantigen" by structurally sequestering the cryptic epitopes.

Step 2 — Conformational unmasking (the "conformeropathy")

Pedchenko et al. (NEJM 2010 ⚠ PMID:20660402, Molecular Architecture of the Goodpasture Autoantigen in Anti-GBM Nephritis) showed that:

"the autoantibodies bind neoepitopes formed on α3 and α5 NC1 subunits upon disruption of the quaternary structure of the native α345NC1 hexamer, and hexamer disruption is concomitant with conformational changes that transition subunits into immunogens."

An environmental insult (oxidants from smoke, infection, mechanical disruption) dissociates the hexamer, exposing E_A/E_B. Autoantibodies to the α5(IV)NC1 chain are also pathogenic, defining a broader α3/α5 conformeropathy (Pedchenko 2016 ⚠, PMC5600521).

Step 3 — Loss of tolerance and antibody production

An HLA-DRB1*15:01–restricted CD4⁺ T-cell response to α3(IV)NC1 peptides drives B-cell help; B cells (CL:0000236) differentiate into plasma cells producing high-affinity, complement-fixing IgG1/IgG3 anti-GBM antibodies. The autoantibody titer correlates with disease activity.

Step 4 — Antibody binding, complement activation, effector recruitment

Circulating IgG binds the exposed α3(IV)NC1 along the GBM in a linear, ribbon-like immunofluorescence pattern. This activates the classical complement pathway (C3, C5a), generating chemoattractants that recruit neutrophils (CL:0000775) and monocytes/macrophages (CL:0000235). Effector cells release proteases and reactive oxygen species, producing fibrinoid necrosis of capillary loops.

Step 5 — Crescent formation and tissue destruction

GBM rupture permits fibrin and inflammatory cells into Bowman's space, triggering parietal epithelial and podocyte proliferation → cellular crescents → crescentic (extracapillary) glomerulonephritis. In the lung, alveolar capillary basement-membrane injury causes diffuse alveolar hemorrhage. Smoking increases alveolar antigen accessibility, explaining the smoking–lung-hemorrhage link.

Causal chain (upstream → downstream)

HLA-DRB1*15:01 susceptibility + environmental insult → hexamer dissociation/oxidation → exposure of cryptic E_A/E_B on α3/α5(IV)NC1 → T-cell-dependent anti-GBM IgG production → linear GBM antibody deposition → classical complement activation + neutrophil recruitment → capillary fibrinoid necrosis → crescentic GN (kidney) and alveolar hemorrhage (lung) → RPGN/ESRD and respiratory failure.

Ontology suggestions

  • Biological processes (GO): GO:0006956 complement activation; GO:0006958 complement activation, classical pathway; GO:0002455 humoral immune response mediated by circulating immunoglobulin; GO:0050900 leukocyte migration; GO:0006954 inflammatory response; GO:0002544 chronic inflammation; GO:0030198 extracellular matrix organization.
  • Cell types (CL): CL:0000236 B cell; CL:0000775 neutrophil; CL:0000235 macrophage; CL:0000084 T cell; CL:1000746 glomerular visceral epithelial cell (podocyte); CL:1000698 kidney resident parietal epithelial cell (crescent precursor).
  • Pathways: Reactome R-HSA-2559639 (Collagen type IV sulfilimine cross-linking by peroxidasin); Reactome complement cascade R-HSA-166658.
  • Protein dysfunction: No protein misfolding mutation — pathology is a quaternary conformational change exposing cryptic epitopes (a structural neoepitope phenomenon).

7. Anatomical Structures Affected

  • Primary organs: Kidney (UBERON:0002113) — specifically the renal glomerulus (UBERON:0000074) and glomerular basement membrane (UBERON:0002164); Lung (UBERON:0002048) — pulmonary alveolus (UBERON:0002299) and alveolar basement membrane.
  • Body systems: renal/urinary and respiratory; secondarily hematologic (hemorrhagic anemia).
  • Tissue/cell level: glomerular capillary endothelium and podocytes; alveolar capillary endothelium/type I pneumocytes; the target is the specialized type IV collagen network of these basement membranes (α3α4α5, restricted to GBM, alveolus, cochlea, eye, testis — explaining organ selectivity).
  • Subcellular (GO Cellular Component): GO:0005604 basement membrane; GO:0005581 collagen trimer; GO:0005615 extracellular space.
  • Lateralization: bilateral (both kidneys, both lungs) — diffuse, antigen-driven.

