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Inheritance

1

Complex non-Mendelian inheritance

Glomerulonephritis as a whole is not a Mendelian disorder. Even in the complement-mediated arm, where the largest set of implicated genes is known, transmission is complex: familial clustering is the exception, and both dominant and recessive patterns have been described within the few multiplex families reported. This is the reason the complement genes below are curated as SUSCEPTIBILITY rather than as causal Mendelian loci.

Show evidence (1 reference)

PMID:20301598 SUPPORT Human Clinical

"C3G is a complex genetic disorder that is rarely inherited in a simple mendelian fashion. Multiple affected persons within a single nuclear family are reported only occasionally, with both dominant and recessive inheritance being described."

GeneReviews states the transmission pattern directly for the complement-mediated arm, and is the attribution for treating the complement genes as susceptibility loci rather than Mendelian causes.

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Subtypes

7

IgA nephropathy (Berger disease) MONDO:0005342

Mesangial deposition of galactose-deficient IgA1-containing immune complexes arising from mucosal immune dysregulation. Curated in full as the standalone dismech entry IgA_Nephropathy.

Membranous Nephropathy MONDO:0005376

In-situ subepithelial immune-complex formation against podocyte surface antigens, chiefly PLA2R1 and THSD7A, presenting with nephrotic-range proteinuria rather than a nephritic picture. Curated in full as the standalone dismech entry Membranous_Nephropathy.

Show evidence (1 reference)

PMID:35484394 SUPPORT Human Clinical

"Membranous nephropathy (MN) is characterized histomorphologically by the presence of immune deposits in the subepithelial space of the glomerular filtration barrier; its clinical hallmarks are nephrotic range proteinuria with oedema."

Establishes membranous nephropathy as a subepithelial immune-deposit lesion whose presentation is nephrotic rather than nephritic.

Lupus Nephritis MONDO:0005556

Renal manifestation of systemic lupus erythematosus, in which immune complexes containing nuclear antigens deposit in the mesangium and along the capillary wall, producing a class-dependent spectrum from mesangial to diffuse proliferative to membranous lesions. Curated in full as the standalone dismech entry Lupus_Nephritis.

Show evidence (1 reference)

PMID:36483271 SUPPORT Human Clinical

"Lupus nephritis is a severe organ manifestation of systemic lupus erythematosus, and its pathogenesis involves complex etiology and mechanisms."

Establishes lupus nephritis as the renal organ manifestation of SLE, the basis for listing it as an etiologic subtype of glomerulonephritis alongside the other immune-complex forms.

Acute post-streptococcal glomerulonephritis MONDO:0001870

Acute infection-related immune-complex glomerulonephritis following group A streptococcal throat or skin infection, with streptococcal pyrogenic exotoxin B (SpeB) and nephritis-associated plasmin receptor (NAPlr) as the identified nephritogenic antigens.

Show evidence (1 reference)

PMID:39341789 SUPPORT Human Clinical

"Streptococcal pyrogenic exotoxin B and nephritis-associated plasmin receptor are identified nephritogenic antigens (nephritogens)."

Names the two established streptococcal nephritogens that initiate the post-streptococcal immune-complex lesion.

Anti-glomerular basement membrane (Goodpasture) disease MONDO:0009303

Directly pathogenic autoantibody against the NC1 domain of the alpha-3 chain of type IV collagen in the glomerular and alveolar basement membrane, causing widespread crescent formation with frequent alveolar hemorrhage. Curated in full as the standalone dismech entry Anti-GBM_Disease.

Show evidence (1 reference)

PMID:28515156 SUPPORT Human Clinical

"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"

Establishes anti-GBM disease as a directly antibody-mediated basement membrane lesion, distinguishing it from immune-complex GN.

ANCA-associated pauci-immune necrotizing crescentic GN MONDO:0019988

Pauci-immune necrotizing and crescentic glomerulonephritis driven by anti-neutrophil cytoplasmic antibodies targeting proteinase-3 or myeloperoxidase, with little or no glomerular immunoglobulin deposition.

Show evidence (1 reference)

PMID:36109667 SUPPORT Human Clinical

"that share features of pauci-immune small-vessel vasculitis and the positivity of ANCA targeting proteinase-3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA)"

Defines the pauci-immune, ANCA-specificity-based character of this GN subtype.

Membranoproliferative glomerulonephritis (including C3 glomerulopathy) MONDO:0002461

Mesangial proliferation with capillary wall double contours on light microscopy. Divided by immunofluorescence into immune-complex-mediated MPGN and complement-mediated C3 glomerulopathy, the latter driven by uncontrolled alternative-pathway activation.

Show evidence (1 reference)

PMID:42284585 SUPPORT Human Clinical

"C3 glomerulopathy (C3G) is a clinicopathologic entity characterized by glomerular inflammation with dominant staining for C3 on immunofluorescence microscopy."

Defines the complement-mediated arm of the membranoproliferative pattern by its C3-dominant immunofluorescence signature.

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Pathophysiology

11

Nephritogenic Antigen Exposure and Loss of Tolerance

The initiating step is the appearance of a nephritogenic antigen-antibody pairing. This may be a foreign antigen from infection (streptococcal SpeB or NAPlr, hepatitis B or C, staphylococcal or endocarditis-associated antigen), a self antigen against which tolerance is lost (the alpha-3 chain of type IV collagen in anti-GBM disease, myeloperoxidase or proteinase-3 in ANCA disease, PLA2R1 in membranous nephropathy, nuclear antigens in lupus nephritis), or an aberrantly glycosylated self immunoglobulin (galactose-deficient IgA1). GN is correspondingly grouped by immunopathogenesis rather than by histological pattern, because the lesion pattern does not identify the cause.

plasma cell CL:0000786 B cell CL:0000236

adaptive immune response GO:0002250 ⚠ ABNORMAL immunoglobulin production GO:0002377

Downstream

Glomerular Immune Complex Deposition Antigen-antibody complexes formed in the circulation or in situ localize within the glomerulus.

Anti-GBM Autoantibody Binding to Type IV Collagen Loss of tolerance to the alpha-3(IV)NC1 autoantigen yields directly pathogenic antibody that binds the basement membrane.

ANCA-Mediated Neutrophil Activation Autoantibody against myeloperoxidase or proteinase-3 activates primed neutrophils at the glomerular capillary.

Subepithelial Immune Deposition and Podocyte Injury Antibody against a podocyte surface antigen forms in-situ subepithelial deposits, the membranous/nephrotic arm.

Show evidence (3 references)

PMID:36635359 SUPPORT Human Clinical

"These disorders are currently classified largely on the basis of histopathological lesion patterns, but these patterns do not align well with their diverse pathological mechanisms and hence do not inform optimal therapy."

Supports modeling GN by initiating immunopathogenic mechanism rather than by histological lesion pattern.

PMID:36635359 SUPPORT Human Clinical

"we propose grouping GN disorders into five categories according to their immunopathogenesis: infection-related GN, autoimmune GN, alloimmune GN, autoinflammatory GN and monoclonal gammopathy-related GN."

Supplies the five-category immunopathogenic scheme this entry's description adopts, and is the citation for the two categories named there but deliberately not modelled as subtypes (alloimmune and monoclonal gammopathy-related GN).

PMID:37764071 SUPPORT Human Clinical

"The mechanisms responsible range from the direct damage of glomerular cells to the formation and deposition of immunocomplexes to molecular mimicry to the secretion of superantigens."

Enumerates the distinct routes by which an infectious trigger initiates glomerular injury, supporting a multi-route trigger node.

Glomerular Immune Complex Deposition

Circulating immune complexes are trapped in the glomerulus, or complexes form in situ when antibody binds an antigen already planted in the capillary wall. Deposit location determines the clinical syndrome: mesangial and subendothelial deposits sit on the blood side of the basement membrane, where they are accessible to circulating inflammatory cells and produce a nephritic, proliferative lesion; subepithelial deposits are separated from the circulation by the basement membrane and instead injure the podocyte.

mesangial cell CL:0000650 glomerular capillary endothelial cell CL:1001005

immune complex clearance GO:0002434 ↓ DECREASED

renal glomerulus UBERON:0000074

Downstream

Complement Activation Deposited immunoglobulin fixes complement via the classical pathway.

Show evidence (1 reference)

PMID:39341789 SUPPORT Human Clinical

"Deposition of circulating immune complexes or in situ formation of immune complexes in glomeruli, or both, results in glomerulonephritis."

States both routes — circulating deposition and in-situ formation — by which immune complexes produce glomerulonephritis.

Anti-GBM Autoantibody Binding to Type IV Collagen

In anti-GBM disease, autoantibody binds a conformational epitope on the non-collagenous (NC1) domain of the alpha-3 chain of type IV collagen, an antigen normally sequestered within the hexameric collagen network of the glomerular and alveolar basement membrane. Because the antibody engages a fixed structural antigen along the whole capillary wall, injury is near-simultaneous across all glomeruli, which is why this subtype so characteristically produces widespread crescents and rapidly progressive disease, frequently with concurrent alveolar hemorrhage.

antigen binding GO:0003823

glomerular basement membrane UBERON:0005777

Downstream

Complement Activation Basement-membrane-bound IgG fixes complement along the capillary wall.

Glomerular Capillary Wall Injury and Necrosis Direct antibody-mediated injury to the basement membrane breaches the capillary wall.

Show evidence (2 references)

PMID:37981425 SUPPORT Human Clinical

"typically characterized by autoimmunity against the α3 chain of type IV collagen"

Names the target antigen of this node directly. The same source records that rare seronegative cases may instead target laminin-521, which is why the node description says "typically" rather than invariably.

PMID:28515156 SUPPORT Human Clinical

"The majority of patients develop widespread glomerular crescent formation, presenting with features of rapidly progressive GN, and 40%-60% will have concurrent alveolar hemorrhage."

Links the anti-GBM lesion to widespread crescent formation, RPGN, and pulmonary involvement. Marked PARTIAL because it evidences the consequences of the lesion rather than the molecular identity of the antigen, which the preceding item supplies.

ANCA-Mediated Neutrophil Activation

In pauci-immune GN, cytokine-primed neutrophils translocate myeloperoxidase and proteinase-3 to their surface, where circulating ANCA engages them and triggers full activation: adhesion to the glomerular endothelium, respiratory burst, degranulation, and release of neutrophil extracellular traps. Because injury is delivered by the activated neutrophil rather than by deposited complexes, immunofluorescence shows little or no immunoglobulin — the defining "pauci-immune" feature. Complement, particularly the C5a-C5aR axis, amplifies the priming loop and is the target of avacopan.

neutrophil CL:0000775

neutrophil activation GO:0042119 ↑ INCREASED neutrophil extracellular trap formation GO:0140645 ↑ INCREASED

Downstream

Glomerular Capillary Wall Injury and Necrosis Neutrophil oxidants and granule proteases produce fibrinoid necrosis of the capillary tuft.

Show evidence (4 references)

PMID:32446935 SUPPORT In Vitro

"normal-density neutrophils were activated by MPO-ANCA and monoclonal anti-PR3 antibody"

Direct demonstration that both MPO-ANCA and anti-PR3 antibody activate human neutrophils, which is the core claim of this node and the basis for the GO:0042119 annotation.

PMID:38837706 SUPPORT In Vitro

"ANCA-induced neutrophil respiratory burst and NETosis"

Establishes respiratory burst and NET formation as ANCA-induced effector responses of isolated human neutrophils, supporting the GO:0140645 annotation.

PMID:38837706 SUPPORT In Vitro

"the importance of C5a and anti-neutrophil cytoplasmic antibody (ANCA)-induced neutrophil activation in the pathogenesis of ANCA-associated vasculitis"

Supports the C5a-amplification limb of this node's description, which is the mechanistic rationale for the avacopan treatment link.

+ 1 more reference

Alternative Pathway Complement Dysregulation

In C3 glomerulopathy the fluid-phase alternative pathway escapes regulation, through acquired autoantibodies such as C3 nephritic factor that stabilize the C3 convertase, or through rare variants in complement genes (C3, CFH, CFI, CFB, CD46, CFHR1, CFHR5, DGKE). Continuous C3 turnover deposits C3 fragments in the glomerulus without accompanying immunoglobulin, giving the C3-dominant immunofluorescence pattern that defines the entity. This is an autoinflammatory route into GN: no adaptive antigen-antibody pairing is required.

complement activation, alternative pathway GO:0006957 ↑ INCREASED

Downstream

Complement Activation Unregulated convertase activity drives sustained C3 cleavage and glomerular C3 deposition.

Show evidence (1 reference)

PMID:20301598 SUPPORT Human Clinical

"C3 glomerulopathy (C3G) is a complex ultra-rare complement-mediated renal disease caused by uncontrolled activation of the complement alternative pathway (AP) in the fluid phase"

Establishes uncontrolled fluid-phase alternative-pathway activation as the causal mechanism of the complement-mediated arm.

Complement Activation

Complement is the principal amplifier converting antibody or convertase deposition into tissue injury. Classical-pathway activation by deposited IgG or IgM, lectin-pathway activation, and alternative-pathway amplification all converge on C3 cleavage, generating the anaphylatoxins C3a and C5a and the C5b-9 membrane attack complex. C5a is a potent neutrophil chemoattractant and primer; C5b-9 injures glomerular cells sublytically. Consumption of complement is clinically visible as a depressed serum C3 in post-infectious GN, C3 glomerulopathy, and lupus nephritis.

complement activation GO:0006956 ↑ INCREASED complement activation, classical pathway GO:0006958 ↑ INCREASED

Downstream

Leukocyte Recruitment and Glomerular Inflammation C3a and C5a recruit and prime neutrophils and monocytes at the glomerulus.

Show evidence (1 reference)

PMID:20301598 SUPPORT Human Clinical

"Individuals with C3G typically present with hematuria, proteinuria, hematuria and proteinuria, acute nephritic syndrome or nephrotic syndrome, and low levels of the complement component C3."

Links complement consumption to the measurable low serum C3 and to the nephritic presentation.

Leukocyte Recruitment and Glomerular Inflammation

Complement fragments, Fc-receptor engagement on deposited complexes, and activated resident glomerular cells recruit neutrophils and monocytes into the capillary tuft and mesangium. Infiltrating and resident cells release cytokines, chemokines, reactive oxygen species, and proteases. Effector CD4 T cell (Th1/Th17) and CD8 T cell responses contribute substantially to the severe crescentic phenotype. Mesangial and endothelial cells proliferate, producing the endocapillary and mesangial hypercellularity seen on biopsy.

macrophage CL:0000235 neutrophil CL:0000775 CD4-positive T cell CL:0000624 CD8-positive T cell CL:0000625

leukocyte migration GO:0050900 ↑ INCREASED inflammatory response GO:0006954 ↑ INCREASED

Downstream

Glomerular Capillary Wall Injury and Necrosis Leukocyte-derived oxidants and proteases damage the endothelium and basement membrane.

Show evidence (3 references)

PMID:39300109 SUPPORT Human Clinical

"using spatial and single-cell transcriptome analysis, we characterize inflammatory niches in kidney samples from 34 patients with ANCA-GN and identify proinflammatory, cytokine-producing CD4+ and CD8+ T cells as a pathogenic signature"

Direct tissue-level evidence that cytokine-producing CD4+ and CD8+ T cells populate inflammatory niches in the GN kidney, supporting both the leukocyte-recruitment claim and the CD4/CD8 cell-type annotations on this node; marked PARTIAL because the cohort is ANCA-associated GN rather than GN generally.

PMID:36635359 SUPPORT Human Clinical

"macrophage infiltrates, which accelerates glomerular inflammation and injury"

Evidences the macrophage cell-type annotation and the increased inflammatory response asserted on this node.

PMID:36635359 SUPPORT Human Clinical

"leukocytes pass through tight glomerular capillaries at a higher pressure and flow velocity compared with other capillary beds, which promotes the release of NETs"

Evidences leukocyte trafficking through the glomerular capillary bed and the neutrophil cell-type annotation, supporting the leukocyte-migration process asserted here.

Glomerular Capillary Wall Injury and Necrosis

The converging effector mechanisms damage the three-layered filtration barrier. Endothelial injury and basement membrane degradation breach the capillary wall, allowing erythrocytes to escape into the urinary space — the dysmorphic hematuria and red cell casts that define a glomerular bleeding source — and permitting protein leak. In severe necrotizing disease, fibrinoid necrosis and frank rupture of the capillary wall spill fibrin and plasma proteins into Bowman's space.

glomerular capillary endothelial cell CL:1001005

glomerular filtration GO:0003094 ⚠ ABNORMAL

glomerular basement membrane UBERON:0005777

Downstream

Crescent Formation Capillary wall rupture spills fibrin and plasma into Bowman's space, triggering parietal epithelial proliferation.

Hematuria Breaches in the capillary wall allow erythrocytes to enter the urinary space.

Proteinuria Loss of barrier integrity permits protein leak into the filtrate.

Decreased glomerular filtration rate Inflammatory occlusion of the capillary tuft reduces filtration surface.

Show evidence (3 references)

PMID:36635359 SUPPORT Human Clinical

"followed by focal capillary necrosis in the glomerulus"

Directly evidences focal necrosis of the glomerular capillary, which is the lesion this node is named for.

PMID:36635359 SUPPORT Human Clinical

"Acute GN most frequently presents with high blood pressure (hypertension), proteinuria (excessive protein in the urine) and haematuria (blood in the urine)"

Evidences the downstream consequences asserted on this node's outgoing edges — protein leak and erythrocyte escape into the urinary space.

PMID:36635359 SUPPORT Human Clinical

"'Glomerulonephritis' (GN) is a term used to describe a group of heterogeneous immune-mediated disorders characterized by inflammation of the filtration units of the kidney (the glomeruli)."

Establishes inflammatory injury of the glomerular filtration unit as the defining lesion shared across GN. Marked PARTIAL because it is a definitional statement and does not by itself evidence endothelial injury or basement-membrane breach.

Subepithelial Immune Deposition and Podocyte Injury

The nephrotic arm of GN, exemplified by membranous nephropathy. Antibody against a podocyte surface antigen (PLA2R1, THSD7A, and a growing list of minor antigens) forms immune deposits in the subepithelial space. Because the basement membrane separates these deposits from the circulation, circulating leukocytes are not recruited and the lesion is not inflammatory; instead, locally generated C5b-9 injures the podocyte, disorganizing its actin cytoskeleton. The consequence is nephrotic-range proteinuria without the hematuria-dominant nephritic picture. This node is the point of contact with the conserved podocytopathy module.

podocyte CL:0000653

actin cytoskeleton organization GO:0030036 ⚠ ABNORMAL

Downstream

Proteinuria Podocyte injury and foot process effacement break the size-selective filtration barrier.

Show evidence (2 references)

PMID:35484394 SUPPORT Human Clinical

"In patients with primary MN, autoimmunity is driven by circulating autoantibodies that bind to one or more antigens on the surface of glomerular podocytes."

Establishes the podocyte as the direct antibody target in this arm, justifying conformance to the podocyte-injury module rather than to the nephritic inflammatory chain.

PMID:35484394 SUPPORT Human Clinical

"the discovery of pathogenic circulating autoantibodies against phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type 1 domain-containing protein 7A (THSD7A)"

Names the two established podocyte autoantigens of primary membranous nephropathy.

Crescent Formation

Where the capillary wall has ruptured, fibrin, plasma proteins, and inflammatory cells enter Bowman's space and drive proliferation of parietal epithelial cells, with recruited macrophages, into the characteristic crescent. Crescents are the histological correlate of rapidly progressive glomerulonephritis: they compress the tuft, obliterate Bowman's space, and, if they organize into fibrous crescents, render the glomerulus irrecoverable. Crescentic disease is the shared severe endpoint of anti-GBM disease, ANCA-associated GN, and severe immune-complex GN, and is what makes prompt immunosuppression time-critical.

parietal epithelial cell CL:1000452 macrophage CL:0000235

epithelial cell proliferation GO:0050673 ↑ INCREASED

Downstream

Crescentic glomerulonephritis Extensive crescent formation is the defining histological lesion.