8. Temporal Development

  • Onset: acute/subacute in adults; bimodal age distribution — a peak in young men (20–30 yr, often with pulmonary–renal disease) and a second in older adults (60–70 yr, more women, often renal-limited).
  • Progression: characteristically rapidly progressive — kidney function can decline from normal to dialysis-dependence over days. Untreated, prognosis is dismal.
  • Course pattern: classic single-positive disease is monophasic (one episode, no relapse if antibody is cleared). Relapse is <3% (NDT treatment-standard review ✔). Double-positive (anti-GBM + ANCA) patients behave more like ANCA-associated vasculitis with relapsing-remitting disease (~50% relapse).
  • Critical window: the therapeutic window is extremely narrow — outcomes hinge on starting plasma exchange/immunosuppression before oliguria/dialysis dependence is established. Patients dialysis-dependent >7 days before treatment "very rarely recover independent kidney function."

9. Inheritance and Population

Epidemiology (✔ systematic review/meta-analysis, PMID:38493958 — 47 studies, 2,830 patients)

  • Incidence: "The overall incidence of anti-GBM disease ranged from 0.60 to 1.79 per million population per annum." (≈0.5–1 case/million/year is the commonly quoted figure.)
  • Anti-GBM accounts for ~8.0% of rapidly progressive GN and ~12.8% of crescentic GN cases (pooled).
  • Anti-GBM antibody positivity: 88.8%; ANCA co-positivity (double-positive): 27.4%; pulmonary hemorrhage: 32.6%.

Inheritance

  • Not Mendelian — complex/multifactorial with strong HLA association. No vertical inheritance pattern, no penetrance/expressivity/anticipation/mosaicism/founder-effect parameters apply in the classic genetic sense.
  • Rare familial clustering in HLA-identical siblings is reported (Clin Kidney J 2020), consistent with shared HLA-DR15 susceptibility rather than a transmitted causal variant.

Demographics

  • Sex: historically male predominance (~3:2) overall, but the older renal-limited peak skews female.
  • Ethnicity: "reported in all racial groups but is primarily a disease of white populations," with ~83% of race-identified cases in white individuals; relatively more common in those of European and East Asian descent. HLA-DRB1*15:01 frequency shapes geographic risk.
  • Geographic clustering / seasonality: small temporal/geographic clusters reported (e.g., post-infection clusters; a noted rise during the COVID-19 pandemic period in Madrid, PMC12457157 ⚠).

10. Diagnostics

Serology (cornerstone)

  • Circulating anti-GBM antibodies by ELISA (anti-α3(IV)NC1) — high sensitivity/specificity; titer tracks activity. LOINC examples: LOINC:40663-6 (Glomerular basement membrane Ab [Units/vol] in Serum by Immunoassay).
  • ANCA panel (MPO/PR3) — must be tested in every patient: ~27–40% are double-positive, which changes prognosis and maintenance therapy.

Histopathology (definitive)

  • Renal biopsy: diffuse crescentic glomerulonephritis on light microscopy; the pathognomonic finding is linear (ribbon-like) IgG deposition along the GBM on direct immunofluorescence (often with linear C3). Quantifying % crescents and % globally sclerosed glomeruli is essential for prognosis.
  • Lung: capillaritis with hemorrhage; hemosiderin-laden macrophages on BAL.

Supporting laboratory / functional

  • Urinalysis: dysmorphic hematuria, RBC casts, sub-nephrotic proteinuria; rising creatinine/falling GFR.
  • Anemia (hemorrhagic/iron-deficiency).
  • Imaging: chest CT/X-ray showing bilateral alveolar infiltrates (RadLex); DLCO is paradoxically increased during active alveolar hemorrhage (a useful functional clue).
  • Genetic testing: not diagnostic (no causal gene). HLA typing is research/risk-stratification only.

Differential diagnosis

ANCA-associated vasculitis (GPA/MPA), lupus nephritis, other causes of pulmonary–renal syndrome, IgA/IgA-vasculitis nephritis, thrombotic microangiopathy, and (importantly) double-positive anti-GBM/ANCA disease. Distinguishing feature: linear (anti-GBM) vs pauci-immune (ANCA) vs granular (immune-complex) IF staining.

11. Outcome / Prognosis

Survival (✔ meta-analysis PMID:38493958)

  • 1-year patient survival: 76.2%; 1-year kidney survival: 30.2%.

Landmark prognostic cohort (Levy et al., Ann Intern Med 2001 ⚠ PMID:11712875; n=71, plasma exchange + prednisolone + cyclophosphamide)

  • Patients presenting with creatinine <500 µmol/L (<5.7 mg/dL): ~100% patient and 95% renal survival at 1 year (84%/74% longer-term).
  • Patients presenting dialysis-dependent / creatinine very high / ~100% crescents: dismal renal recovery.

Strongest prognostic factors

  1. Baseline serum creatinine / dialysis dependence at presentation (the single most powerful predictor).
  2. Oliguria.
  3. Percentage of glomeruli with crescents and normal-glomeruli percentage (✔ meta-analysis: "Kidney function on diagnosis and normal glomeruli percentage were identified as strong prognostic factors").
  4. Time from symptom onset to treatment.

For dialysis-dependent patients, only ~8% recovered independent kidney function at 1 year (recent series ~17–20%); recovery is essentially confined to those with <100% crescents, <50% glomerulosclerosis, non-oliguric, and dialysis started <72 h (NDT review ✔).

Disease course / complications

  • Pulmonary hemorrhage: high remission with treatment (90–100%) but acutely life-threatening.
  • Complications: ESRD requiring dialysis/transplant; treatment-related infection (immunosuppression), hemorrhage.
  • Relapse: <3% in classic single-positive disease; high in double-positive disease.

12. Treatment

The triad of plasma exchange + corticosteroids + cyclophosphamide remains standard of care; it transformed a near-uniformly fatal disease into a treatable one. Specifics below are from the 2026 NDT treatment-standard review (✔).

Standard induction

  • Plasma exchange (PLEX) — MAXO:0000548 (therapeutic plasmapheresis) / NCIT:C15304 (Plasmapheresis): "Daily 40–60 mL/kg exchange for 5% human albumin solution" until antibody fully suppressed, "typically 14 days." Removes circulating pathogenic IgG. (Use fresh frozen plasma replacement if pulmonary hemorrhage/recent biopsy.)
  • Glucocorticoids — MAXO:0000058 / NCIT:C15986 (Pharmacotherapy), agent corticosteroid: "Prednisolone 1 mg/kg/day (maximum 60 mg) orally," tapered to 20 mg by 6 weeks then off by 6 months. Suppresses inflammation.
  • Cyclophosphamide — MAXO:0000647 (chemotherapy/cytotoxic), agent cyclophosphamide CHEBI:4027: "2–3 mg/kg/day (ideal body weight; maximum 200 mg) orally for 2–3 months," dose-reduced in age >55 or dialysis dependence. Suppresses new autoantibody production.

Emerging / alternative agents

  • Rituximab (anti-CD20, B-cell depletion; NCIT:C1702): "2× 1 g at day 0 and 14 OR 375 mg/m² weekly ×4"; used when cyclophosphamide is contraindicated or in refractory disease. A 2025 review of 67 patients reported 91% patient survival, 67% kidney survival (✔). Evidence base remains limited.
  • Imlifidase (IdeS, IgG-degrading enzyme of S. pyogenes; NCIT term for imlifidase): "Cleaves all circulating (and potentially tissue bound) IgG at the hinge region" with onset in 2–6 h. Phase 2: 67% dialysis-independent at 6 months vs 18% historic controls; pivotal Phase 3 GOOD-IDES-02 (NCT05679401) completed recruitment, results anticipated late 2025. Dose 0.25–0.5 mg/kg single dose. Potential paradigm shift for rapid antibody clearance.