Nephron Loss and Progressive Kidney Failure Organized fibrous crescents destroy the glomerulus irreversibly.

Show evidence (1 reference)

PMID:28515156 SUPPORT Human Clinical

"although presentation with oligoanuria, a high proportion of glomerular crescents, or kidney failure requiring dialysis augur badly for renal prognosis"

Ties crescent burden directly to adverse kidney outcome, supporting crescent formation as the severity-determining node.

Nephron Loss and Progressive Kidney Failure

Glomeruli that are not repaired sclerose. Loss of filtering units imposes hyperfiltration on those remaining, and persistent proteinuria drives tubulointerstitial inflammation and fibrosis. The result is progressive nephron loss and chronic kidney disease, which for a substantial minority of patients ends in kidney failure requiring dialysis or transplantation. This convergent endpoint is why glomerulonephritis collectively accounts for a large share of the global chronic kidney disease burden.

extracellular matrix organization GO:0030198 ↑ INCREASED tissue remodeling GO:0048771 ⚠ ABNORMAL

Downstream

Chronic kidney disease Cumulative nephron loss manifests as chronic kidney disease.

Stage 5 chronic kidney disease Continued attrition ends in kidney failure requiring kidney replacement therapy.

Show evidence (2 references)

PMID:42284585 SUPPORT Human Clinical

"Both entities are progressive, with about 60% of patients progressing to end-stage kidney disease (ESKD) within 10 years."

Quantifies progression to kidney failure in the complement-mediated arm, supporting the convergent progressive endpoint.

PMID:39341789 SUPPORT Human Clinical

"This condition significantly predisposes individuals to later-life chronic kidney disease and concurrent renal complications"

Shows that even the classically self-limited post-infectious form carries long-term chronic kidney disease risk.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

14

Blood 1

Pulmonary hemorrhage HP:0040223

Show evidence (1 reference)

PMID:28515156 SUPPORT Human Clinical

"The majority of patients develop widespread glomerular crescent formation, presenting with features of rapidly progressive GN, and 40%-60% will have concurrent alveolar hemorrhage."

Quantifies concurrent alveolar hemorrhage in the anti-GBM subtype.

Cardiovascular 1

Hypertension HP:0000822

Show evidence (1 reference)

PMID:39341789 SUPPORT Human Clinical

"The affected individuals present with macroscopic haematuria, oliguria, facial oedema, and hypertension"

Lists hypertension among the presenting features of the acute nephritic syndrome.

Genitourinary 6

Hematuria HP:0000790

Show evidence (1 reference)

PMID:20301598 SUPPORT Human Clinical

"Individuals with C3G typically present with hematuria, proteinuria, hematuria and proteinuria, acute nephritic syndrome or nephrotic syndrome, and low levels of the complement component C3."

Documents hematuria as a presenting feature of glomerulonephritis.

Proteinuria HP:0000093

Show evidence (1 reference)

PMID:20301598 SUPPORT Human Clinical

"Individuals with C3G typically present with hematuria, proteinuria, hematuria and proteinuria, acute nephritic syndrome or nephrotic syndrome, and low levels of the complement component C3."

Documents proteinuria as a presenting feature of glomerulonephritis.

Oliguria HP:0100520

Show evidence (1 reference)

PMID:28515156 SUPPORT Human Clinical

"although presentation with oligoanuria, a high proportion of glomerular crescents, or kidney failure requiring dialysis augur badly for renal prognosis"

Documents oligoanuria as a presenting feature and adverse prognostic marker.

Acute kidney injury HP:0001919

Show evidence (1 reference)

PMID:37764071 SUPPORT Human Clinical

"findings include nephritic syndrome, characterized by micro/macrohematuria, proteinuria that can also reach the nephrotic range, edema, arterial hypertension, and acute renal failure"

Lists acute renal failure among the presenting features of the nephritic syndrome in infection-related glomerulonephritis.

Chronic kidney disease HP:0012622

Show evidence (1 reference)

PMID:39341789 SUPPORT Human Clinical

"This condition significantly predisposes individuals to later-life chronic kidney disease and concurrent renal complications"

Documents progression to chronic kidney disease following glomerulonephritis.

Stage 5 chronic kidney disease HP:0003774

Show evidence (1 reference)

PMID:42284585 SUPPORT Human Clinical

"Both entities are progressive, with about 60% of patients progressing to end-stage kidney disease (ESKD) within 10 years."

Quantifies progression to kidney failure in complement-mediated glomerulonephritis.

Metabolism 3

Edema HP:0000969

Show evidence (1 reference)

PMID:35484394 SUPPORT Human Clinical

"its clinical hallmarks are nephrotic range proteinuria with oedema"

Documents edema accompanying nephrotic-range proteinuria in the membranous arm.

Hypoalbuminemia HP:0003073

Show evidence (1 reference)

PMID:39341789 SUPPORT Human Clinical

"urinalysis reveal hypoalbuminemia, proteinuria, increased serum creatinine and urea, reduced estimated glomerular filtration rate"

Documents hypoalbuminemia alongside proteinuria in the laboratory profile of glomerulonephritis.

Hypercholesterolemia HP:0003124

Show evidence (1 reference)

PMID:29176657 SUPPORT Human Clinical

"These abnormalities include elevated plasma levels of cholesterol, triglycerides and the apolipoprotein B-containing lipoproteins VLDL and IDL"

Characterizes the dyslipidemia of nephrotic syndrome, including raised plasma cholesterol, in the nephrotic-overlap arm of glomerulonephritis.

Other 3

Decreased glomerular filtration rate HP:0012213

Show evidence (1 reference)

PMID:36635359 SUPPORT Human Clinical

"'Glomerulonephritis' (GN) is a term used to describe a group of heterogeneous immune-mediated disorders characterized by inflammation of the filtration units of the kidney (the glomeruli)."

Supports inflammatory involvement of the glomerular filtration unit; marked PARTIAL because the quoted definition does not itself state that measured GFR falls.

Crescentic glomerulonephritis HP:0008653

Show evidence (1 reference)

PMID:28515156 SUPPORT Human Clinical

"The majority of patients develop widespread glomerular crescent formation, presenting with features of rapidly progressive GN, and 40%-60% will have concurrent alveolar hemorrhage."

Documents widespread crescent formation and its association with rapidly progressive disease.

Decreased circulating complement C3 concentration HP:0005421

Show evidence (1 reference)

PMID:20301598 SUPPORT Human Clinical

"Individuals with C3G typically present with hematuria, proteinuria, hematuria and proteinuria, acute nephritic syndrome or nephrotic syndrome, and low levels of the complement component C3."

Documents low serum C3 as a characteristic laboratory finding.

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Genetic Associations

12

CFH (GENETIC_VARIANT)

Gene: CFH hgnc:4883 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:20301598 SUPPORT Human Clinical

"Some individuals will have biallelic or heterozygous pathogenic variants identified by molecular genetic testing in one or more of the genes that have been implicated in the pathogenesis of C3G (i.e., C3, CD46, CFB, CFH, CFHR1, CFHR5, CFI, and DGKE)."

Lists CFH among the complement genes implicated in C3 glomerulopathy, and notes that only some affected individuals carry an identifiable variant.

C3 (GENETIC_VARIANT)

Gene: C3 hgnc:1318 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:20301598 SUPPORT Human Clinical

"Some individuals will have biallelic or heterozygous pathogenic variants identified by molecular genetic testing in one or more of the genes that have been implicated in the pathogenesis of C3G (i.e., C3, CD46, CFB, CFH, CFHR1, CFHR5, CFI, and DGKE)."

Lists C3 among the complement genes implicated in C3 glomerulopathy.

CFHR5 (GENETIC_VARIANT)

Gene: CFHR5 hgnc:24668 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:20301598 SUPPORT Human Clinical

"Some individuals will have biallelic or heterozygous pathogenic variants identified by molecular genetic testing in one or more of the genes that have been implicated in the pathogenesis of C3G (i.e., C3, CD46, CFB, CFH, CFHR1, CFHR5, CFI, and DGKE)."

Lists CFHR5 among the complement genes implicated in C3 glomerulopathy.

CFI (GENETIC_VARIANT)

Gene: CFI hgnc:5394 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:20301598 SUPPORT Human Clinical

"Some individuals will have biallelic or heterozygous pathogenic variants identified by molecular genetic testing in one or more of the genes that have been implicated in the pathogenesis of C3G (i.e., C3, CD46, CFB, CFH, CFHR1, CFHR5, CFI, and DGKE)."

Lists CFI among the complement genes implicated in C3 glomerulopathy.

CFB (GENETIC_VARIANT)

Gene: CFB hgnc:1037 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:20301598 SUPPORT Human Clinical

"Some individuals will have biallelic or heterozygous pathogenic variants identified by molecular genetic testing in one or more of the genes that have been implicated in the pathogenesis of C3G (i.e., C3, CD46, CFB, CFH, CFHR1, CFHR5, CFI, and DGKE)."

Lists CFB among the complement genes implicated in C3 glomerulopathy.

CD46 (GENETIC_VARIANT)

Gene: CD46 hgnc:6953 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:20301598 SUPPORT Human Clinical

"Some individuals will have biallelic or heterozygous pathogenic variants identified by molecular genetic testing in one or more of the genes that have been implicated in the pathogenesis of C3G (i.e., C3, CD46, CFB, CFH, CFHR1, CFHR5, CFI, and DGKE)."

Lists CD46 among the complement genes implicated in C3 glomerulopathy.

DGKE (GENETIC_VARIANT)

Gene: DGKE hgnc:2852 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:20301598 SUPPORT Human Clinical

"Some individuals will have biallelic or heterozygous pathogenic variants identified by molecular genetic testing in one or more of the genes that have been implicated in the pathogenesis of C3G (i.e., C3, CD46, CFB, CFH, CFHR1, CFHR5, CFI, and DGKE)."

Lists DGKE among the genes implicated in C3 glomerulopathy.

PRTN3 (GWAS)

Gene: PRTN3 hgnc:9495 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:36109667 SUPPORT Human Clinical

"In patients with GPA and MPA, the genetic associations are stronger with ANCA specificity (PR3- versus MPO-ANCA) than with the clinical diagnosis, which, in keeping with the known clinical and prognostic differences between PR3-ANCA-positive and MPO-ANCA-positive patients, supports an ANCA-based..."

Establishes that genetic risk tracks with PR3 versus MPO autoantigen specificity rather than with the clinical diagnosis.

MPO (GWAS)

Gene: MPO hgnc:7218 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:36109667 SUPPORT Human Clinical

"Interestingly, MPO-ANCA-positive patients with either MPA or EGPA have overlapping genetic determinants, thus strengthening the concept that this EGPA subset is closely related to the other AAV syndromes."

Shows shared genetic determinants across MPO-ANCA-positive syndromes, supporting the autoantigen as the organising axis.

PLA2R1 (GWAS)

Gene: PLA2R1 hgnc:9042 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:21323541 SUPPORT Human Clinical

"Chromosome 2q24 contains the gene encoding M-type phospholipase A(2) receptor (PLA(2)R1) (SNP rs4664308, P=8.6×10(-29)), previously shown to be the target of an autoimmune response."

Genome-wide significant association of PLA2R1 with idiopathic membranous nephropathy across three white populations.

HLA-DQA1 (GWAS)

Gene: HLA-DQA1 hgnc:4942 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:21323541 SUPPORT Human Clinical

"The odds ratio for idiopathic membranous nephropathy with homozygosity for both risk alleles was 78.5 (95% confidence interval, 34.6 to 178.2)."

Quantifies the joint HLA-DQA1/PLA2R1 risk, the largest effect size in the genetics of this arm of glomerulonephritis.

APOL1 (GENETIC_VARIANT)

Gene: APOL1 hgnc:618 relationship_type: MODIFIER

Show evidence (2 references)

PMID:20647424 SUPPORT Human Clinical

"focal segmental glomerulosclerosis (FSGS) and hypertension-attributed end-stage kidney disease (H-ESKD) are associated with two independent sequence variants in the APOL1 gene on chromosome 22"

Original identification of the two APOL1 risk variants underlying the excess burden of kidney disease in African Americans.

PMID:36763808 SUPPORT Human Clinical

"Time to kidney failure was faster in the high-risk APOL1 genotype than low-risk APOL1 genotype or membranous nephropathy participants that were not Black."

Demonstrates the progression-modifying effect within a glomerulonephritis subtype specifically, supporting the MODIFIER typing rather than a subtype-susceptibility typing.

💊

Medical Actions

9

Corticosteroid Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: corticosteroid CHEBI:50858

Glucocorticoids are the backbone of induction therapy for inflammatory GN, suppressing leukocyte recruitment and cytokine production at the glomerulus. They are given with a second agent in severe crescentic disease and are used selectively — not universally — in indolent subtypes, where toxicity may outweigh benefit. In infection-related GN, treating the infection takes precedence over immunosuppression.

Mechanism Target:

INHIBITS Leukocyte Recruitment and Glomerular Inflammation — Broad suppression of the glomerular inflammatory infiltrate and its cytokine output.

Show evidence (1 reference)

PMID:28515156 SUPPORT Human Clinical

"Treatment aims to rapidly remove pathogenic autoantibody, typically with the use of plasma exchange, along with steroids and cytotoxic therapy to prevent ongoing autoantibody production and tissue inflammation."

Documents corticosteroids as a component of standard induction therapy in severe antibody-mediated GN.

Cyclophosphamide

Action: Pharmacotherapy NCIT:C15986

Agent: cyclophosphamide NCIT:C405

Alkylating cytotoxic therapy used for induction in severe crescentic and rapidly progressive glomerulonephritis, suppressing the B cell clones producing pathogenic autoantibody. Gonadotoxicity and malignancy risk limit cumulative exposure, which is why rituximab has displaced it in many settings.

Mechanism Target:

INHIBITS Nephritogenic Antigen Exposure and Loss of Tolerance — Suppresses the lymphocyte clones generating pathogenic autoantibody.

Show evidence (1 reference)

PMID:28515156 SUPPORT Human Clinical

"along with steroids and cytotoxic therapy to prevent ongoing autoantibody production and tissue inflammation"

Documents cytotoxic therapy as standard induction alongside corticosteroids to halt autoantibody production.

Rituximab

Action: Pharmacotherapy NCIT:C15986

Agent: rituximab NCIT:C1702

Anti-CD20 monoclonal antibody depleting B cells and thereby the precursors of autoantibody-secreting plasma cells. Now a first-line induction and maintenance option in ANCA-associated GN and the preferred immunosuppressive therapy in PLA2R-associated membranous nephropathy.

Mechanism Target:

INHIBITS Nephritogenic Antigen Exposure and Loss of Tolerance — B cell depletion removes the source of pathogenic autoantibody.

Show evidence (1 reference)

PMID:31269364 SUPPORT Human Clinical

"B-cell anomalies play a role in the pathogenesis of membranous nephropathy. B-cell depletion with rituximab may therefore be noninferior to treatment with cyclosporine for inducing and maintaining a complete or partial remission of proteinuria in patients with this condition."

States the mechanistic rationale linking B cell depletion to the autoantibody-driven lesion, and the proteinuria endpoint it addresses.

Show evidence (2 references)

PMID:20647199 SUPPORT Human Clinical

"Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease."

RAVE randomized trial establishing rituximab as non-inferior to cyclophosphamide for remission induction in severe ANCA-associated disease.

PMID:31269364 SUPPORT Human Clinical

"Rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months."

MENTOR randomized trial supporting rituximab in the membranous/podocyte arm of glomerulonephritis.

Plasma Exchange

Action: Plasmapheresis NCIT:C15304

Extracorporeal removal of circulating pathogenic autoantibody. The clearest indication is anti-GBM disease, where the antibody is directly pathogenic and outcome depends on removing it before crescents organize; it is also used in severe ANCA-associated disease with pulmonary hemorrhage. Benefit is greatest when started early, before dialysis dependence.

Mechanism Target:

INHIBITS Anti-GBM Autoantibody Binding to Type IV Collagen — Removes circulating anti-GBM antibody, cutting off the supply of pathogenic autoantibody to the basement membrane.

Show evidence (1 reference)

PMID:28515156 SUPPORT Human Clinical

"Treatment aims to rapidly remove pathogenic autoantibody, typically with the use of plasma exchange"

States the mechanistic rationale for plasma exchange as removal of the pathogenic autoantibody.

Show evidence (1 reference)

PMID:28515156 SUPPORT Human Clinical

"Retrospective cohort studies suggest that when this combination of treatment is started early, the majority of patients will have good renal outcome"

Supports early combination therapy including plasma exchange as outcome-determining.

Avacopan

Action: Pharmacotherapy NCIT:C15986

Agent: avacopan NCIT:C174788

Oral C5a receptor antagonist that blocks the C5a-driven neutrophil priming and recruitment loop central to ANCA-associated glomerulonephritis. Its development is a direct application of the complement mechanism to therapy, and it permits substantial reduction of glucocorticoid exposure.

Mechanism Target:

INHIBITS Complement Activation — Blockade of the C5a receptor interrupts complement-driven neutrophil recruitment and priming at the glomerulus.

Show evidence (1 reference)

PMID:33596356 SUPPORT Human Clinical

"The C5a receptor inhibitor avacopan is being studied for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis."

Identifies avacopan's molecular target as the C5a receptor, the complement node this treatment link asserts.

Show evidence (1 reference)

PMID:33596356 SUPPORT Human Clinical

"In this trial involving patients with ANCA-associated vasculitis, avacopan was noninferior but not superior to prednisone taper with respect to remission at week 26 and was superior to prednisone taper with respect to sustained remission at week 52."

ADVOCATE randomized trial establishing avacopan's efficacy relative to a prednisone taper, the basis for its glucocorticoid-sparing role.

Renin-Angiotensin System Blockade and Supportive Antiproteinuric Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: ACE inhibitor NCIT:C247 angiotensin II receptor blocker NCIT:C66930 statin (HMG-CoA reductase inhibitor) NCIT:C1655

Non-immunosuppressive background therapy given across essentially every subtype of glomerulonephritis, independent of the initiating immune mechanism. ACE inhibitors and angiotensin II receptor blockers lower intraglomerular pressure and proteinuria, and lipid-lowering agents address the dyslipidemia of chronic glomerular disease. Unlike the mechanism-directed immunosuppressants above, this is the one intervention that applies at the root level: it acts on the shared downstream progression pathway rather than on any one subtype's trigger.

Mechanism Target:

INHIBITS Nephron Loss and Progressive Kidney Failure — Reduction of intraglomerular pressure and proteinuria slows the proteinuria-driven tubulointerstitial injury that carries surviving nephrons toward sclerosis, independent of the upstream immune trigger.

Show evidence (1 reference)

PMID:20301598 SUPPORT Human Clinical

"Nonspecific therapies used to treat numerous chronic glomerular diseases, including angiotensin-converting enzyme inhibitors, angiotensin II type-1 receptor blockers, and lipid-lowering agents (in particular hydroxymethylglutaryl coenzyme A reductase inhibitors)."

GeneReviews management guidance naming RAS blockade and lipid-lowering therapy as the nonspecific measures used across chronic glomerular diseases, which is the basis for curating this at the root level rather than per subtype.

SGLT2 Inhibition

Action: Pharmacotherapy NCIT:C15986

Agent: SGLT2 inhibitor NCIT:C98083 dapagliflozin CHEBI:85078

Sodium-glucose cotransporter-2 inhibition, added to RAS blockade as contemporary background therapy for proteinuric chronic kidney disease irrespective of diabetes status. Like RAS blockade it acts on the shared progression pathway rather than on any subtype's immune trigger, so it belongs at the root level. The pivotal trial enrolled a CKD population, including glomerulonephritis, rather than a GN-specific cohort — the evidence is therefore for the shared downstream node, not for any one subtype.

Mechanism Target:

INHIBITS Nephron Loss and Progressive Kidney Failure — Slows the rate of GFR decline and progression to kidney failure along the shared nephron-loss pathway.

Show evidence (1 reference)

PMID:32970396 SUPPORT Human Clinical

"Among patients with chronic kidney disease, regardless of the presence or absence of diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or card"

DAPA-CKD randomized trial establishing that SGLT2 inhibition slows progression in chronic kidney disease independent of diabetes, the basis for curating it as root-level background therapy.

Kidney Replacement Therapy

Action: renal replacement therapy Ontology label: Renal Replacement Therapy NCIT:C126400

Dialysis or kidney transplantation once glomerulonephritis has progressed to kidney failure. Curated because Stage 5 chronic kidney disease is a terminal node of this entry's pathograph and the entry would otherwise model the endpoint without the intervention that addresses it. Note that several glomerulonephritis subtypes recur in the allograft, which is a subtype-specific consideration handled on those entries.

Show evidence (1 reference)

PMID:20301598 SUPPORT Human Clinical

"When ESRD develops, treatment options are limited to dialysis or transplantation."

GeneReviews management guidance for the kidney-failure endpoint of complement-mediated glomerulonephritis.

Surveillance of Kidney Function and Complement Status

Action: Supportive Care NCIT:C15747

Structured monitoring rather than an intervention: serial assessment of kidney function and of the complement pathway, with fundus examination where complement-mediated disease carries a retinal risk. Curated from the GeneReviews Surveillance recommendations.

Show evidence (1 reference)

PMID:20301598 SUPPORT Human Clinical

"Close monitoring of renal function by a nephrologist with familiarity with the C3G disease spectrum, complete biannual assessment of the complement pathway, periodic eye examinations to evaluate the fundus."

GeneReviews Surveillance schedule, the source for the monitoring components curated here.

🌍

Environmental Factors

1

Streptococcal and other infectious triggers

Infection initiates glomerulonephritis by several distinct routes: deposition of circulating immune complexes, planting of antigen in the capillary wall with in-situ complex formation, molecular mimicry between anti-pathogen antibody and intrinsic glomerular matrix proteins, direct damage to glomerular cells, and superantigen-driven T cell activation. Group A streptococcus is the classic trigger, but hepatitis B and C, staphylococci, endocarditis pathogens, HIV, and parasites are all implicated. The relationship is bidirectional: urinary immunoglobulin loss and immunosuppressive treatment in turn raise infection risk.

Show evidence (2 references)

PMID:37764071 SUPPORT Human Clinical

"The mechanisms responsible range from the direct damage of glomerular cells to the formation and deposition of immunocomplexes to molecular mimicry to the secretion of superantigens."

Enumerates the distinct mechanisms linking infection to glomerular injury.

PMID:37764071 SUPPORT Human Clinical

"infections are more frequent than in the general population due to the loss of immunoglobulins in urine and the immunosuppressive agents used to treat the autoimmune disease that decrease the activity of the immune system"

Documents the reverse arm of the infection-glomerulonephritis relationship.

Mechanism Target:

TRIGGERS Nephritogenic Antigen Exposure and Loss of Tolerance — Infection supplies the nephritogenic antigen, or breaks tolerance by molecular mimicry or superantigen effect, initiating the immune response that injures the glomerulus.

Show evidence (1 reference)

PMID:39341789 SUPPORT Human Clinical

"Streptococcal pyrogenic exotoxin B and nephritis-associated plasmin receptor are identified nephritogenic antigens (nephritogens)."

Names the specific streptococcal antigens that trigger the nephritogenic immune response.

🔬

Biochemical Markers

3

Anti-PLA2R autoantibody (Positive)

Show evidence (2 references)

PMID:19571279 SUPPORT Human Clinical

"Serum samples from 26 of 37 patients (70%) with idiopathic but not secondary membranous nephropathy specifically identified a 185-kD glycoprotein in nonreduced glomerular extract."

Quantifies detection in primary but not secondary membranous nephropathy, supporting both the presence and the specificity claim.

PMID:19571279 SUPPORT Human Clinical

"PLA(2)R is present in normal podocytes and in immune deposits in patients with idiopathic membranous nephropathy, indicating that PLA(2)R is a major antigen in this disease."

Localizes the antigen to the podocyte and to the subepithelial immune deposits, tying the biomarker to the pathophysiology node rather than leaving it a free-standing serology.

Serum complement C3 (Decreased)

Show evidence (1 reference)

PMID:20301598 SUPPORT Human Clinical

"low levels of the complement component C3"

GeneReviews lists depressed serum C3 among the typical presenting laboratory findings of complement-mediated glomerulonephritis.

Urinary and serum omics-derived candidate biomarkers (Under investigation)

Show evidence (1 reference)

PMID:38689160 SUPPORT Human Clinical

"This review shows the potential of metabolomic and proteomic analysis to discover new disease biomarkers that may influence diagnostics and disease management. Further larger-scale research is required to establish the validity of the study outcomes, including the several proposed biomarkers."

Supports the existence of a candidate-biomarker field while explicitly stating that validity is not yet established; marked PARTIAL for that reason.

🔬

Diagnosis

2

Kidney biopsy with light microscopy, immunofluorescence, and electron microscopy

Kidney biopsy is the central diagnostic act in glomerulonephritis, because the clinical presentation — hematuria, proteinuria, hypertension, falling GFR — is shared across mechanistically unrelated subtypes and cannot distinguish them. All three modalities are needed: light microscopy defines the proliferative pattern, immunofluorescence separates immune-complex (granular), anti-GBM (linear), pauci-immune (scant), C3-dominant, and monoclonal light-chain patterns, and electron microscopy localizes deposits to the mesangial, subendothelial, or subepithelial compartment. Because deposit location and immunofluorescence pattern are precisely what map to the distinct upstream mechanisms modelled in this entry's pathophysiology, the biopsy is the observation that assigns a patient to a causal arm.

Kidney biopsy NCIT:C51699

Results: Immunofluorescence pattern and electron-microscopic deposit location together assign the case to an immune-complex, anti-GBM, pauci-immune, or complement-mediated arm; crescent burden and interstitial fibrosis grade the severity and reversibility.

Show evidence (3 references)

PMID:20301598 SUPPORT Human Clinical

"The definitive diagnosis of C3G requires a renal biopsy with specialized immunofluorescence and electron microscopy studies both for diagnosis and to distinguish between the two major subtypes of C3G: C3 glomerulonephritis (C3GN) and dense deposit disease (DDD)."

States that renal biopsy with immunofluorescence and electron microscopy is required both to diagnose and to subtype complement-mediated glomerulonephritis.

PMID:36635359 SUPPORT Human Clinical

"These disorders are currently classified largely on the basis of histopathological lesion patterns"

Confirms that histopathological lesion pattern is the prevailing basis of classification, hence the central diagnostic role of biopsy; marked PARTIAL because the same source argues those patterns align poorly with mechanism.

PMID:37869232 SUPPORT Human Clinical

"Only 4 studies (23.5%) used light microscopy (LM), immunofluorescence (IF), and electron microscopy (EM) for diagnosis."

Documents that the full three-modality biopsy standard is frequently not met in practice, a recognised source of ascertainment bias in subtype distribution data.

Mechanism-directed serologic panel

Serology narrows the mechanism before and alongside biopsy, and each assay maps onto a specific pathophysiology arm modelled here: ANCA with PR3/MPO specificity for the pauci-immune neutrophil arm; anti-GBM antibody for the anti-alpha3(IV) arm; anti-PLA2R for the subepithelial podocyte arm; C3 and C4 for complement consumption; ANA and anti-dsDNA for lupus nephritis; hepatitis B/C, HIV and streptococcal serology (ASO, anti-DNase B) for the infection-related arm; and serum/urine electrophoresis with free light chains for monoclonal gammopathy-related disease. Anti-PLA2R is the one assay that has become a genuine non-invasive substitute for biopsy in a defined setting; the others remain adjuncts to it.

Autoantibody and complement serology NCIT:C181397

Results: A positive result assigns the mechanism: PR3/MPO-ANCA (pauci-immune), anti-GBM (linear anti-basement-membrane), anti-PLA2R (membranous), low C3 (post-infectious, C3 glomerulopathy, or lupus nephritis).

Show evidence (3 references)

PMID:35484394 SUPPORT Human Clinical

"the discovery of pathogenic circulating autoantibodies against phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type 1 domain-containing protein 7A (THSD7A)"

Establishes the circulating podocyte autoantibodies that underpin serologic diagnosis of the membranous arm.

PMID:36109667 SUPPORT Human Clinical

"the positivity of ANCA targeting proteinase-3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA)"

Establishes PR3 and MPO ANCA specificity as the serologic discriminator of the pauci-immune arm.

PMID:20301598 SUPPORT Human Clinical

"low levels of the complement component C3"

Supports serum C3 measurement as part of the mechanism-directed workup.

📊

Prevalence

1

Africa (biopsy-proven primary glomerular disease, 8 countries)

Unknown Unknown

Pooled biopsy-series distribution rather than a population rate: among 6,494 biopsied individuals in 17 African studies, FSGS 26.10%, minimal change disease 22.40%, membranous nephropathy 8.40%, MPGN 6.40%, mesangioproliferative GN 6.40%, post-infectious GN 2.60%, IgA nephropathy 2.60%, and crescentic GN 1.40%. This is a subtype *distribution* among biopsies, not an incidence in the general population, and is subject to biopsy referral and ascertainment bias. No reliable global incidence exists for aggregate glomerulonephritis, because biopsy policy, coding, age structure, and infection burden differ between settings.

Show evidence (1 reference)

PMID:37869232 SUPPORT Human Clinical

"Seventeen eligible articles (n = 6,494 individuals) from 8 African countries met the inclusion criteria. The overall pooled prevalence of FSGS, MCD, MN, MPGN, MesPGN, PIGN, IgAN and CresGN was 26.10%, 22.40%, 8.40%, 6.40%, 6.40%, 2.60%, 2.60%, 1.40%, respectively."

Quantifies the relative distribution of glomerular disease subtypes in a large pooled African biopsy series.

🔬

Clinical Trials

4

NCT06419205 PHASE_II RECRUITING

ADX-097, a targeted complement inhibitor, given subcutaneously across three complement-implicated glomerulonephritis subtypes at once. Included at the root level precisely because its enrolment spans IgAN, lupus nephritis, and C3 glomerulopathy — it is a trial of the shared complement mechanism rather than of a single subtype.

Show evidence (1 reference)

clinicaltrials:NCT06419205 SUPPORT Human Clinical

"Immunoglobulin A Nephropathy (IgAN), Lupus Nephritis (LN), or Complement Component 3 Glomerulopathy (C3G)"

Confirms the multi-subtype enrolment that makes this a root-level rather than subtype-level trial.

NCT05732402 ACTIVE_NOT_RECRUITING

RUBY-3, an open-label multiple-ascending-dose study of povetacicept in autoantibody-associated glomerular disease, registered as Phase 1/2 (no single-phase enum value applies, so `phase` is omitted rather than misstated). Targets the autoantibody-producing B-cell compartment upstream of the deposition nodes, across four subtypes.

Show evidence (1 reference)

clinicaltrials:NCT05732402 SUPPORT Human Clinical

"immunoglobulin A (IgA) nephropathy (IgAN), primary membranous nephropathy (pMN), lupus-related kidney disease (lupus nephritis - LN), or anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV)"

Documents enrolment spanning four of the curated glomerulonephritis subtypes.

NCT05083364 COMPLETED

AROC3-1001, an RNA-interference agent silencing C3 synthesis in complement-mediated renal disease; registered as Phase 1/2a, so `phase` is omitted for the same reason as above. Mechanistically the inverse of the downstream C5a blockade curated under avacopan — it removes the substrate rather than blocking the receptor.

Show evidence (1 reference)

clinicaltrials:NCT05083364 SUPPORT Human Clinical

"in adult patients with complement-mediated renal disease (C3 Glomerulopathy"

Confirms the complement-mediated glomerulonephritis population targeted by C3 knockdown.

NCT06277427 NOT_APPLICABLE RECRUITING

BCMA-targeting CAR-T cells in refractory ANCA-associated vasculitis and lupus nephritis. The registry records no phase for this study.

Show evidence (1 reference)

clinicaltrials:NCT06277427 SUPPORT Human Clinical

"BCMA is the molecule expressed on memory B cells, plasmablasts and plasma cells, and therefore is an ideal target for the elimination of potential pathogenic antibody secreting cells."

States the mechanistic rationale — depletion of the antibody-secreting compartment feeding the autoantibody-driven arms of the pathograph.

{ }

Source YAML

click to show

name: Glomerulonephritis
creation_date: "2026-08-12T00:00:00Z"
category: Complex
parents:
- Kidney Disease
- Autoimmune Disease
disease_term:
  preferred_term: Glomerulonephritis
  term:
    id: MONDO:0002462
    label: glomerulonephritis
synonyms:
- GN
- glomerular nephritis
- Bright's disease
description: >-
  Glomerulonephritis (GN) is not a single disease but a heterogeneous group of
  immune-mediated disorders characterized by inflammation of the glomerulus, the
  filtration unit of the kidney, and collectively a leading cause of chronic
  kidney disease worldwide. Mechanistically distinct initiating lesions — immune
  complexes deposited from the circulation or formed in situ against a planted or
  intrinsic glomerular antigen, directly pathogenic anti-glomerular basement
  membrane (anti-GBM) autoantibody, ANCA-driven pauci-immune neutrophil
  activation, or uncontrolled alternative-pathway complement activation — converge
  on complement activation, leukocyte recruitment, and injury to the glomerular
  capillary wall. The resulting nephritic presentation combines hematuria (often
  with dysmorphic red cells), proteinuria, hypertension, edema, and a falling
  glomerular filtration rate. Severe necrotizing injury ruptures the capillary
  wall and drives parietal epithelial cell proliferation into crescents, producing
  rapidly progressive glomerulonephritis; unresolved injury leads to
  glomerulosclerosis, tubulointerstitial fibrosis, and progressive kidney failure.
  Because histopathological lesion patterns align poorly with these underlying
  mechanisms, contemporary practice increasingly groups GN by immunopathogenesis
  (infection-related, autoimmune, alloimmune, autoinflammatory/complement-mediated,
  and monoclonal gammopathy-related), which is what links mechanism to therapy.
notes: >-
  This is a deliberately mechanism-level root entry for the glomerulonephritis
  concept (MONDO:0002462). Syndrome-wide statements about a single causal gene,
  inheritance pattern, incidence, or prognosis are not biologically valid for GN
  as a whole; those belong on the etiologic subtype entries. Several subtypes are
  curated as standalone dismech entries in their own right — IgA_Nephropathy,
  Membranous_Nephropathy, Lupus_Nephritis, Anti-GBM_Disease,
  Granulomatosis_with_Polyangiitis, and Microscopic_Polyangiitis — and this entry
  models the shared final common pathway rather than duplicating them.

  Membership of `has_subtypes` is decided by whether the entity is an etiologic
  subtype of GN with a MONDO term, NOT by whether it also exists as a standalone
  dismech entry — the two are orthogonal, and most listed subtypes are both.
  Lupus nephritis was initially omitted on the mistaken ground that a standalone
  entry made listing redundant; that criterion would equally have excluded IgA
  nephropathy, membranous nephropathy, and anti-GBM disease, which are listed, so
  lupus nephritis is listed too. The two Anders categories that remain unlisted —
  alloimmune GN and monoclonal gammopathy-related GN — are excluded on the
  different and still-valid ground that neither has a suitable MONDO subtype term
  at this level; they are named in the description and evidenced on the trigger
  node instead.

  Relationship to the `nephrotic_podocyte_injury` module: nephritic glomerular
  inflammation and nephrotic podocytopathy are distinct mechanisms and are kept
  distinct here. The main causal chain in this entry is the nephritic arm
  (immune deposition -> complement -> leukocyte recruitment -> capillary wall
  injury -> crescents). Only the single node representing subepithelial
  deposition with podocyte injury — the membranous/nephrotic arm — declares
  `conforms_to` against that module, which is where nephrotic-range proteinuria
  from podocyte foot process effacement is properly modeled. This entry therefore
  relates to, rather than duplicates, `nephrotic_podocyte_injury`.

  Deep research for this entry was run with Edison (falcon). The automated NEC
  preflight returned SKIP because MONDO records no causal gene for MONDO:0002462
  (correctly — GN is not monogenic), so the manual gene/OMIM/synonym check of
  CLAUDE.md section 2b was used instead and passed. Two ontology errors in the
  Edison report were caught and not propagated: it labelled HP:0031263 as
  "Crescentic glomerulonephritis" (that ID is actually "Abnormal renal corpuscle
  morphology"; the correct term is HP:0008653), and it gave HP:0003774 the stale
  label "End-stage renal disease" (current label is "Stage 5 chronic kidney
  disease").