Treatment-decision rules

  • Treat pulmonary hemorrhage aggressively regardless of renal status: "Treatment is always recommended when alveolar haemorrhage is present, regardless of the presence or severity of kidney disease."
  • Dialysis-dependent with 100% crescents and no lung hemorrhage: intensive immunosuppression often withheld (futile renal recovery, high infection risk) — individualized.

Supportive / prophylactic care

Pneumocystis jirovecii prophylaxis, antifungal and peptic-ulcer prophylaxis, osteoporosis prevention during high-dose steroids/cyclophosphamide. MAXO:0000950 (supportive care).

Maintenance & transplantation

  • Classic single-positive disease: maintenance immunosuppression not routinely required (monophasic).
  • Double-positive disease: treat maintenance as for ANCA-associated vasculitis.
  • Kidney transplantation (MAXO:0010039 organ transplantation): delay until ≥6 months of sustained anti-GBM seronegativity; transplanting with circulating antibody risks recurrence "up to 50%," but with seronegativity recurrence is rare.

Pharmacogenomics

No validated PGx markers specific to anti-GBM; standard cyclophosphamide considerations (gonadal toxicity, fertility preservation counseling) apply.

13. Prevention

  • Primary prevention: no vaccine/screening (rare, sporadic). Risk-factor modification is the main lever — smoking cessation and avoiding hydrocarbon/solvent exposure, especially in HLA-DR15 carriers (e.g., after lithotripsy or in Alport transplant recipients).
  • Secondary prevention: early recognition of pulmonary–renal syndrome and urgent anti-GBM/ANCA serology + biopsy — the closest analog to "early detection," because outcome is time-critical.
  • Tertiary prevention: monitor antibody titers to confirm clearance before transplantation; treat double-positive patients with maintenance therapy to prevent relapse; infection prophylaxis during immunosuppression.
  • Genetic counseling: limited utility — HLA association is a risk factor, not a deterministic inherited mutation; familial recurrence is rare.

14. Other Species / Natural Disease

  • Taxonomy: primarily a human disease (NCBITaxon:9606).
  • Natural animal disease: spontaneous anti-GBM/Goodpasture-like disease is uncommon in domestic animals; isolated case reports exist in dogs and horses. The α3α4α5(IV) collagen network is evolutionarily conserved across mammals, so the antigen exists in all species.
  • Comparative biology: the conserved type IV collagen network and sulfilimine crosslinks (found broadly across Metazoa) underlie why rodent immunization models faithfully reproduce human disease. Orthologs: mouse Col4a3, Col4a4, Col4a5.
  • Zoonosis: none — autoimmune, not transmissible.

15. Model Organisms

  • Experimental autoimmune glomerulonephritis (EAG): the principal model — rats (WKY strain) and mice immunized with α3(IV)NC1 or GBM preparations develop crescentic GN and linear IgG deposition, recapitulating human kidney pathology. Used to define T-cell epitopes and HLA-restricted responses.
  • Nephrotoxic nephritis (NTN / "anti-GBM nephritis"): heterologous anti-GBM antiserum injected into rodents — a workhorse model of crescentic GN effector mechanisms (complement, neutrophils, macrophages). Caveat: models antibody effector injury, not the spontaneous loss of tolerance.
  • HLA-transgenic mice (DR15 / DR4 / DR1): demonstrate HLA-restricted susceptibility/protection, directly modeling the human HLA association.
  • Col4a3-knockout mouse (Alport model): lacks the antigen; used to study de novo anti-GBM/alloimmunity after antigen re-exposure (analogous to post-transplant Alport anti-GBM).
  • Model characteristics: EAG reproduces linear IF, crescents, and pulmonary involvement (variably); limitations — rodent disease is often less fulminant in the lung, and tolerance-breaking is artificially induced rather than spontaneous.
  • Resources: MGI for Col4a3/4/5; rat models via RGD; immunization protocols in primary EAG literature.