  The KDIGO 2021 glomerular-disease guideline (PMID:34556256) is the
  authoritative management source for this disease area but is deliberately not
  cited here: PubMed holds no abstract for it (it is a 276-page journal
  supplement), so no snippet can be verified against a cached reference and any
  quotation would be unverifiable by the evidence validator. Management claims
  are grounded in GeneReviews and in primary trial reports instead.
has_subtypes:
- name: IgA Nephropathy
  display_name: IgA nephropathy (Berger disease)
  description: >-
    Mesangial deposition of galactose-deficient IgA1-containing immune complexes
    arising from mucosal immune dysregulation. Curated in full as the standalone
    dismech entry IgA_Nephropathy.
  subtype_term:
    preferred_term: IgA nephropathy
    term:
      id: MONDO:0005342
      label: IgA glomerulonephritis
- name: Membranous Nephropathy
  description: >-
    In-situ subepithelial immune-complex formation against podocyte surface
    antigens, chiefly PLA2R1 and THSD7A, presenting with nephrotic-range
    proteinuria rather than a nephritic picture. Curated in full as the standalone
    dismech entry Membranous_Nephropathy.
  subtype_term:
    preferred_term: Membranous nephropathy
    term:
      id: MONDO:0005376
      label: membranous glomerulonephritis
  evidence:
  - reference: PMID:35484394
    reference_title: "Membranous nephropathy: new pathogenic mechanisms and their clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Membranous nephropathy (MN) is characterized histomorphologically by the
      presence of immune deposits in the subepithelial space of the glomerular
      filtration barrier; its clinical hallmarks are nephrotic range proteinuria
      with oedema.
    explanation: >-
      Establishes membranous nephropathy as a subepithelial immune-deposit lesion
      whose presentation is nephrotic rather than nephritic.
- name: Lupus Nephritis
  description: >-
    Renal manifestation of systemic lupus erythematosus, in which immune
    complexes containing nuclear antigens deposit in the mesangium and along the
    capillary wall, producing a class-dependent spectrum from mesangial to
    diffuse proliferative to membranous lesions. Curated in full as the
    standalone dismech entry Lupus_Nephritis.
  subtype_term:
    preferred_term: Lupus nephritis
    term:
      id: MONDO:0005556
      label: lupus nephritis
  evidence:
  - reference: PMID:36483271
    reference_title: "Lupus Nephritis: Current Perspectives and Moving Forward."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lupus nephritis is a severe organ manifestation of systemic lupus
      erythematosus, and its pathogenesis involves complex etiology and
      mechanisms.
    explanation: >-
      Establishes lupus nephritis as the renal organ manifestation of SLE, the
      basis for listing it as an etiologic subtype of glomerulonephritis
      alongside the other immune-complex forms.
- name: Post-Streptococcal GN
  display_name: Acute post-streptococcal glomerulonephritis
  description: >-
    Acute infection-related immune-complex glomerulonephritis following group A
    streptococcal throat or skin infection, with streptococcal pyrogenic exotoxin
    B (SpeB) and nephritis-associated plasmin receptor (NAPlr) as the identified
    nephritogenic antigens.
  subtype_term:
    preferred_term: Acute poststreptococcal glomerulonephritis
    term:
      id: MONDO:0001870
      label: acute poststreptococcal glomerulonephritis
  evidence:
  - reference: PMID:39341789
    reference_title: "Mechanisms that potentially contribute to the development of post-streptococcal glomerulonephritis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Streptococcal pyrogenic exotoxin B and nephritis-associated plasmin
      receptor are identified nephritogenic antigens (nephritogens).
    explanation: >-
      Names the two established streptococcal nephritogens that initiate the
      post-streptococcal immune-complex lesion.
- name: Anti-GBM Disease
  display_name: Anti-glomerular basement membrane (Goodpasture) disease
  description: >-
    Directly pathogenic autoantibody against the NC1 domain of the alpha-3 chain
    of type IV collagen in the glomerular and alveolar basement membrane, causing
    widespread crescent formation with frequent alveolar hemorrhage. Curated in
    full as the standalone dismech entry Anti-GBM_Disease.
  subtype_term:
    preferred_term: Anti-glomerular basement membrane disease
    term:
      id: MONDO:0009303
      label: anti-glomerular basement membrane disease
  evidence:
  - reference: PMID:28515156
    reference_title: "Anti-Glomerular Basement Membrane Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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: >-
      Establishes anti-GBM disease as a directly antibody-mediated basement
      membrane lesion, distinguishing it from immune-complex GN.
- name: ANCA-Associated GN
  display_name: ANCA-associated pauci-immune necrotizing crescentic GN
  description: >-
    Pauci-immune necrotizing and crescentic glomerulonephritis driven by
    anti-neutrophil cytoplasmic antibodies targeting proteinase-3 or
    myeloperoxidase, with little or no glomerular immunoglobulin deposition.
  subtype_term:
    preferred_term: Pauci-immune glomerulonephritis with ANCA
    term:
      id: MONDO:0019988
      label: pauci-immune glomerulonephritis with ANCA
  evidence:
  - reference: PMID:36109667
    reference_title: "Genetics of ANCA-associated vasculitis: role in pathogenesis, classification and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      that share features of pauci-immune small-vessel vasculitis and the
      positivity of ANCA targeting proteinase-3 (PR3-ANCA) or myeloperoxidase
      (MPO-ANCA)
    explanation: >-
      Defines the pauci-immune, ANCA-specificity-based character of this GN
      subtype.
- name: Membranoproliferative GN
  display_name: Membranoproliferative glomerulonephritis (including C3 glomerulopathy)
  description: >-
    Mesangial proliferation with capillary wall double contours on light
    microscopy. Divided by immunofluorescence into immune-complex-mediated MPGN
    and complement-mediated C3 glomerulopathy, the latter driven by uncontrolled
    alternative-pathway activation.
  subtype_term:
    preferred_term: Membranoproliferative glomerulonephritis
    term:
      id: MONDO:0002461
      label: membranoproliferative glomerulonephritis
  evidence:
  - reference: PMID:42284585
    reference_title: "C3 Glomerulopathy: recent advances and an update on management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      C3 glomerulopathy (C3G) is a clinicopathologic entity characterized by
      glomerular inflammation with dominant staining for C3 on immunofluorescence
      microscopy.
    explanation: >-
      Defines the complement-mediated arm of the membranoproliferative pattern by
      its C3-dominant immunofluorescence signature.
pathophysiology:
- name: Nephritogenic Antigen Exposure and Loss of Tolerance
  description: >-
    The initiating step is the appearance of a nephritogenic antigen-antibody
    pairing. This may be a foreign antigen from infection (streptococcal SpeB or
    NAPlr, hepatitis B or C, staphylococcal or endocarditis-associated antigen), a
    self antigen against which tolerance is lost (the alpha-3 chain of type IV
    collagen in anti-GBM disease, myeloperoxidase or proteinase-3 in ANCA disease,
    PLA2R1 in membranous nephropathy, nuclear antigens in lupus nephritis), or an
    aberrantly glycosylated self immunoglobulin (galactose-deficient IgA1). GN is
    correspondingly grouped by immunopathogenesis rather than by histological
    pattern, because the lesion pattern does not identify the cause.
  role: trigger
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: adaptive immune response
    term:
      id: GO:0002250
      label: adaptive immune response
    modifier: ABNORMAL
  - preferred_term: immunoglobulin production
    term:
      id: GO:0002377
      label: immunoglobulin production
  cell_types:
  - preferred_term: plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  evidence:
  - reference: PMID:36635359
    reference_title: "Glomerulonephritis: immunopathogenesis and immunotherapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These disorders are currently classified largely on the basis of
      histopathological lesion patterns, but these patterns do not align well
      with their diverse pathological mechanisms and hence do not inform optimal
      therapy.
    explanation: >-
      Supports modeling GN by initiating immunopathogenic mechanism rather than by
      histological lesion pattern.
  - reference: PMID:36635359
    reference_title: "Glomerulonephritis: immunopathogenesis and immunotherapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we propose grouping GN disorders into five categories according to their
      immunopathogenesis: infection-related GN, autoimmune GN, alloimmune GN,
      autoinflammatory GN and monoclonal gammopathy-related GN.
    explanation: >-
      Supplies the five-category immunopathogenic scheme this entry's
      description adopts, and is the citation for the two categories named there
      but deliberately not modelled as subtypes (alloimmune and monoclonal
      gammopathy-related GN).
  - reference: PMID:37764071
    reference_title: "Autoimmunity and Infection in Glomerular Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mechanisms responsible range from the direct damage of glomerular cells
      to the formation and deposition of immunocomplexes to molecular mimicry to
      the secretion of superantigens.
    explanation: >-
      Enumerates the distinct routes by which an infectious trigger initiates
      glomerular injury, supporting a multi-route trigger node.
  downstream:
  - target: Glomerular Immune Complex Deposition
    causal_link_type: DIRECT
    description: >-
      Antigen-antibody complexes formed in the circulation or in situ localize
      within the glomerulus.
  - target: Anti-GBM Autoantibody Binding to Type IV Collagen
    causal_link_type: DIRECT
    description: >-
      Loss of tolerance to the alpha-3(IV)NC1 autoantigen yields directly
      pathogenic antibody that binds the basement membrane.
  - target: ANCA-Mediated Neutrophil Activation
    causal_link_type: DIRECT
    description: >-
      Autoantibody against myeloperoxidase or proteinase-3 activates primed
      neutrophils at the glomerular capillary.
  - target: Subepithelial Immune Deposition and Podocyte Injury
    causal_link_type: DIRECT
    description: >-
      Antibody against a podocyte surface antigen forms in-situ subepithelial
      deposits, the membranous/nephrotic arm.

- name: Glomerular Immune Complex Deposition
  description: >-
    Circulating immune complexes are trapped in the glomerulus, or complexes form
    in situ when antibody binds an antigen already planted in the capillary wall.
    Deposit location determines the clinical syndrome: mesangial and subendothelial
    deposits sit on the blood side of the basement membrane, where they are
    accessible to circulating inflammatory cells and produce a nephritic,
    proliferative lesion; subepithelial deposits are separated from the circulation
    by the basement membrane and instead injure the podocyte.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: mesangial cell
    term:
      id: CL:0000650
      label: mesangial cell
  - preferred_term: glomerular capillary endothelial cell
    term:
      id: CL:1001005
      label: glomerular capillary endothelial cell
  biological_processes:
  - preferred_term: immune complex clearance
    term:
      id: GO:0002434
      label: immune complex clearance
    modifier: DECREASED
  locations:
  - preferred_term: renal glomerulus
    term:
      id: UBERON:0000074
      label: renal glomerulus
  evidence:
  - reference: PMID:39341789
    reference_title: "Mechanisms that potentially contribute to the development of post-streptococcal glomerulonephritis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Deposition of circulating immune complexes or in situ formation of immune
      complexes in glomeruli, or both, results in glomerulonephritis.
    explanation: >-
      States both routes — circulating deposition and in-situ formation — by which
      immune complexes produce glomerulonephritis.
  downstream:
  - target: Complement Activation
    causal_link_type: DIRECT
    description: >-
      Deposited immunoglobulin fixes complement via the classical pathway.

- name: Anti-GBM Autoantibody Binding to Type IV Collagen
  description: >-
    In anti-GBM disease, autoantibody binds a conformational epitope on the
    non-collagenous (NC1) domain of the alpha-3 chain of type IV collagen, an
    antigen normally sequestered within the hexameric collagen network of the
    glomerular and alveolar basement membrane. Because the antibody engages a
    fixed structural antigen along the whole capillary wall, injury is
    near-simultaneous across all glomeruli, which is why this subtype so
    characteristically produces widespread crescents and rapidly progressive
    disease, frequently with concurrent alveolar hemorrhage.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: antigen binding
    term:
      id: GO:0003823
      label: antigen binding
  locations:
  - preferred_term: glomerular basement membrane
    term:
      id: UBERON:0005777
      label: glomerular basement membrane
  evidence:
  - reference: PMID:37981425
    reference_title: "Laminin-521: a novel target for pathogenic autoantibodies in anti-glomerular basement membrane disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      typically characterized by autoimmunity against the α3 chain of type IV
      collagen
    explanation: >-
      Names the target antigen of this node directly. The same source records
      that rare seronegative cases may instead target laminin-521, which is why
      the node description says "typically" rather than invariably.
  - reference: PMID:28515156
    reference_title: "Anti-Glomerular Basement Membrane Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of patients develop widespread glomerular crescent formation,
      presenting with features of rapidly progressive GN, and 40%-60% will have
      concurrent alveolar hemorrhage.
    explanation: >-
      Links the anti-GBM lesion to widespread crescent formation, RPGN, and
      pulmonary involvement. Marked PARTIAL because it evidences the
      consequences of the lesion rather than the molecular identity of the
      antigen, which the preceding item supplies.
  downstream:
  - target: Complement Activation
    causal_link_type: DIRECT
    description: >-
      Basement-membrane-bound IgG fixes complement along the capillary wall.
  - target: Glomerular Capillary Wall Injury and Necrosis
    causal_link_type: DIRECT
    description: >-
      Direct antibody-mediated injury to the basement membrane breaches the
      capillary wall.

- name: ANCA-Mediated Neutrophil Activation
  description: >-
    In pauci-immune GN, cytokine-primed neutrophils translocate myeloperoxidase
    and proteinase-3 to their surface, where circulating ANCA engages them and
    triggers full activation: adhesion to the glomerular endothelium, respiratory
    burst, degranulation, and release of neutrophil extracellular traps. Because
    injury is delivered by the activated neutrophil rather than by deposited
    complexes, immunofluorescence shows little or no immunoglobulin — the defining
    "pauci-immune" feature. Complement, particularly the C5a-C5aR axis, amplifies
    the priming loop and is the target of avacopan.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: neutrophil activation
    term:
      id: GO:0042119
      label: neutrophil activation
    modifier: INCREASED
  - preferred_term: neutrophil extracellular trap formation
    term:
      id: GO:0140645
      label: neutrophil extracellular trap formation
    modifier: INCREASED
  notes: >-
    Neutrophil degranulation and firm adhesion to the glomerular endothelium are
    part of the textbook description of this step but are not separately
    evidenced here: no abstract-level source among the references cited by this
    entry states them, and the GO annotations on this node are deliberately
    limited to the two processes that are directly evidenced below. A
    `GO:0043312` (neutrophil degranulation) annotation was removed for this
    reason rather than left standing on an inferential basis.
  evidence:
  - reference: PMID:32446935
    reference_title: "ANCA autoantigen gene expression highlights neutrophil heterogeneity where expression in normal-density neutrophils correlates with ANCA-induced activation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      normal-density neutrophils were activated by MPO-ANCA and monoclonal
      anti-PR3 antibody
    explanation: >-
      Direct demonstration that both MPO-ANCA and anti-PR3 antibody activate
      human neutrophils, which is the core claim of this node and the basis for
      the GO:0042119 annotation.
  - reference: PMID:38837706
    reference_title: "FTY720 ameliorates experimental MPO-ANCA-associated vasculitis by regulating fatty acid oxidation via the neutrophil PPARα-CPT1a pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      ANCA-induced neutrophil respiratory burst and NETosis
    explanation: >-
      Establishes respiratory burst and NET formation as ANCA-induced effector
      responses of isolated human neutrophils, supporting the GO:0140645
      annotation.
  - reference: PMID:38837706
    reference_title: "FTY720 ameliorates experimental MPO-ANCA-associated vasculitis by regulating fatty acid oxidation via the neutrophil PPARα-CPT1a pathway."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the importance of C5a and anti-neutrophil cytoplasmic antibody
      (ANCA)-induced neutrophil activation in the pathogenesis of
      ANCA-associated vasculitis
    explanation: >-
      Supports the C5a-amplification limb of this node's description, which is
      the mechanistic rationale for the avacopan treatment link.
  - reference: PMID:36109667
    reference_title: "Genetics of ANCA-associated vasculitis: role in pathogenesis, classification and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with GPA and MPA, the genetic associations are stronger with
      ANCA specificity (PR3- versus MPO-ANCA) than with the clinical diagnosis
    explanation: >-
      Supports ANCA specificity, rather than clinical syndrome label, as the
      mechanistically meaningful axis of this arm. Marked PARTIAL because it is
      a statement about genetic association architecture and does not itself
      evidence the neutrophil biology this node asserts.
  downstream:
  - target: Glomerular Capillary Wall Injury and Necrosis
    causal_link_type: DIRECT
    description: >-
      Neutrophil oxidants and granule proteases produce fibrinoid necrosis of the
      capillary tuft.

- name: Alternative Pathway Complement Dysregulation
  role: trigger
  description: >-
    In C3 glomerulopathy the fluid-phase alternative pathway escapes regulation,
    through acquired autoantibodies such as C3 nephritic factor that stabilize the
    C3 convertase, or through rare variants in complement genes (C3, CFH, CFI,
    CFB, CD46, CFHR1, CFHR5, DGKE). Continuous C3 turnover deposits C3 fragments
    in the glomerulus without accompanying immunoglobulin, giving the C3-dominant
    immunofluorescence pattern that defines the entity. This is an
    autoinflammatory route into GN: no adaptive antigen-antibody pairing is
    required.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: complement activation, alternative pathway
    term:
      id: GO:0006957
      label: complement activation, alternative pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:20301598
    reference_title: "C3 Glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      C3 glomerulopathy (C3G) is a complex ultra-rare complement-mediated renal
      disease caused by uncontrolled activation of the complement alternative
      pathway (AP) in the fluid phase
    explanation: >-
      Establishes uncontrolled fluid-phase alternative-pathway activation as the
      causal mechanism of the complement-mediated arm.
  downstream:
  - target: Complement Activation
    causal_link_type: DIRECT
    description: >-
      Unregulated convertase activity drives sustained C3 cleavage and glomerular
      C3 deposition.

- name: Complement Activation
  description: >-
    Complement is the principal amplifier converting antibody or convertase
    deposition into tissue injury. Classical-pathway activation by deposited IgG
    or IgM, lectin-pathway activation, and alternative-pathway amplification all
    converge on C3 cleavage, generating the anaphylatoxins C3a and C5a and the
    C5b-9 membrane attack complex. C5a is a potent neutrophil chemoattractant and
    primer; C5b-9 injures glomerular cells sublytically. Consumption of complement
    is clinically visible as a depressed serum C3 in post-infectious GN, C3
    glomerulopathy, and lupus nephritis.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: complement activation
    term:
      id: GO:0006956
      label: complement activation
    modifier: INCREASED
  - preferred_term: complement activation, classical pathway
    term:
      id: GO:0006958
      label: complement activation, classical pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:20301598
    reference_title: "C3 Glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals with C3G typically present with hematuria, proteinuria,
      hematuria and proteinuria, acute nephritic syndrome or nephrotic syndrome,
      and low levels of the complement component C3.
    explanation: >-
      Links complement consumption to the measurable low serum C3 and to the
      nephritic presentation.
  downstream:
  - target: Leukocyte Recruitment and Glomerular Inflammation
    causal_link_type: DIRECT
    description: >-
      C3a and C5a recruit and prime neutrophils and monocytes at the glomerulus.

- name: Leukocyte Recruitment and Glomerular Inflammation
  description: >-
    Complement fragments, Fc-receptor engagement on deposited complexes, and
    activated resident glomerular cells recruit neutrophils and monocytes into the
    capillary tuft and mesangium. Infiltrating and resident cells release
    cytokines, chemokines, reactive oxygen species, and proteases. Effector CD4 T
    cell (Th1/Th17) and CD8 T cell responses contribute substantially to the
    severe crescentic phenotype. Mesangial and endothelial cells proliferate,
    producing the endocapillary and mesangial hypercellularity seen on biopsy.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: CD4-positive T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  - preferred_term: CD8-positive T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: leukocyte migration
    term:
      id: GO:0050900
      label: leukocyte migration
    modifier: INCREASED
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:39300109
    reference_title: "Immune profiling-based targeting of pathogenic T cells with ustekinumab in ANCA-associated glomerulonephritis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      using spatial and single-cell transcriptome analysis, we characterize
      inflammatory niches in kidney samples from 34 patients with ANCA-GN and
      identify proinflammatory, cytokine-producing CD4+ and CD8+ T cells as a
      pathogenic signature
    explanation: >-
      Direct tissue-level evidence that cytokine-producing CD4+ and CD8+ T cells
      populate inflammatory niches in the GN kidney, supporting both the
      leukocyte-recruitment claim and the CD4/CD8 cell-type annotations on this
      node; marked PARTIAL because the cohort is ANCA-associated GN rather than
      GN generally.
  - reference: PMID:36635359
    reference_title: "Glomerulonephritis: immunopathogenesis and immunotherapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      macrophage infiltrates, which accelerates glomerular inflammation and
      injury
    explanation: >-
      Evidences the macrophage cell-type annotation and the increased
      inflammatory response asserted on this node.
  - reference: PMID:36635359
    reference_title: "Glomerulonephritis: immunopathogenesis and immunotherapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      leukocytes pass through tight glomerular capillaries at a higher pressure
      and flow velocity compared with other capillary beds, which promotes the
      release of NETs
    explanation: >-
      Evidences leukocyte trafficking through the glomerular capillary bed and
      the neutrophil cell-type annotation, supporting the leukocyte-migration
      process asserted here.
  downstream:
  - target: Glomerular Capillary Wall Injury and Necrosis
    causal_link_type: DIRECT
    description: >-
      Leukocyte-derived oxidants and proteases damage the endothelium and basement
      membrane.

- name: Glomerular Capillary Wall Injury and Necrosis
  description: >-
    The converging effector mechanisms damage the three-layered filtration
    barrier. Endothelial injury and basement membrane degradation breach the
    capillary wall, allowing erythrocytes to escape into the urinary space — the
    dysmorphic hematuria and red cell casts that define a glomerular bleeding
    source — and permitting protein leak. In severe necrotizing disease, fibrinoid
    necrosis and frank rupture of the capillary wall spill fibrin and plasma
    proteins into Bowman's space.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: glomerular capillary endothelial cell
    term:
      id: CL:1001005
      label: glomerular capillary endothelial cell
  biological_processes:
  - preferred_term: glomerular filtration
    term:
      id: GO:0003094
      label: glomerular filtration
    modifier: ABNORMAL
  locations:
  - preferred_term: glomerular basement membrane
    term:
      id: UBERON:0005777
      label: glomerular basement membrane
  evidence:
  - reference: PMID:36635359
    reference_title: "Glomerulonephritis: immunopathogenesis and immunotherapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      followed by focal capillary necrosis in the glomerulus
    explanation: >-
      Directly evidences focal necrosis of the glomerular capillary, which is
      the lesion this node is named for.
  - reference: PMID:36635359
    reference_title: "Glomerulonephritis: immunopathogenesis and immunotherapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Acute GN most frequently presents with high blood pressure (hypertension),
      proteinuria (excessive protein in the urine) and haematuria (blood in the
      urine)
    explanation: >-
      Evidences the downstream consequences asserted on this node's outgoing
      edges — protein leak and erythrocyte escape into the urinary space.
  - reference: PMID:36635359
    reference_title: "Glomerulonephritis: immunopathogenesis and immunotherapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      'Glomerulonephritis' (GN) is a term used to describe a group of
      heterogeneous immune-mediated disorders characterized by inflammation of the
      filtration units of the kidney (the glomeruli).
    explanation: >-
      Establishes inflammatory injury of the glomerular filtration unit as the
      defining lesion shared across GN. Marked PARTIAL because it is a
      definitional statement and does not by itself evidence endothelial injury
      or basement-membrane breach.
  downstream:
  - target: Crescent Formation
    causal_link_type: DIRECT
    description: >-
      Capillary wall rupture spills fibrin and plasma into Bowman's space,
      triggering parietal epithelial proliferation.
  - target: Hematuria
    causal_link_type: DIRECT
    description: >-
      Breaches in the capillary wall allow erythrocytes to enter the urinary
      space.
  - target: Proteinuria
    causal_link_type: DIRECT
    description: >-
      Loss of barrier integrity permits protein leak into the filtrate.
  - target: Decreased glomerular filtration rate
    causal_link_type: DIRECT
    description: >-
      Inflammatory occlusion of the capillary tuft reduces filtration surface.

- name: Subepithelial Immune Deposition and Podocyte Injury
  description: >-
    The nephrotic arm of GN, exemplified by membranous nephropathy. Antibody
    against a podocyte surface antigen (PLA2R1, THSD7A, and a growing list of
    minor antigens) forms immune deposits in the subepithelial space. Because the
    basement membrane separates these deposits from the circulation, circulating
    leukocytes are not recruited and the lesion is not inflammatory; instead,
    locally generated C5b-9 injures the podocyte, disorganizing its actin
    cytoskeleton. The consequence is nephrotic-range proteinuria without the
    hematuria-dominant nephritic picture. This node is the point of contact with
    the conserved podocytopathy module.
  biological_scale: CELLULAR
  conforms_to: "nephrotic_podocyte_injury#Podocyte Injury"
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  biological_processes:
  - preferred_term: actin cytoskeleton organization
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:35484394
    reference_title: "Membranous nephropathy: new pathogenic mechanisms and their clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with primary MN, autoimmunity is driven by circulating
      autoantibodies that bind to one or more antigens on the surface of
      glomerular podocytes.
    explanation: >-
      Establishes the podocyte as the direct antibody target in this arm,
      justifying conformance to the podocyte-injury module rather than to the
      nephritic inflammatory chain.
  - reference: PMID:35484394
    reference_title: "Membranous nephropathy: new pathogenic mechanisms and their clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the discovery of pathogenic circulating autoantibodies against phospholipase
      A2 receptor 1 (PLA2R1) and thrombospondin type 1 domain-containing protein
      7A (THSD7A)
    explanation: >-
      Names the two established podocyte autoantigens of primary membranous
      nephropathy.
  downstream:
  - target: Proteinuria
    causal_link_type: DIRECT
    description: >-
      Podocyte injury and foot process effacement break the size-selective
      filtration barrier.

- name: Crescent Formation
  description: >-
    Where the capillary wall has ruptured, fibrin, plasma proteins, and
    inflammatory cells enter Bowman's space and drive proliferation of parietal
    epithelial cells, with recruited macrophages, into the characteristic
    crescent. Crescents are the histological correlate of rapidly progressive
    glomerulonephritis: they compress the tuft, obliterate Bowman's space, and, if
    they organize into fibrous crescents, render the glomerulus irrecoverable.
    Crescentic disease is the shared severe endpoint of anti-GBM disease,
    ANCA-associated GN, and severe immune-complex GN, and is what makes prompt
    immunosuppression time-critical.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: parietal epithelial cell
    term:
      id: CL:1000452
      label: parietal epithelial cell
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: epithelial cell proliferation
    term:
      id: GO:0050673
      label: epithelial cell proliferation
    modifier: INCREASED
  evidence:
  - reference: PMID:28515156
    reference_title: "Anti-Glomerular Basement Membrane Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      although presentation with oligoanuria, a high proportion of glomerular
      crescents, or kidney failure requiring dialysis augur badly for renal
      prognosis
    explanation: >-
      Ties crescent burden directly to adverse kidney outcome, supporting crescent
      formation as the severity-determining node.
  downstream:
  - target: Crescentic glomerulonephritis
    causal_link_type: DIRECT
    description: >-
      Extensive crescent formation is the defining histological lesion.
  - target: Nephron Loss and Progressive Kidney Failure
    causal_link_type: DIRECT
    description: >-
      Organized fibrous crescents destroy the glomerulus irreversibly.