Key References (verify PMIDs before KB ingestion)

  1. ✔ Hellmark/Saus/Hudson et al. Identification of the α3 chain of type IV collagen as the common autoantigen in anti-basement-membrane disease and Goodpasture syndrome. PMID:8589284. — "Reactivity to alpha 3(IV) NC1 domains is both sufficient and necessary…"
  2. ⚠ Pedchenko V, et al. Molecular Architecture of the Goodpasture Autoantigen in Anti-GBM Nephritis. N Engl J Med 2010;363:343–354. PMID:20660402. — conformeropathy / neoepitope mechanism.
  3. ⚠ Vanacore R, et al. A sulfilimine bond identified in collagen IV. Science 2009;325:1230–1234. PMID:19729652. — immune-privilege crosslink (PMC2876822).
  4. ✔ Systematic review & meta-analysis (47 studies, 2,830 patients). PMID:38493958. — incidence 0.60–1.79/million/yr; 1-yr patient survival 76.2%, kidney survival 30.2%; pulmonary hemorrhage 32.6%; ANCA 27.4%.
  5. ⚠ Levy JB, et al. Long-term outcome of anti-GBM antibody disease treated with plasma exchange and immunosuppression. Ann Intern Med 2001;134:1033. PMID:11712875. — creatinine-stratified prognosis.
  6. ✔ Levy JB, et al. Clinical features and outcome of patients with both ANCA and anti-GBM antibodies. Kidney Int 2004. PMID:15458448.
  7. ✔ McAdoo SP, et al. Patients double-seropositive for ANCA and anti-GBM antibodies… Kidney Int 2017. PMID:28506760.
  8. ⚠ McAdoo SP, Pusey CD. Anti-Glomerular Basement Membrane Disease. Clin J Am Soc Nephrol 2017;12:1162. PMID:28515156 (review).
  9. ⚠ Phelps RG, Rees AJ. The HLA complex in Goodpasture's disease. Kidney Int 1999. PMID:10231356 — DRB1*15:01 risk, DRB1*07:01 protection.
  10. ⚠ Anti-GBM disease — treatment standard. Nephrol Dial Transplant 2026;41:42. — regimen, rituximab, imlifidase/GOOD-IDES-02 (NCT05679401).

Sources (URLs): - PubMed 8589284 — α3(IV) autoantigen - NEJM — Molecular Architecture of the Goodpasture Autoantigen (Pedchenko 2010) - Antibodies to α5(IV) are pathogenic — PMC5600521 - PubMed 38493958 — Epidemiology/outcomes systematic review & meta-analysis - Levy 2001 — Ann Intern Med long-term outcome - PubMed 15458448 — ANCA + anti-GBM double-positive (Levy 2004) - PubMed 28506760 — double-seropositive renal survival/relapse (McAdoo 2017) - CJASN 2017 — McAdoo & Pusey review - NDT 2026 — Anti-GBM disease treatment standard - HLA-DRB1 susceptibility — ScienceDirect/Kidney Int - Medscape — Anti-GBM Antibody Disease (HLA, demographics) - Merck Manual — Anti-GBM Disease (triggers) - Vanacore 2009 Science — sulfilimine bond (PMC2876822) - Goodpasture conformeropathy review — PMC6482832 - Alemtuzumab-related anti-GBM — PMC7573726 - OMIM 233450 — Goodpasture syndrome

Summary for KB population

The existing kb/disorders/Anti-GBM_Disease.yaml already captures the correct backbone (MONDO:0009303, α3(IV)NC1 autoantigen, HLA-DRB1*15:01, the 3-node B-cell→complement/neutrophil→crescentic-GN/alveolar-hemorrhage pathophysiology chain, and plasma exchange treatment). This report supplies the evidence to flesh it out: add the conformeropathy/neoepitope mechanism node (PMID:20660402, 8589284) with the sulfilimine immune-privilege detail (PMID:19729652); add double-positive ANCA as a distinct trajectory; add quantitative phenotype frequencies (pulmonary hemorrhage 32.6%) and outcomes (1-yr survival 76.2%/30.2%) from PMID:38493958; add cyclophosphamide, corticosteroids, rituximab, and imlifidase treatments with MAXO/NCIT/CHEBI terms and the GOOD-IDES-02 trial (NCT05679401); and add smoking/hydrocarbon/lithotripsy/alemtuzumab environmental triggers. Re-fetch and substring-verify every ⚠ PMID with just fetch-reference before adding any evidence snippet.