- name: Nephron Loss and Progressive Kidney Failure
  description: >-
    Glomeruli that are not repaired sclerose. Loss of filtering units imposes
    hyperfiltration on those remaining, and persistent proteinuria drives
    tubulointerstitial inflammation and fibrosis. The result is progressive
    nephron loss and chronic kidney disease, which for a substantial minority of
    patients ends in kidney failure requiring dialysis or transplantation. This
    convergent endpoint is why glomerulonephritis collectively accounts for a
    large share of the global chronic kidney disease burden.
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  - preferred_term: tissue remodeling
    term:
      id: GO:0048771
      label: tissue remodeling
    modifier: ABNORMAL
  evidence:
  - reference: PMID:42284585
    reference_title: "C3 Glomerulopathy: recent advances and an update on management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both entities are progressive, with about 60% of patients progressing to
      end-stage kidney disease (ESKD) within 10 years.
    explanation: >-
      Quantifies progression to kidney failure in the complement-mediated arm,
      supporting the convergent progressive endpoint.
  - reference: PMID:39341789
    reference_title: "Mechanisms that potentially contribute to the development of post-streptococcal glomerulonephritis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This condition significantly predisposes individuals to later-life chronic
      kidney disease and concurrent renal complications
    explanation: >-
      Shows that even the classically self-limited post-infectious form carries
      long-term chronic kidney disease risk.
  downstream:
  - target: Chronic kidney disease
    causal_link_type: DIRECT
    description: >-
      Cumulative nephron loss manifests as chronic kidney disease.
  - target: Stage 5 chronic kidney disease
    causal_link_type: DIRECT
    description: >-
      Continued attrition ends in kidney failure requiring kidney replacement
      therapy.
phenotypes:
- category: Laboratory
  name: Hematuria
  description: >-
    Glomerular bleeding through breaches in the capillary wall. Characteristically
    the red cells are dysmorphic and accompanied by red cell casts formed in the
    tubule, which together localize the bleeding to the glomerulus. May be
    microscopic or macroscopic; in IgA nephropathy visible hematuria classically
    occurs synchronously with a mucosal infection.
  phenotype_term:
    preferred_term: Hematuria
    term:
      id: HP:0000790
      label: Hematuria
  evidence:
  - reference: PMID:20301598
    reference_title: "C3 Glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals with C3G typically present with hematuria, proteinuria,
      hematuria and proteinuria, acute nephritic syndrome or nephrotic syndrome,
      and low levels of the complement component C3.
    explanation: >-
      Documents hematuria as a presenting feature of glomerulonephritis.
- category: Laboratory
  name: Proteinuria
  description: >-
    Protein leak across the damaged filtration barrier, ranging from modest
    amounts in proliferative nephritic lesions to nephrotic-range proteinuria when
    the podocyte is the primary target. Proteinuria is both the main prognostic
    marker and the principal treatment response endpoint across GN subtypes.
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: PMID:20301598
    reference_title: "C3 Glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals with C3G typically present with hematuria, proteinuria,
      hematuria and proteinuria, acute nephritic syndrome or nephrotic syndrome,
      and low levels of the complement component C3.
    explanation: >-
      Documents proteinuria as a presenting feature of glomerulonephritis.
- category: Laboratory
  name: Decreased glomerular filtration rate
  description: >-
    Inflammatory occlusion of the capillary tuft and loss of filtration surface
    reduce GFR, acutely in rapidly progressive disease and progressively in
    chronic GN.
  phenotype_term:
    preferred_term: Decreased glomerular filtration rate
    term:
      id: HP:0012213
      label: Decreased glomerular filtration rate
  evidence:
  - reference: PMID:36635359
    reference_title: "Glomerulonephritis: immunopathogenesis and immunotherapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      'Glomerulonephritis' (GN) is a term used to describe a group of
      heterogeneous immune-mediated disorders characterized by inflammation of the
      filtration units of the kidney (the glomeruli).
    explanation: >-
      Supports inflammatory involvement of the glomerular filtration unit; marked
      PARTIAL because the quoted definition does not itself state that measured
      GFR falls.
- category: Clinical
  name: Hypertension
  description: >-
    Sodium and water retention from reduced filtration, together with intrarenal
    vascular injury and renin-angiotensin activation, raise blood pressure. A
    core component of the acute nephritic syndrome and an independent driver of
    progression once chronic.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: PMID:39341789
    reference_title: "Mechanisms that potentially contribute to the development of post-streptococcal glomerulonephritis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The affected individuals present with macroscopic haematuria, oliguria,
      facial oedema, and hypertension
    explanation: >-
      Lists hypertension among the presenting features of the acute nephritic
      syndrome.
- category: Clinical
  name: Edema
  description: >-
    Periorbital and peripheral edema from sodium retention in nephritic disease,
    and from hypoalbuminemia when proteinuria reaches nephrotic range.
  phenotype_term:
    preferred_term: Edema
    term:
      id: HP:0000969
      label: Edema
  evidence:
  - reference: PMID:35484394
    reference_title: "Membranous nephropathy: new pathogenic mechanisms and their clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      its clinical hallmarks are nephrotic range proteinuria with oedema
    explanation: >-
      Documents edema accompanying nephrotic-range proteinuria in the membranous
      arm.
- category: Clinical
  name: Oliguria
  description: >-
    Reduced urine output in severe acute glomerulonephritis, reflecting a sharp
    fall in filtration; oligoanuria at presentation is an adverse prognostic sign
    in crescentic disease.
  phenotype_term:
    preferred_term: Oliguria
    term:
      id: HP:0100520
      label: Oliguria
  evidence:
  - reference: PMID:28515156
    reference_title: "Anti-Glomerular Basement Membrane Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      although presentation with oligoanuria, a high proportion of glomerular
      crescents, or kidney failure requiring dialysis augur badly for renal
      prognosis
    explanation: >-
      Documents oligoanuria as a presenting feature and adverse prognostic marker.
- category: Laboratory
  name: Acute kidney injury
  description: >-
    An abrupt fall in filtration, characteristic of rapidly progressive
    glomerulonephritis, where untreated disease can destroy kidney function within
    days to weeks.
  phenotype_term:
    preferred_term: Acute kidney injury
    term:
      id: HP:0001919
      label: Acute kidney injury
  evidence:
  - reference: PMID:37764071
    reference_title: "Autoimmunity and Infection in Glomerular Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      findings include nephritic syndrome, characterized by micro/macrohematuria,
      proteinuria that can also reach the nephrotic range, edema, arterial
      hypertension, and acute renal failure
    explanation: >-
      Lists acute renal failure among the presenting features of the nephritic
      syndrome in infection-related glomerulonephritis.
- category: Laboratory
  name: Hypoalbuminemia
  description: >-
    Falling serum albumin as urinary protein loss outstrips hepatic synthesis.
    Prominent when proteinuria reaches nephrotic range — the membranous and
    nephrotic-overlap arm of the entry — and the proximate cause of the edema
    curated above.
  phenotype_term:
    preferred_term: Hypoalbuminemia
    term:
      id: HP:0003073
      label: Hypoalbuminemia
  evidence:
  - reference: PMID:39341789
    reference_title: "Mechanisms that potentially contribute to the development of post-streptococcal glomerulonephritis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      urinalysis reveal hypoalbuminemia, proteinuria, increased serum creatinine
      and urea, reduced estimated glomerular filtration rate
    explanation: >-
      Documents hypoalbuminemia alongside proteinuria in the laboratory profile
      of glomerulonephritis.
- category: Laboratory
  name: Hypercholesterolemia
  description: >-
    Dyslipidemia accompanying nephrotic-range protein loss, with raised plasma
    cholesterol and apolipoprotein B-containing lipoproteins. Clinically
    consequential rather than incidental: it is the reason lipid-lowering agents
    appear in the supportive-therapy regimen curated below.
  phenotype_term:
    preferred_term: Hypercholesterolemia
    term:
      id: HP:0003124
      label: Hypercholesterolemia
  evidence:
  - reference: PMID:29176657
    reference_title: "Dyslipidaemia in nephrotic syndrome: mechanisms and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These abnormalities include elevated plasma levels of cholesterol,
      triglycerides and the apolipoprotein B-containing lipoproteins VLDL and IDL
    explanation: >-
      Characterizes the dyslipidemia of nephrotic syndrome, including raised
      plasma cholesterol, in the nephrotic-overlap arm of glomerulonephritis.
- category: Histopathology
  name: Crescentic glomerulonephritis
  description: >-
    Proliferation of parietal epithelial cells and macrophages filling Bowman's
    space. The histological hallmark of rapidly progressive glomerulonephritis and
    the strongest biopsy predictor of kidney outcome.
  phenotype_term:
    preferred_term: Crescentic glomerulonephritis
    term:
      id: HP:0008653
      label: Crescentic glomerulonephritis
  evidence:
  - reference: PMID:28515156
    reference_title: "Anti-Glomerular Basement Membrane Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of patients develop widespread glomerular crescent formation,
      presenting with features of rapidly progressive GN, and 40%-60% will have
      concurrent alveolar hemorrhage.
    explanation: >-
      Documents widespread crescent formation and its association with rapidly
      progressive disease.
- category: Laboratory
  name: Decreased circulating complement C3 concentration
  description: >-
    Complement consumption lowers serum C3 in post-infectious glomerulonephritis,
    C3 glomerulopathy, membranoproliferative GN, and lupus nephritis. A low C3
    narrows the differential diagnosis considerably and is a routine part of the
    serologic workup.
  phenotype_term:
    preferred_term: Decreased circulating complement C3 concentration
    term:
      id: HP:0005421
      label: Decreased circulating complement C3 concentration
  evidence:
  - reference: PMID:20301598
    reference_title: "C3 Glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals with C3G typically present with hematuria, proteinuria,
      hematuria and proteinuria, acute nephritic syndrome or nephrotic syndrome,
      and low levels of the complement component C3.
    explanation: >-
      Documents low serum C3 as a characteristic laboratory finding.
- category: Clinical
  name: Pulmonary hemorrhage
  description: >-
    Alveolar hemorrhage occurs when the target autoantigen is shared between the
    glomerular and alveolar basement membrane (anti-GBM disease) or when
    small-vessel vasculitis involves the pulmonary capillary bed
    (ANCA-associated disease). The pulmonary-renal syndrome is a medical
    emergency.
  phenotype_term:
    preferred_term: Pulmonary hemorrhage
    term:
      id: HP:0040223
      label: Pulmonary hemorrhage
  evidence:
  - reference: PMID:28515156
    reference_title: "Anti-Glomerular Basement Membrane Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of patients develop widespread glomerular crescent formation,
      presenting with features of rapidly progressive GN, and 40%-60% will have
      concurrent alveolar hemorrhage.
    explanation: >-
      Quantifies concurrent alveolar hemorrhage in the anti-GBM subtype.
- category: Clinical
  name: Chronic kidney disease
  description: >-
    The convergent long-term outcome of unresolved glomerular injury, driven by
    nephron loss, glomerulosclerosis, and tubulointerstitial fibrosis.
  phenotype_term:
    preferred_term: Chronic kidney disease
    term:
      id: HP:0012622
      label: Chronic kidney disease
  evidence:
  - reference: PMID:39341789
    reference_title: "Mechanisms that potentially contribute to the development of post-streptococcal glomerulonephritis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This condition significantly predisposes individuals to later-life chronic
      kidney disease and concurrent renal complications
    explanation: >-
      Documents progression to chronic kidney disease following glomerulonephritis.
- category: Clinical
  name: Stage 5 chronic kidney disease
  description: >-
    Kidney failure requiring dialysis or transplantation. A substantial minority
    of patients with progressive glomerulonephritis reach this endpoint; in C3
    glomerulopathy roughly 60% do so within ten years.
  phenotype_term:
    preferred_term: Stage 5 chronic kidney disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
  evidence:
  - reference: PMID:42284585
    reference_title: "C3 Glomerulopathy: recent advances and an update on management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both entities are progressive, with about 60% of patients progressing to
      end-stage kidney disease (ESKD) within 10 years.
    explanation: >-
      Quantifies progression to kidney failure in complement-mediated
      glomerulonephritis.
diagnosis:
- name: Kidney biopsy with light microscopy, immunofluorescence, and electron microscopy
  description: >-
    Kidney biopsy is the central diagnostic act in glomerulonephritis, because the
    clinical presentation — hematuria, proteinuria, hypertension, falling GFR — is
    shared across mechanistically unrelated subtypes and cannot distinguish them.
    All three modalities are needed: light microscopy defines the proliferative
    pattern, immunofluorescence separates immune-complex (granular), anti-GBM
    (linear), pauci-immune (scant), C3-dominant, and monoclonal light-chain
    patterns, and electron microscopy localizes deposits to the mesangial,
    subendothelial, or subepithelial compartment. Because deposit location and
    immunofluorescence pattern are precisely what map to the distinct upstream
    mechanisms modelled in this entry's pathophysiology, the biopsy is the
    observation that assigns a patient to a causal arm.
  diagnosis_term:
    preferred_term: Kidney biopsy
    term:
      id: NCIT:C51699
      label: Kidney Biopsy
  results: >-
    Immunofluorescence pattern and electron-microscopic deposit location together
    assign the case to an immune-complex, anti-GBM, pauci-immune, or
    complement-mediated arm; crescent burden and interstitial fibrosis grade the
    severity and reversibility.
  evidence:
  - reference: PMID:20301598
    reference_title: "C3 Glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The definitive diagnosis of C3G requires a renal biopsy with specialized
      immunofluorescence and electron microscopy studies both for diagnosis and to
      distinguish between the two major subtypes of C3G: C3 glomerulonephritis
      (C3GN) and dense deposit disease (DDD).
    explanation: >-
      States that renal biopsy with immunofluorescence and electron microscopy is
      required both to diagnose and to subtype complement-mediated
      glomerulonephritis.
  - reference: PMID:36635359
    reference_title: "Glomerulonephritis: immunopathogenesis and immunotherapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These disorders are currently classified largely on the basis of
      histopathological lesion patterns
    explanation: >-
      Confirms that histopathological lesion pattern is the prevailing basis of
      classification, hence the central diagnostic role of biopsy; marked PARTIAL
      because the same source argues those patterns align poorly with mechanism.
  - reference: PMID:37869232
    reference_title: "Prevalence and distribution of primary glomerular diseases in Africa: a systematic review and meta-analysis of observational studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Only 4 studies (23.5%) used light microscopy (LM), immunofluorescence (IF),
      and electron microscopy (EM) for diagnosis.
    explanation: >-
      Documents that the full three-modality biopsy standard is frequently not met
      in practice, a recognised source of ascertainment bias in subtype
      distribution data.
- name: Mechanism-directed serologic panel
  description: >-
    Serology narrows the mechanism before and alongside biopsy, and each assay maps
    onto a specific pathophysiology arm modelled here: ANCA with PR3/MPO
    specificity for the pauci-immune neutrophil arm; anti-GBM antibody for the
    anti-alpha3(IV) arm; anti-PLA2R for the subepithelial podocyte arm; C3 and C4
    for complement consumption; ANA and anti-dsDNA for lupus nephritis; hepatitis
    B/C, HIV and streptococcal serology (ASO, anti-DNase B) for the
    infection-related arm; and serum/urine electrophoresis with free light chains
    for monoclonal gammopathy-related disease. Anti-PLA2R is the one assay that has
    become a genuine non-invasive substitute for biopsy in a defined setting;
    the others remain adjuncts to it.
  diagnosis_term:
    preferred_term: Autoantibody and complement serology
    term:
      id: NCIT:C181397
      label: Autoantibody Measurement
  results: >-
    A positive result assigns the mechanism: PR3/MPO-ANCA (pauci-immune), anti-GBM
    (linear anti-basement-membrane), anti-PLA2R (membranous), low C3
    (post-infectious, C3 glomerulopathy, or lupus nephritis).
  evidence:
  - reference: PMID:35484394
    reference_title: "Membranous nephropathy: new pathogenic mechanisms and their clinical implications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the discovery of pathogenic circulating autoantibodies against phospholipase
      A2 receptor 1 (PLA2R1) and thrombospondin type 1 domain-containing protein
      7A (THSD7A)
    explanation: >-
      Establishes the circulating podocyte autoantibodies that underpin serologic
      diagnosis of the membranous arm.
  - reference: PMID:36109667
    reference_title: "Genetics of ANCA-associated vasculitis: role in pathogenesis, classification and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the positivity of ANCA targeting proteinase-3 (PR3-ANCA) or myeloperoxidase
      (MPO-ANCA)
    explanation: >-
      Establishes PR3 and MPO ANCA specificity as the serologic discriminator of
      the pauci-immune arm.
  - reference: PMID:20301598
    reference_title: "C3 Glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      low levels of the complement component C3
    explanation: >-
      Supports serum C3 measurement as part of the mechanism-directed workup.
prevalence:
- population: Africa (biopsy-proven primary glomerular disease, 8 countries)
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    Pooled biopsy-series distribution rather than a population rate: among 6,494
    biopsied individuals in 17 African studies, FSGS 26.10%, minimal change
    disease 22.40%, membranous nephropathy 8.40%, MPGN 6.40%,
    mesangioproliferative GN 6.40%, post-infectious GN 2.60%, IgA nephropathy
    2.60%, and crescentic GN 1.40%. This is a subtype *distribution* among
    biopsies, not an incidence in the general population, and is subject to biopsy
    referral and ascertainment bias. No reliable global incidence exists for
    aggregate glomerulonephritis, because biopsy policy, coding, age structure,
    and infection burden differ between settings.
  evidence:
  - reference: PMID:37869232
    reference_title: "Prevalence and distribution of primary glomerular diseases in Africa: a systematic review and meta-analysis of observational studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seventeen eligible articles (n = 6,494 individuals) from 8 African countries
      met the inclusion criteria. The overall pooled prevalence of FSGS, MCD, MN,
      MPGN, MesPGN, PIGN, IgAN and CresGN was 26.10%, 22.40%, 8.40%, 6.40%, 6.40%,
      2.60%, 2.60%, 1.40%, respectively.
    explanation: >-
      Quantifies the relative distribution of glomerular disease subtypes in a
      large pooled African biopsy series.
biochemical:
- name: Anti-PLA2R autoantibody
  presence: Positive
  specificity: >-
    High for primary membranous nephropathy; absent in secondary membranous
    nephropathy and in other glomerulonephritis subtypes.
  notes: >-
    The one serologic marker in glomerulonephritis that is both mechanistically
    causal and clinically validated: it identifies the autoantigen driving the
    subepithelial deposition node, and its titre tracks disease activity closely
    enough that a positive result can substitute for biopsy in defined settings.
    Contrast the omics-derived candidate markers below, which remain unvalidated.
  evidence:
  - reference: PMID:19571279
    reference_title: "M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Serum samples from 26 of 37 patients (70%) with idiopathic but not
      secondary membranous nephropathy specifically identified a 185-kD
      glycoprotein in nonreduced glomerular extract.
    explanation: >-
      Quantifies detection in primary but not secondary membranous nephropathy,
      supporting both the presence and the specificity claim.
  - reference: PMID:19571279
    reference_title: "M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PLA(2)R is present in normal podocytes and in immune deposits in patients
      with idiopathic membranous nephropathy, indicating that PLA(2)R is a major
      antigen in this disease.
    explanation: >-
      Localizes the antigen to the podocyte and to the subepithelial immune
      deposits, tying the biomarker to the pathophysiology node rather than
      leaving it a free-standing serology.
- name: Serum complement C3
  presence: Decreased
  notes: >-
    Consumption of C3 through alternative-pathway activation. A low C3 is the
    routine bedside readout of the complement node in the pathograph, and its
    trajectory differs by subtype — transient in post-infectious GN, persistently
    low in C3 glomerulopathy.
  evidence:
  - reference: PMID:20301598
    reference_title: "C3 Glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      low levels of the complement component C3
    explanation: >-
      GeneReviews lists depressed serum C3 among the typical presenting
      laboratory findings of complement-mediated glomerulonephritis.
- name: Urinary and serum omics-derived candidate biomarkers
  presence: Under investigation
  notes: >-
    Curated deliberately as an unvalidated class rather than as named analytes.
    Proteomic and metabolomic studies in glomerulonephritis have proposed many
    candidates, but the systematic review below concludes that validation is
    still outstanding — so naming individual markers here would overstate the
    evidence.
  evidence:
  - reference: PMID:38689160
    reference_title: "The current use of proteomics and metabolomics in glomerulonephritis: a systematic literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This review shows the potential of metabolomic and proteomic analysis to
      discover new disease biomarkers that may influence diagnostics and disease
      management. Further larger-scale research is required to establish the
      validity of the study outcomes, including the several proposed biomarkers.
    explanation: >-
      Supports the existence of a candidate-biomarker field while explicitly
      stating that validity is not yet established; marked PARTIAL for that
      reason.
inheritance:
- name: Complex non-Mendelian inheritance
  description: >-
    Glomerulonephritis as a whole is not a Mendelian disorder. Even in the
    complement-mediated arm, where the largest set of implicated genes is known,
    transmission is complex: familial clustering is the exception, and both
    dominant and recessive patterns have been described within the few
    multiplex families reported. This is the reason the complement genes below
    are curated as SUSCEPTIBILITY rather than as causal Mendelian loci.
  evidence:
  - reference: PMID:20301598
    reference_title: "C3 Glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      C3G is a complex genetic disorder that is rarely inherited in a simple
      mendelian fashion. Multiple affected persons within a single nuclear
      family are reported only occasionally, with both dominant and recessive
      inheritance being described.
    explanation: >-
      GeneReviews states the transmission pattern directly for the
      complement-mediated arm, and is the attribution for treating the
      complement genes as susceptibility loci rather than Mendelian causes.
genetic:
- name: CFH
  association: GENETIC_VARIANT
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: CFH
    term:
      id: hgnc:4883
      label: CFH
  notes: >-
    Complement factor H is the principal fluid-phase regulator of the alternative
    pathway. Rare variants are among the complement-gene lesions implicated in C3
    glomerulopathy. This is a subtype-level susceptibility gene, not a gene for
    glomerulonephritis as a whole, and only some affected individuals carry an
    identifiable variant.
  evidence:
  - reference: PMID:20301598
    reference_title: "C3 Glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some individuals will have biallelic or heterozygous pathogenic variants
      identified by molecular genetic testing in one or more of the genes that
      have been implicated in the pathogenesis of C3G (i.e., C3, CD46, CFB, CFH,
      CFHR1, CFHR5, CFI, and DGKE).
    explanation: >-
      Lists CFH among the complement genes implicated in C3 glomerulopathy, and
      notes that only some affected individuals carry an identifiable variant.
- name: C3
  association: GENETIC_VARIANT
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: C3
    term:
      id: hgnc:1318
      label: C3
  notes: >-
    Gain-of-function variants in C3 itself can render the alternative-pathway
    convertase resistant to regulation, driving continuous fluid-phase C3 turnover
    and glomerular C3 deposition.
  evidence:
  - reference: PMID:20301598
    reference_title: "C3 Glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some individuals will have biallelic or heterozygous pathogenic variants
      identified by molecular genetic testing in one or more of the genes that
      have been implicated in the pathogenesis of C3G (i.e., C3, CD46, CFB, CFH,
      CFHR1, CFHR5, CFI, and DGKE).
    explanation: >-
      Lists C3 among the complement genes implicated in C3 glomerulopathy.
- name: CFHR5
  association: GENETIC_VARIANT
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: CFHR5
    term:
      id: hgnc:24668
      label: CFHR5
  notes: >-
    CFHR5 lesions are characteristically structural or copy-number rearrangements
    within the CFHR gene cluster rather than point mutations. CFHR5 nephropathy is
    a recognised founder-effect disorder, illustrating that some
    complement-mediated glomerulonephritis is population-specific.
  evidence:
  - reference: PMID:20301598
    reference_title: "C3 Glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some individuals will have biallelic or heterozygous pathogenic variants
      identified by molecular genetic testing in one or more of the genes that
      have been implicated in the pathogenesis of C3G (i.e., C3, CD46, CFB, CFH,
      CFHR1, CFHR5, CFI, and DGKE).
    explanation: >-
      Lists CFHR5 among the complement genes implicated in C3 glomerulopathy.
- name: CFI
  association: GENETIC_VARIANT
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: CFI
    term:
      id: hgnc:5394
      label: CFI
  notes: >-
    Complement factor I is the serine protease that, with its cofactors,
    inactivates C3b. Loss of this regulatory step permits unchecked
    alternative-pathway amplification.
  evidence:
  - reference: PMID:20301598
    reference_title: "C3 Glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some individuals will have biallelic or heterozygous pathogenic variants
      identified by molecular genetic testing in one or more of the genes that
      have been implicated in the pathogenesis of C3G (i.e., C3, CD46, CFB, CFH,
      CFHR1, CFHR5, CFI, and DGKE).
    explanation: >-
      Lists CFI among the complement genes implicated in C3 glomerulopathy.
- name: CFB
  association: GENETIC_VARIANT
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: CFB
    term:
      id: hgnc:1037
      label: CFB
  notes: >-
    Complement factor B forms the catalytic subunit of the alternative-pathway C3
    convertase; variants that stabilise the convertase prolong C3 cleavage.
  evidence:
  - reference: PMID:20301598
    reference_title: "C3 Glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some individuals will have biallelic or heterozygous pathogenic variants
      identified by molecular genetic testing in one or more of the genes that
      have been implicated in the pathogenesis of C3G (i.e., C3, CD46, CFB, CFH,
      CFHR1, CFHR5, CFI, and DGKE).
    explanation: >-
      Lists CFB among the complement genes implicated in C3 glomerulopathy.
- name: CD46
  association: GENETIC_VARIANT
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: CD46
    term:
      id: hgnc:6953
      label: CD46
  notes: >-
    CD46 (membrane cofactor protein) is a membrane-bound complement regulator
    acting as a cofactor for factor I-mediated C3b cleavage.
  evidence:
  - reference: PMID:20301598
    reference_title: "C3 Glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some individuals will have biallelic or heterozygous pathogenic variants
      identified by molecular genetic testing in one or more of the genes that
      have been implicated in the pathogenesis of C3G (i.e., C3, CD46, CFB, CFH,
      CFHR1, CFHR5, CFI, and DGKE).
    explanation: >-
      Lists CD46 among the complement genes implicated in C3 glomerulopathy.
- name: DGKE
  association: GENETIC_VARIANT
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: DGKE
    term:
      id: hgnc:2852
      label: DGKE
  notes: >-
    DGKE encodes diacylglycerol kinase epsilon and is the outlier in this gene
    set: it is not a complement protein, and DGKE-associated disease is thought to
    act through endothelial prothrombotic signalling rather than through
    complement dysregulation, despite producing an overlapping glomerular lesion.
  evidence:
  - reference: PMID:20301598
    reference_title: "C3 Glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some individuals will have biallelic or heterozygous pathogenic variants
      identified by molecular genetic testing in one or more of the genes that
      have been implicated in the pathogenesis of C3G (i.e., C3, CD46, CFB, CFH,
      CFHR1, CFHR5, CFI, and DGKE).
    explanation: >-
      Lists DGKE among the genes implicated in C3 glomerulopathy.
- name: PRTN3
  association: GWAS
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: PRTN3
    term:
      id: hgnc:9495
      label: PRTN3
  notes: >-
    PRTN3 encodes proteinase-3, the autoantigen of PR3-ANCA disease. Genetic
    susceptibility in ANCA-associated glomerulonephritis segregates by ANCA
    specificity rather than by clinical syndrome, which is why the autoantigen
    locus itself is informative.
  evidence:
  - reference: PMID:36109667
    reference_title: "Genetics of ANCA-associated vasculitis: role in pathogenesis, classification and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with GPA and MPA, the genetic associations are stronger with
      ANCA specificity (PR3- versus MPO-ANCA) than with the clinical diagnosis,
      which, in keeping with the known clinical and prognostic differences between
      PR3-ANCA-positive and MPO-ANCA-positive patients, supports an ANCA-based
      re-classification of these disorders.
    explanation: >-
      Establishes that genetic risk tracks with PR3 versus MPO autoantigen
      specificity rather than with the clinical diagnosis.
- name: MPO
  association: GWAS
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: MPO
    term:
      id: hgnc:7218
      label: MPO
  notes: >-
    MPO encodes myeloperoxidase, the autoantigen of MPO-ANCA disease. MPO-ANCA
    positive patients with microscopic polyangiitis and with eosinophilic
    granulomatosis with polyangiitis share genetic determinants.
  evidence:
  - reference: PMID:36109667
    reference_title: "Genetics of ANCA-associated vasculitis: role in pathogenesis, classification and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interestingly, MPO-ANCA-positive patients with either MPA or EGPA have
      overlapping genetic determinants, thus strengthening the concept that this
      EGPA subset is closely related to the other AAV syndromes.
    explanation: >-
      Shows shared genetic determinants across MPO-ANCA-positive syndromes,
      supporting the autoantigen as the organising axis.
- name: PLA2R1
  association: GWAS
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: PLA2R1
    term:
      id: hgnc:9042
      label: PLA2R1
  notes: >-
    PLA2R1 encodes the M-type phospholipase A2 receptor, the dominant podocyte
    autoantigen of primary membranous nephropathy. The gene is unusual in
    carrying both the risk haplotype and the target of the autoantibody, which
    is why it anchors the subepithelial/podocyte arm of this entry.
  evidence:
  - reference: PMID:21323541
    reference_title: "Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chromosome 2q24 contains the gene encoding M-type phospholipase A(2)
      receptor (PLA(2)R1) (SNP rs4664308, P=8.6×10(-29)), previously shown to be
      the target of an autoimmune response.
    explanation: >-
      Genome-wide significant association of PLA2R1 with idiopathic membranous
      nephropathy across three white populations.
- name: HLA-DQA1
  association: GWAS
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: HLA-DQA1
    term:
      id: hgnc:4942
      label: HLA-DQA1
  notes: >-
    Class II HLA is the strongest association in primary membranous nephropathy
    and is the mechanistic link between antigen presentation and the loss of
    tolerance modelled at the head of the pathograph. The risk is multiplicative
    with PLA2R1: homozygosity at both loci carries an odds ratio near 80.
  evidence:
  - reference: PMID:21323541
    reference_title: "Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The odds ratio for idiopathic membranous nephropathy with homozygosity for
      both risk alleles was 78.5 (95% confidence interval, 34.6 to 178.2).
    explanation: >-
      Quantifies the joint HLA-DQA1/PLA2R1 risk, the largest effect size in the
      genetics of this arm of glomerulonephritis.
- name: APOL1
  association: GENETIC_VARIANT
  relationship_type: MODIFIER
  gene_term:
    preferred_term: APOL1
    term:
      id: hgnc:618
      label: APOL1
  notes: >-
    The G1 and G2 risk variants, confined to populations of recent African
    ancestry, are curated here as a MODIFIER rather than as a susceptibility
    locus for any one subtype: their principal effect in glomerulonephritis is
    on the rate of progression through the shared nephron-loss pathway, seen
    even in membranous nephropathy where the initiating autoimmune mechanism is
    unrelated to APOL1.
  evidence:
  - reference: PMID:20647424
    reference_title: "Association of trypanolytic ApoL1 variants with kidney disease in African Americans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      focal segmental glomerulosclerosis (FSGS) and hypertension-attributed
      end-stage kidney disease (H-ESKD) are associated with two independent
      sequence variants in the APOL1 gene on chromosome 22
    explanation: >-
      Original identification of the two APOL1 risk variants underlying the
      excess burden of kidney disease in African Americans.
  - reference: PMID:36763808
    reference_title: "Kidney Disease Progression in Membranous Nephropathy among Black Participants with High-Risk APOL1 Genotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Time to kidney failure was faster in the high-risk APOL1 genotype than
      low-risk APOL1 genotype or membranous nephropathy participants that were
      not Black.
    explanation: >-
      Demonstrates the progression-modifying effect within a glomerulonephritis
      subtype specifically, supporting the MODIFIER typing rather than a
      subtype-susceptibility typing.
environmental:
- name: Streptococcal and other infectious triggers
  description: >-
    Infection initiates glomerulonephritis by several distinct routes: deposition
    of circulating immune complexes, planting of antigen in the capillary wall
    with in-situ complex formation, molecular mimicry between anti-pathogen
    antibody and intrinsic glomerular matrix proteins, direct damage to glomerular
    cells, and superantigen-driven T cell activation. Group A streptococcus is the
    classic trigger, but hepatitis B and C, staphylococci, endocarditis pathogens,
    HIV, and parasites are all implicated. The relationship is bidirectional:
    urinary immunoglobulin loss and immunosuppressive treatment in turn raise
    infection risk.
  evidence:
  - reference: PMID:37764071
    reference_title: "Autoimmunity and Infection in Glomerular Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mechanisms responsible range from the direct damage of glomerular cells
      to the formation and deposition of immunocomplexes to molecular mimicry to
      the secretion of superantigens.
    explanation: >-
      Enumerates the distinct mechanisms linking infection to glomerular injury.
  - reference: PMID:37764071
    reference_title: "Autoimmunity and Infection in Glomerular Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      infections are more frequent than in the general population due to the loss
      of immunoglobulins in urine and the immunosuppressive agents used to treat
      the autoimmune disease that decrease the activity of the immune system
    explanation: >-
      Documents the reverse arm of the infection-glomerulonephritis relationship.
  influences_mechanisms:
  - target: Nephritogenic Antigen Exposure and Loss of Tolerance
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Infection supplies the nephritogenic antigen, or breaks tolerance by
      molecular mimicry or superantigen effect, initiating the immune response
      that injures the glomerulus.
    evidence:
    - reference: PMID:39341789
      reference_title: "Mechanisms that potentially contribute to the development of post-streptococcal glomerulonephritis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Streptococcal pyrogenic exotoxin B and nephritis-associated plasmin
        receptor are identified nephritogenic antigens (nephritogens).
      explanation: >-
        Names the specific streptococcal antigens that trigger the nephritogenic
        immune response.
treatments:
- name: Corticosteroid Therapy
  description: >-
    Glucocorticoids are the backbone of induction therapy for inflammatory GN,
    suppressing leukocyte recruitment and cytokine production at the glomerulus.
    They are given with a second agent in severe crescentic disease and are used
    selectively — not universally — in indolent subtypes, where toxicity may
    outweigh benefit. In infection-related GN, treating the infection takes
    precedence over immunosuppression.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
  target_mechanisms:
  - target: Leukocyte Recruitment and Glomerular Inflammation
    treatment_effect: INHIBITS
    description: >-
      Broad suppression of the glomerular inflammatory infiltrate and its cytokine
      output.
  evidence:
  - reference: PMID:28515156
    reference_title: "Anti-Glomerular Basement Membrane Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment aims to rapidly remove pathogenic autoantibody, typically with the
      use of plasma exchange, along with steroids and cytotoxic therapy to prevent
      ongoing autoantibody production and tissue inflammation.
    explanation: >-
      Documents corticosteroids as a component of standard induction therapy in
      severe antibody-mediated GN.
- name: Cyclophosphamide
  description: >-
    Alkylating cytotoxic therapy used for induction in severe crescentic and
    rapidly progressive glomerulonephritis, suppressing the B cell clones
    producing pathogenic autoantibody. Gonadotoxicity and malignancy risk limit
    cumulative exposure, which is why rituximab has displaced it in many settings.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cyclophosphamide
      term:
        id: NCIT:C405
        label: Cyclophosphamide
  target_mechanisms:
  - target: Nephritogenic Antigen Exposure and Loss of Tolerance
    treatment_effect: INHIBITS
    description: >-
      Suppresses the lymphocyte clones generating pathogenic autoantibody.
  evidence:
  - reference: PMID:28515156
    reference_title: "Anti-Glomerular Basement Membrane Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      along with steroids and cytotoxic therapy to prevent ongoing autoantibody
      production and tissue inflammation
    explanation: >-
      Documents cytotoxic therapy as standard induction alongside corticosteroids
      to halt autoantibody production.
- name: Rituximab
  description: >-
    Anti-CD20 monoclonal antibody depleting B cells and thereby the precursors of
    autoantibody-secreting plasma cells. Now a first-line induction and
    maintenance option in ANCA-associated GN and the preferred immunosuppressive
    therapy in PLA2R-associated membranous nephropathy.
  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: Nephritogenic Antigen Exposure and Loss of Tolerance
    treatment_effect: INHIBITS
    description: >-
      B cell depletion removes the source of pathogenic autoantibody.
    evidence:
    - reference: PMID:31269364
      reference_title: "Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        B-cell anomalies play a role in the pathogenesis of membranous
        nephropathy. B-cell depletion with rituximab may therefore be noninferior
        to treatment with cyclosporine for inducing and maintaining a complete or
        partial remission of proteinuria in patients with this condition.
      explanation: >-
        States the mechanistic rationale linking B cell depletion to the
        autoantibody-driven lesion, and the proteinuria endpoint it addresses.
  evidence:
  - reference: PMID:20647199
    reference_title: "Rituximab versus cyclophosphamide for ANCA-associated vasculitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rituximab therapy was not inferior to daily cyclophosphamide treatment for
      induction of remission in severe ANCA-associated vasculitis and may be
      superior in relapsing disease.
    explanation: >-
      RAVE randomized trial establishing rituximab as non-inferior to
      cyclophosphamide for remission induction in severe ANCA-associated disease.
  - reference: PMID:31269364
    reference_title: "Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rituximab was noninferior to cyclosporine in inducing complete or partial
      remission of proteinuria at 12 months and was superior in maintaining
      proteinuria remission up to 24 months.
    explanation: >-
      MENTOR randomized trial supporting rituximab in the membranous/podocyte arm
      of glomerulonephritis.
- name: Plasma Exchange
  description: >-
    Extracorporeal removal of circulating pathogenic autoantibody. The clearest
    indication is anti-GBM disease, where the antibody is directly pathogenic and
    outcome depends on removing it before crescents organize; it is also used in
    severe ANCA-associated disease with pulmonary hemorrhage. Benefit is greatest
    when started early, before dialysis dependence.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Plasmapheresis
    term:
      id: NCIT:C15304
      label: Plasmapheresis
  target_mechanisms:
  - target: Anti-GBM Autoantibody Binding to Type IV Collagen
    treatment_effect: INHIBITS
    description: >-
      Removes circulating anti-GBM antibody, cutting off the supply of pathogenic
      autoantibody to the basement membrane.
    evidence:
    - reference: PMID:28515156
      reference_title: "Anti-Glomerular Basement Membrane Disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Treatment aims to rapidly remove pathogenic autoantibody, typically with
        the use of plasma exchange
      explanation: >-
        States the mechanistic rationale for plasma exchange as removal of the
        pathogenic autoantibody.
  evidence:
  - reference: PMID:28515156
    reference_title: "Anti-Glomerular Basement Membrane Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Retrospective cohort studies suggest that when this combination of treatment
      is started early, the majority of patients will have good renal outcome
    explanation: >-
      Supports early combination therapy including plasma exchange as
      outcome-determining.
- name: Avacopan
  description: >-
    Oral C5a receptor antagonist that blocks the C5a-driven neutrophil priming and
    recruitment loop central to ANCA-associated glomerulonephritis. Its
    development is a direct application of the complement mechanism to therapy,
    and it permits substantial reduction of glucocorticoid exposure.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: avacopan
      term:
        id: NCIT:C174788
        label: Avacopan
  target_mechanisms:
  - target: Complement Activation
    treatment_effect: INHIBITS
    description: >-
      Blockade of the C5a receptor interrupts complement-driven neutrophil
      recruitment and priming at the glomerulus.
    evidence:
    - reference: PMID:33596356
      reference_title: "Avacopan for the Treatment of ANCA-Associated Vasculitis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The C5a receptor inhibitor avacopan is being studied for the treatment of
        antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.
      explanation: >-
        Identifies avacopan's molecular target as the C5a receptor, the
        complement node this treatment link asserts.
  evidence:
  - reference: PMID:33596356
    reference_title: "Avacopan for the Treatment of ANCA-Associated Vasculitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this trial involving patients with ANCA-associated vasculitis, avacopan
      was noninferior but not superior to prednisone taper with respect to
      remission at week 26 and was superior to prednisone taper with respect to
      sustained remission at week 52.
    explanation: >-
      ADVOCATE randomized trial establishing avacopan's efficacy relative to a
      prednisone taper, the basis for its glucocorticoid-sparing role.
- name: Renin-Angiotensin System Blockade and Supportive Antiproteinuric Therapy
  description: >-
    Non-immunosuppressive background therapy given across essentially every
    subtype of glomerulonephritis, independent of the initiating immune
    mechanism. ACE inhibitors and angiotensin II receptor blockers lower
    intraglomerular pressure and proteinuria, and lipid-lowering agents address
    the dyslipidemia of chronic glomerular disease. Unlike the mechanism-directed
    immunosuppressants above, this is the one intervention that applies at the
    root level: it acts on the shared downstream progression pathway rather than
    on any one subtype's trigger.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ACE inhibitor
      term:
        id: NCIT:C247
        label: ACE Inhibitor
    - preferred_term: angiotensin II receptor blocker
      term:
        id: NCIT:C66930
        label: Angiotensin II Receptor Antagonist
    - preferred_term: statin (HMG-CoA reductase inhibitor)
      term:
        id: NCIT:C1655
        label: HMG-CoA Reductase Inhibitor
  target_mechanisms:
  - target: Nephron Loss and Progressive Kidney Failure
    treatment_effect: INHIBITS
    description: >-
      Reduction of intraglomerular pressure and proteinuria slows the
      proteinuria-driven tubulointerstitial injury that carries surviving
      nephrons toward sclerosis, independent of the upstream immune trigger.
  evidence:
  - reference: PMID:20301598
    reference_title: "C3 Glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nonspecific therapies used to treat numerous chronic glomerular diseases,
      including angiotensin-converting enzyme inhibitors, angiotensin II type-1
      receptor blockers, and lipid-lowering agents (in particular
      hydroxymethylglutaryl coenzyme A reductase inhibitors).
    explanation: >-
      GeneReviews management guidance naming RAS blockade and lipid-lowering
      therapy as the nonspecific measures used across chronic glomerular
      diseases, which is the basis for curating this at the root level rather
      than per subtype.
- name: SGLT2 Inhibition
  description: >-
    Sodium-glucose cotransporter-2 inhibition, added to RAS blockade as
    contemporary background therapy for proteinuric chronic kidney disease
    irrespective of diabetes status. Like RAS blockade it acts on the shared
    progression pathway rather than on any subtype's immune trigger, so it
    belongs at the root level. The pivotal trial enrolled a CKD population,
    including glomerulonephritis, rather than a GN-specific cohort — the
    evidence is therefore for the shared downstream node, not for any one
    subtype.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: SGLT2 inhibitor
      term:
        id: NCIT:C98083
        label: SGLT2 Inhibitor
    - preferred_term: dapagliflozin
      term:
        id: CHEBI:85078
        label: dapagliflozin
  target_mechanisms:
  - target: Nephron Loss and Progressive Kidney Failure
    treatment_effect: INHIBITS
    description: >-
      Slows the rate of GFR decline and progression to kidney failure along the
      shared nephron-loss pathway.
  evidence:
  - reference: PMID:32970396
    reference_title: "Dapagliflozin in Patients with Chronic Kidney Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among patients with chronic kidney disease, regardless of the presence or
      absence of diabetes, the risk of a composite of a sustained decline in the
      estimated GFR of at least 50%, end-stage kidney disease, or death from
      renal or card
    explanation: >-
      DAPA-CKD randomized trial establishing that SGLT2 inhibition slows
      progression in chronic kidney disease independent of diabetes, the basis
      for curating it as root-level background therapy.
- name: Kidney Replacement Therapy
  description: >-
    Dialysis or kidney transplantation once glomerulonephritis has progressed to
    kidney failure. Curated because Stage 5 chronic kidney disease is a terminal
    node of this entry's pathograph and the entry would otherwise model the
    endpoint without the intervention that addresses it. Note that several
    glomerulonephritis subtypes recur in the allograft, which is a
    subtype-specific consideration handled on those entries.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: renal replacement therapy
    term:
      id: NCIT:C126400
      label: Renal Replacement Therapy
  evidence:
  - reference: PMID:20301598
    reference_title: "C3 Glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      When ESRD develops, treatment options are limited to dialysis or
      transplantation.
    explanation: >-
      GeneReviews management guidance for the kidney-failure endpoint of
      complement-mediated glomerulonephritis.
- name: Surveillance of Kidney Function and Complement Status
  description: >-
    Structured monitoring rather than an intervention: serial assessment of
    kidney function and of the complement pathway, with fundus examination where
    complement-mediated disease carries a retinal risk. Curated from the
    GeneReviews Surveillance recommendations.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301598
    reference_title: "C3 Glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Close monitoring of renal function by a nephrologist with familiarity with
      the C3G disease spectrum, complete biannual assessment of the complement
      pathway, periodic eye examinations to evaluate the fundus.
    explanation: >-
      GeneReviews Surveillance schedule, the source for the monitoring
      components curated here.
clinical_trials:
- name: NCT06419205
  phase: PHASE_II
  status: RECRUITING
  description: >-
    ADX-097, a targeted complement inhibitor, given subcutaneously across three
    complement-implicated glomerulonephritis subtypes at once. Included at the
    root level precisely because its enrolment spans IgAN, lupus nephritis, and
    C3 glomerulopathy — it is a trial of the shared complement mechanism rather
    than of a single subtype.
  evidence:
  - reference: clinicaltrials:NCT06419205
    reference_title: "A Phase 2 Study to Evaluate the Safety, Pharmacodynamics, Pharmacokinetics, and Clinical Activity of ADX-097 Administered Subcutaneously in Male and Female Participants Aged 16 Years or Older With Immunoglobulin A Nephropathy (IgAN), Lupus Nephritis (LN), or Complement Component 3 Glomerulopathy (C3G)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunoglobulin A Nephropathy (IgAN), Lupus Nephritis (LN), or Complement
      Component 3 Glomerulopathy (C3G)
    explanation: >-
      Confirms the multi-subtype enrolment that makes this a root-level rather
      than subtype-level trial.
- name: NCT05732402
  status: ACTIVE_NOT_RECRUITING
  description: >-
    RUBY-3, an open-label multiple-ascending-dose study of povetacicept in
    autoantibody-associated glomerular disease, registered as Phase 1/2 (no
    single-phase enum value applies, so `phase` is omitted rather than
    misstated). Targets the autoantibody-producing B-cell compartment upstream
    of the deposition nodes, across four subtypes.
  evidence:
  - reference: clinicaltrials:NCT05732402
    reference_title: "An Open-Label, Multiple-Ascending Dose Study to Assess the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Different Dose Levels of Povetacicept in Subjects With Autoantibody-Associated Glomerular Diseases (RUBY-3)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      immunoglobulin A (IgA) nephropathy (IgAN), primary membranous nephropathy
      (pMN), lupus-related kidney disease (lupus nephritis - LN), or
      anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV)
    explanation: >-
      Documents enrolment spanning four of the curated glomerulonephritis
      subtypes.
- name: NCT05083364
  status: COMPLETED
  description: >-
    AROC3-1001, an RNA-interference agent silencing C3 synthesis in
    complement-mediated renal disease; registered as Phase 1/2a, so `phase` is
    omitted for the same reason as above. Mechanistically the inverse of the
    downstream C5a blockade curated under avacopan — it removes the substrate
    rather than blocking the receptor.
  evidence:
  - reference: clinicaltrials:NCT05083364
    reference_title: "A Phase 1/2a Dose-Escalating Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and/or Pharmacodynamics of ARO-C3 in Adult Healthy Volunteers and in Adult Patients With Complement-Mediated Renal Disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in adult patients with complement-mediated renal disease (C3 Glomerulopathy
    explanation: >-
      Confirms the complement-mediated glomerulonephritis population targeted by
      C3 knockdown.
- name: NCT06277427
  phase: NOT_APPLICABLE
  status: RECRUITING
  description: >-
    BCMA-targeting CAR-T cells in refractory ANCA-associated vasculitis and
    lupus nephritis. The registry records no phase for this study.
  evidence:
  - reference: clinicaltrials:NCT06277427
    reference_title: "Refractory ANCA Associated Vasculitis and Lupus Nephritis Treated With BCMA-targeting CAR-T Cells"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      BCMA is the molecule expressed on memory B cells, plasmablasts and plasma
      cells, and therefore is an ideal target for the elimination of potential
      pathogenic antibody secreting cells.
    explanation: >-
      States the mechanistic rationale — depletion of the antibody-secreting
      compartment feeding the autoantibody-driven arms of the pathograph.
references:
- reference: PMID:20301598
  title: "C3 Glomerulopathy."
  tags:
  - GeneReviews
- reference: PMID:36635359
  title: "Glomerulonephritis: immunopathogenesis and immunotherapy."

📚

References & Deep Research

References

2

PMID:20301598

C3 Glomerulopathy.

No top-level findings curated for this source.

PMID:36635359

Glomerulonephritis: immunopathogenesis and immunotherapy.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 31 citations 2026-08-12T10:45:16.970579

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Glomerulonephritis
MONDO ID: (if available)
Category: Complex

Research Objectives

Please provide a comprehensive research report on Glomerulonephritis covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Glomerulonephritis: comprehensive disease-characteristics report

Executive summary and scope

Glomerulonephritis (GN) is not one disease but a heterogeneous group of disorders characterized by inflammation and immune-mediated injury of renal glomeruli. Histologic patterns alone do not consistently identify cause; current expert thinking increasingly divides GN into infection-related, autoimmune, alloimmune, autoinflammatory/complement-mediated, and monoclonal gammopathy-related categories because this better links mechanism to treatment. Acute disease commonly produces hematuria, proteinuria, hypertension, edema, and reduced glomerular filtration; severe crescentic disease can cause rapidly progressive kidney failure. Kidney biopsy remains central because these clinical manifestations are nonspecific. (anders2023glomerulonephritisimmunopathogenesisand pages 1-2)

The principal evidence limitation is therefore conceptual: syndrome-level statements about a single causal gene, inheritance pattern, incidence, treatment, or prognosis are usually invalid. Those fields must be recorded by etiologic subtype.

A useful overview of the major mechanistic classes follows.

Class / examples	Initiating cause	Biopsy / serologic signature	Key genes / pathways	Typical clinical course	Current mechanism-aligned treatment
Infection-related GN (post-streptococcal GN; bacterial/viral/parasitic infection-associated GN)	Infection-triggered glomerular injury via immune-complex deposition, direct glomerular cell damage, molecular mimicry, and/or superantigen effects; control of infection is central (subtype-specific) (anders2023glomerulonephritisimmunopathogenesisand pages 1-2, casuscelli2023autoimmunityandinfection pages 1-2)	Kidney biopsy required for subtype distinction in many cases; immune-complex/complement-associated patterns may be seen; supportive serologies depend on trigger (for example antistreptolysin O/anti-DNase B in post-streptococcal disease) (anders2023glomerulonephritisimmunopathogenesisand pages 1-2, casuscelli2023autoimmunityandinfection pages 1-2)	Innate immunity, immune complexes, complement activation; immunopathogenesis-based GN framework classifies this separately from autoimmune GN (anders2023glomerulonephritisimmunopathogenesisand pages 1-2, casuscelli2023autoimmunityandinfection pages 1-2)	Often acute nephritic presentation with hematuria, proteinuria, hypertension; may be self-limited or progress depending on pathogen, host factors, and delay in treatment (anders2023glomerulonephritisimmunopathogenesisand pages 1-2, casuscelli2023autoimmunityandinfection pages 1-2)	Treat infection first; supportive nephritic care, then selective immunosuppression only when appropriate to subtype/severity (anders2023glomerulonephritisimmunopathogenesisand pages 1-2, casuscelli2023autoimmunityandinfection pages 1-2)
IgA nephropathy / IgA vasculitis nephritis	Mucosal immune dysregulation with aberrant IgA biology and nephritogenic immune-complex deposition; genetic and environmental factors both contribute (subtype-specific) (park2024glomerularspatialtranscriptomics pages 1-2, davies2024thecurrentuse pages 1-2)	Mesangial IgA-dominant deposition on biopsy; mesangial proliferation is both diagnostic and prognostic in IgAN; clinical presentation ranges from asymptomatic urinary abnormalities to acute GN (park2024glomerularspatialtranscriptomics pages 1-2)	Multi-hit IgA pathway; podocyte injury marker TCF21 upregulated in IgAN; vascular-development, adhesion, and extracellular-matrix programs enriched in proliferative IgAN; GWAS-informed susceptibility noted in recent reviews (park2024glomerularspatialtranscriptomics pages 1-2, davies2024thecurrentuse pages 1-2)	Usually chronic/indolent but heterogeneous; about ~20% of IgAN patients progress to ESKD in the cited 2024 study summary; IgA vasculitis nephritis tends to be more severe in adults (park2024glomerularspatialtranscriptomics pages 1-2)	Optimized supportive care first; corticosteroids in selected higher-risk disease; emerging mechanism-based agents include targeted-release budesonide, B-cell/APRIL-directed therapies, SGLT2 inhibitors, endothelin receptor antagonists, and complement inhibitors (subtype-specific, evidence strength varies) (park2024glomerularspatialtranscriptomics pages 1-2, davies2024thecurrentuse pages 1-2)
Lupus nephritis (LN)	Autoimmune GN driven by systemic lupus with autoantibodies, immune complexes, complement activation, and kidney-resident/immune-cell interactions (subtype-specific) (anders2023glomerulonephritisimmunopathogenesisand pages 1-2, roveta2024lupusnephritisfrom pages 1-2, reisneto2024iibraziliansociety pages 1-2)	Kidney biopsy is the gold standard; creatinine and urinalysis are baseline tests; class III/IV ± V classification guides therapy; serologies are subtype specific to SLE/LN (roveta2024lupusnephritisfrom pages 1-2, reisneto2024iibraziliansociety pages 1-2)	Autoantibodies, complement, inflammatory kidney-stroma/immune-cell crosstalk; biomarkers under development in serum/urine; ancestry-associated risk gradients noted in recent reviews (roveta2024lupusnephritisfrom pages 1-2, reisneto2024iibraziliansociety pages 1-2)	Relapsing-remitting or chronic progressive; occurs in up to 50% of adult SLE and 80% of juvenile-onset SLE; about 30% may progress to ESKD within 15 years in one 2024 consensus summary (reisneto2024iibraziliansociety pages 1-2)	Induction: MMF, cyclophosphamide, MMF+tacrolimus, or MMF+belimumab; maintenance: MMF or azathioprine first line; rituximab for refractory disease; newer targeted agents include voclosporin and belimumab, with additional complement/B-cell pathway trials ongoing (roveta2024lupusnephritisfrom pages 1-2, reisneto2024iibraziliansociety pages 1-2, lichtnekert2022lupusnephritiscurrent pages 14-15)
ANCA-associated pauci-immune GN	Autoimmune small-vessel vasculitis with pathogenic neutrophil-directed autoimmunity; severe crescentic GN phenotype is typical (subtype-specific) (anders2023glomerulonephritisimmunopathogenesisand pages 1-2, engesser2024immuneprofilingbasedtargeting pages 1-2)	Pauci-immune necrotizing/crescentic GN on biopsy with supportive ANCA serology; histologic scores such as Berden, RRS, and MCCS help prognosis (engesser2024immuneprofilingbasedtargeting pages 1-2)	Th1/Th17/Tc1/Tc17 inflammatory programs; complement C5a axis is therapeutically relevant; spatial/single-cell data identified pathogenic cytokine-producing T cells (engesser2024immuneprofilingbasedtargeting pages 1-2)	Often rapidly progressive with AKI/RPGN; kidney failure risk remains substantial without prompt treatment (anders2023glomerulonephritisimmunopathogenesisand pages 1-2, engesser2024immuneprofilingbasedtargeting pages 1-2)	Standard therapy remains glucocorticoids plus cyclophosphamide and/or rituximab; avacopan aligns with C5a-pathway biology; exploratory precision approach: ustekinumab in 4 relapsing ANCA-GN patients showed improvement over 26 weeks (engesser2024immuneprofilingbasedtargeting pages 1-2)
Anti-GBM disease	Autoimmune GN caused by antibodies to the glomerular basement membrane; classic severe crescentic GN/RPGN subtype (anders2023glomerulonephritisimmunopathogenesisand pages 1-2)	Linear GBM-directed immunostaining on biopsy with circulating anti-GBM antibodies; biopsy remains central for confirmation and severity assessment (anders2023glomerulonephritisimmunopathogenesisand pages 1-2)	Autoantibody-mediated injury to glomerular filtration barrier; downstream crescent formation and necroinflammation (anders2023glomerulonephritisimmunopathogenesisand pages 1-2)	Typically acute, aggressive, rapidly progressive kidney failure; may include pulmonary involvement in Goodpasture spectrum (anders2023glomerulonephritisimmunopathogenesisand pages 1-2)	Rapid immunosuppression plus plasma exchange to remove pathogenic antibodies, alongside corticosteroids/cytotoxic therapy (anders2023glomerulonephritisimmunopathogenesisand pages 1-2)
C3 glomerulopathy / C3 glomerulonephritis	Autoinflammatory/complement-mediated GN from dysregulated alternative complement pathway (subtype-specific) (anders2023glomerulonephritisimmunopathogenesisand pages 1-2, OpenTargets Search: glomerulonephritis)	C3-dominant biopsy pattern distinguishes this complement-mediated class; complement serologies/genetic workup may support diagnosis (anders2023glomerulonephritisimmunopathogenesisand pages 1-2, OpenTargets Search: glomerulonephritis)	Strong disease-target associations include CFH, C3, CFHR5, CFB, CFHR1, CFI; complement dysregulation is the defining pathway (OpenTargets Search: glomerulonephritis)	Often chronic with recurrent/persistent hematuria-proteinuria and CKD progression; course is heterogeneous (anders2023glomerulonephritisimmunopathogenesisand pages 1-2, OpenTargets Search: glomerulonephritis)	Mechanism-aligned therapy focuses on complement inhibition and complement-directed trial enrollment; supportive CKD/proteinuria management remains important (anders2023glomerulonephritisimmunopathogenesisand pages 1-2, OpenTargets Search: glomerulonephritis)
Monoclonal gammopathy-related GN (for example MGRS-associated GN)	Nephrotoxic monoclonal immunoglobulin or light/heavy chain–related glomerular injury from plasma-cell or B-cell clone (subtype-specific) (anders2023glomerulonephritisimmunopathogenesisand pages 1-2)	Biopsy pattern varies by deposit type; identification of a pathogenic monoclonal protein/clone is central to classification (anders2023glomerulonephritisimmunopathogenesisand pages 1-2)	Monoclonal immunoglobulin-driven injury; clone biology rather than generic histology should drive treatment (anders2023glomerulonephritisimmunopathogenesisand pages 1-2)	Often chronic/progressive unless the responsible clone is controlled; renal phenotype depends on deposit composition and location (anders2023glomerulonephritisimmunopathogenesisand pages 1-2)	Clone-directed therapy: plasma-cell– or B-cell–targeted treatment rather than nonspecific GN immunosuppression alone (anders2023glomerulonephritisimmunopathogenesisand pages 1-2)
Alloimmune GN (transplant-related alloimmune glomerular injury)	Alloimmune responses to non-self renal antigens after transplantation; distinct from autoimmune GN (anders2023glomerulonephritisimmunopathogenesisand pages 1-2)	Diagnosis relies on biopsy plus transplant immunopathology context; antibody/complement staining patterns may support alloimmune injury (anders2023glomerulonephritisimmunopathogenesisand pages 1-2)	Adaptive alloimmunity, antigen presentation, antibody-mediated injury, complement activation (anders2023glomerulonephritisimmunopathogenesisand pages 1-2)	Variable; may be subacute or chronic and contribute to graft dysfunction/loss (anders2023glomerulonephritisimmunopathogenesisand pages 1-2)	Mechanism-aligned approach is suppression of adaptive immunity with transplant-directed immunosuppression optimization (anders2023glomerulonephritisimmunopathogenesisand pages 1-2)

Table: This table summarizes the major mechanistic glomerulonephritis classes and key subtype-specific features relevant to diagnosis, pathobiology, course, and treatment. It is useful as a compact knowledge-base scaffold because GN is heterogeneous and treatment increasingly follows mechanism rather than histology alone.

1. Disease information

Definition and identifiers

Preferred name: glomerulonephritis.
Synonyms: GN; glomerular nephritis; nephritic glomerular disease. “Nephritis” is broader and should not be treated as an exact synonym because it includes tubulointerstitial disease.
MONDO: MONDO:0002462. Subtype examples include C3 glomerulonephritis, MONDO:0013892; primary membranoproliferative GN, MONDO:0018904; and immunoglobulin-mediated MPGN, MONDO:0014005. (OpenTargets Search: glomerulonephritis)
MeSH: Glomerulonephritis; individual forms have additional descriptors.
ICD-10-CM: GN is distributed across N00–N08 according to acute/chronic status and morphologic lesion; rapidly progressive nephritic syndrome is N01 and unspecified nephritic syndrome N05. A single ICD code should not replace subtype coding.
ICD-11: classified within glomerular diseases according to clinical/pathologic subtype.
OMIM/Orphanet: no single syndrome-wide entry is biologically adequate. Entries apply to specific inherited forms, such as complement-mediated disease or CFHR5 nephropathy.

The report synthesizes aggregated disease-level resources, published cohorts, biopsies, trials, and model studies. It contains no individual EHR-level patient data. A recent expert definition states that GN comprises “heterogeneous immune-mediated disorders characterized by inflammation of the filtration units of the kidney.” (anders2023glomerulonephritisimmunopathogenesisand pages 1-2)

2. Etiology, risks, protective factors, and gene–environment interaction

Causal classes

Autoimmune: ANCA-associated GN, anti-GBM disease, lupus nephritis (LN), IgA nephropathy (IgAN), and IgA vasculitis nephritis.
Infection-related: post-streptococcal and infection-associated GN linked to bacterial, viral, fungal, or parasitic disease. Mechanisms include immune-complex deposition, direct cellular damage, molecular mimicry, and superantigens. (casuscelli2023autoimmunityandinfection pages 1-2)
Complement/autoinflammatory: C3 glomerulopathy caused by alternative-pathway dysregulation.
Monoclonal gammopathy-related: nephrotoxic monoclonal immunoglobulin produced by a B-cell or plasma-cell clone.
Alloimmune: glomerular injury in a transplanted kidney.
Secondary immune-complex disease: chronic infection, autoimmune disease, malignancy, drugs, or systemic inflammatory disease.

Genetic susceptibility

There is no universal GN gene. High-confidence subtype-specific associations include CFH, C3, CFHR5, CFB, CFHR1, CFI, CFHR2, and occasionally DGKE in complement-mediated/MPGN phenotypes. OpenTargets ranks CFH, DGKE, and CFHR5 among the strongest GN associations and links these findings to published and expert-panel evidence. (OpenTargets Search: glomerulonephritis)

Other important susceptibility relationships include HLA loci in autoimmune GN, PLA2R1 in membranous nephropathy, and APOL1 G1/G2 risk genotypes—especially in people with recent African ancestry—as modifiers of FSGS-pattern disease and adverse kidney outcomes rather than causes of all GN. African biopsy data show marked geographic heterogeneity and identify APOL1 risk variants as a plausible contributor to the high FSGS burden. (ekrikpo2023prevalenceanddistribution pages 1-3)

Variant interpretation: complement-gene variants may be pathogenic, likely pathogenic, or VUS under ACMG/AMP criteria; interpretation requires phenotype, segregation, functional complement studies, and population frequency. Most causal variants are germline and rare. CFHR rearrangements may be copy-number/structural variants; CFH/C3/CFB variants can be missense or loss-/gain-of-function depending on the gene and allele. Somatic variants are not a routine cause of GN, although an acquired hematologic clone can cause monoclonal gammopathy-related GN. Chromosomal aneuploidy, karyotyping, FISH, mitochondrial testing, and repeat-expansion testing are not routine syndrome-level tests.

Environmental and host risk factors

Risk depends on subtype: infection exposure; autoimmune predisposition; older age and frailty; ancestry; systemic lupus; chronic liver or gastrointestinal disease; malignancy; smoking; obesity; hypertension; and nephrotoxic or immune-modulating drugs can contribute. Infection and GN are bidirectional: pathogens can trigger GN, whereas urinary immunoglobulin loss and immunosuppressive treatment increase subsequent infection risk. Post-streptococcal disease peaks at approximately ages 3–12 and has male predominance. (casuscelli2023autoimmunityandinfection pages 1-2)

Gene–environment paradigm: inherited complement dysregulation may remain clinically silent until infection activates complement; mucosal infection or microbiome perturbation can amplify production of nephritogenic IgA in genetically susceptible IgAN; inflammatory interferon states can interact with APOL1 high-risk genotypes. This is probabilistic, not simple Mendelian causation.

Protective factors

No broadly validated genetic protective allele prevents GN. Practical protective factors are subtype-specific: vaccination and prompt infection treatment; avoidance of tobacco, obesity, excessive sodium, and nephrotoxins; blood-pressure and proteinuria control; disease control before pregnancy; and adherence to maintenance therapy. Evidence is strongest for preventing progression and complications, not for preventing every incident GN case.

3. Phenotypes

Phenotype	Type and characteristics	Suggested HPO term
Microscopic or gross hematuria	Laboratory/sign; often episodic in IgAN and persistent in active proliferative GN	HP:0000790 Hematuria
Proteinuria	Laboratory abnormality; mild to nephrotic-range; major prognostic and response marker	HP:0000093 Proteinuria
Reduced GFR/AKI	Laboratory/functional; abrupt in RPGN or progressive in chronic GN	HP:0001919 Acute kidney injury, HP:0012622 Chronic kidney disease
Hypertension	Clinical sign; common in acute nephritic and chronic disease	HP:0000822 Hypertension
Edema	Physical sign; periorbital/peripheral to generalized	HP:0000969 Edema
Oliguria	Symptom/sign in severe acute disease	HP:0100520 Oliguria
Hypoalbuminemia/hyperlipidemia	Laboratory abnormalities in nephrotic overlap	HP:0003073 Hypoalbuminemia, HP:0003124 Hypercholesterolemia
Glomerular crescents	Histopathologic manifestation of severe capillary-wall injury	HP:0031263 Crescentic glomerulonephritis
Kidney failure	Advanced outcome requiring dialysis/transplantation	HP:0003774 End-stage renal disease

Acute GN commonly combines hypertension, hematuria, and proteinuria. IgAN ranges from asymptomatic urinary abnormalities to acute GN; approximately 20% progressed to ESKD in the population summarized by a 2024 spatial-transcriptomic study. (anders2023glomerulonephritisimmunopathogenesisand pages 1-2, park2024glomerularspatialtranscriptomics pages 1-2)

Age, severity, and frequency vary sharply by subtype: post-infectious GN is common in children; IgAN often begins in adolescence or early/middle adulthood; LN is concentrated in patients with SLE and may be especially frequent in juvenile-onset disease; ANCA-GN is predominantly adult/older-adult; genetic complement disease can begin in childhood or adulthood. Symptoms can be episodic, relapsing-remitting, rapidly progressive, or chronically progressive.

Quality of life: fatigue, edema, dietary restrictions, medication toxicity, recurrent admissions, dialysis, infertility concerns, and infection anxiety impair physical, social, and occupational functioning. GN-specific EQ-5D/SF-36 estimates cannot be generalized across subtypes; these should be captured with CKD- and disease-specific patient-reported outcome instruments.

4. Genetic, molecular, and epigenetic information

GN is usually multifactorial/polygenic, except for defined monogenic complement or structural disorders. Complement-associated genes should be stored as subtype-level causal/modifier genes: CFH, CFI, CFB, C3, CFHR1–5, DGKE. PLA2R1 is principally a susceptibility/antigen-related locus in membranous nephropathy, and MS4A1/CD20, NR3C1, TNFSF13B/BAFF, and complement genes are therapeutic targets rather than necessarily causal genes. (OpenTargets Search: glomerulonephritis)

For knowledge-base ingestion:

Record exact HGVS variants only from ClinVar/ClinGen or a diagnostic report; do not infer a pathogenic variant from a gene association.
Record germline inheritance by specific disorder—AD, AR, or complex susceptibility may all occur in complement disease. Penetrance is often incomplete and trigger-dependent; expressivity is variable.
Founder effects are established for some subtype/population-specific alleles, including CFHR5 nephropathy and APOL1 risk haplotypes, but there is no syndrome-wide carrier frequency.
Genetic anticipation is not characteristic. Germline mosaicism is possible in principle but not a defining GN feature.
DNA methylation, chromatin accessibility, interferon-regulated transcription, and immune-cell epigenetic states are active research areas, not clinical diagnostic markers.

A 2024 IgAN spatial study found 77 upregulated and 55 downregulated genes in proliferative M1-IgAN versus controls; TCF21 was consistently increased as an early podocyte-injury marker, while adhesion, vascular-development, and extracellular-matrix programs were enriched. (park2024glomerularspatialtranscriptomics pages 1-2)

5. Environmental and infectious information

Relevant agents include group A streptococci, Staphylococcus aureus, infective-endocarditis pathogens, hepatitis B and C viruses, HIV, SARS-CoV-2, and selected parasites. Pathogen attribution requires clinical microbiology and subtype-specific evidence; detection of an organism alone does not prove causation. Infection can act through circulating immune complexes, planted antigens, complement activation, molecular mimicry, or superantigens. (casuscelli2023autoimmunityandinfection pages 1-2)

Drug-related or exposure-related glomerular injury can follow immune-checkpoint inhibitors, anti-TNF agents, selected antibiotics, hydralazine, propylthiouracil, levamisole-adulterated cocaine, and other agents, depending on phenotype. Smoking and air pollution are plausible inflammatory/vascular modifiers but not established universal causes. High sodium intake, obesity, and poor blood-pressure control principally accelerate progression.

6. Mechanism and pathophysiology

Causal chain

Trigger or loss of tolerance → antibody/immune-complex, complement, clone, or T-cell activation → deposition or in-situ glomerular binding → endothelial, mesangial, GBM, and podocyte injury → leukocyte recruitment and capillary-wall rupture → hematuria/proteinuria and reduced filtration → parietal epithelial-cell proliferation/crescents → extracellular-matrix deposition, glomerulosclerosis, tubulointerstitial fibrosis, and CKD. (anders2023glomerulonephritisimmunopathogenesisand pages 1-2)

Upstream processes are antigen generation, mucosal immune dysregulation, autoantibody formation, complement dysregulation, and clone formation. Downstream processes include cytokine release, oxidative injury, necrosis, crescent formation, podocyte loss, maladaptive repair, and fibrosis. Effector Th1/Th17 and CD8 T-cell responses are implicated in crescentic GN, while podocytes function both as filtration-barrier cells and immune-responsive cells. (linke2022pathogenictcellresponses pages 21-22)

Suggested GO biological processes: complement activation (GO:0006956), inflammatory response (GO:0006954), adaptive immune response (GO:0002250), immune-complex clearance (GO:0002434), leukocyte migration (GO:0050900), apoptotic process (GO:0006915), extracellular-matrix organization (GO:0030198), and tissue remodeling (GO:0048771).

Suggested Cell Ontology classes: podocyte (CL:0000653), glomerular endothelial cell, mesangial cell, parietal epithelial cell, macrophage (CL:0000235), neutrophil (CL:0000775), CD4 T cell (CL:0000624), CD8 T cell (CL:0000625), B cell (CL:0000236), and plasma cell (CL:0000786).

Molecular profiling and 2023–2024 advances

A 2024 systematic review included 27 omics studies and 1,818 participants: 18 proteomic and 9 metabolomic studies; samples were urine in 19 studies, blood in 4, and biopsy tissue in 6. Proposed signatures addressed diagnosis, phenotype, progression, and treatment response, but most remain unvalidated. The clinically important precedent is anti-PLA2R discovery in membranous nephropathy; candidate FSGS proteins include LAMP1 and ACSL4. The authors concluded that “further larger-scale research is required.” (davies2024thecurrentuse pages 1-2, davies2024thecurrentuse pages 13-15)

Spatial profiling of IgAN demonstrates molecular heterogeneity even among histologically similar glomeruli. In ANCA-GN, single-cell/spatial profiling of 34 patients identified cytokine-producing Th1/Th17 and cytotoxic T-cell niches and nominated IL-12/23 blockade as a therapeutic strategy. (park2024glomerularspatialtranscriptomics pages 1-2, engesser2024immuneprofilingbasedtargeting pages 1-2)

Metabolic changes include local hypoxia, oxidative stress, altered lipid handling, mitochondrial dysfunction, and increased matrix synthesis; these are generally downstream/shared CKD programs rather than diagnostic biochemical defects.

7. Anatomical structures affected

The primary organ is the kidney, usually bilaterally. The primary site is the renal glomerulus—capillary endothelium, glomerular basement membrane, mesangium, podocytes, slit diaphragm, and Bowman capsule/parietal epithelium. Secondary tubulointerstitial inflammation and fibrosis are major determinants of irreversible function loss. Suggested anatomy terms include UBERON:0002113 kidney, UBERON:0000074 renal glomerulus, and UBERON:0001229 renal tubule.

Relevant subcellular compartments include the podocyte actin cytoskeleton, slit diaphragm, GBM extracellular matrix, lysosome/endosome, mitochondrion, nucleus/chromatin, and complement-active extracellular space. Suggested GO cellular components include extracellular matrix (GO:0031012), basement membrane (GO:0005604), cell–cell junction (GO:0005911), mitochondrion (GO:0005739), lysosome (GO:0005764), and nucleus (GO:0005634).

Secondary organs depend on cause: lungs in anti-GBM disease and ANCA vasculitis; skin, joints, gut, and lungs in systemic vasculitis; cardiovascular system in hypertension/CKD; and multiple organs in SLE. GN is generally bilateral rather than lateralized.

8. Temporal development

Acute: infection-related GN and some immune-complex flares.
Rapidly progressive: ANCA, anti-GBM, and severe immune-complex crescentic GN; this is a treatment emergency.
Relapsing-remitting: LN, ANCA vasculitis, and some IgA/complement diseases.
Slowly progressive: IgAN, C3 glomerulopathy, and persistent immune-complex disease.
Self-limited: many childhood post-streptococcal cases, although adult/infection-associated cases can have poor outcomes.

Stages are best represented as active urinary/inflammatory disease, partial response, complete response/remission, relapse, chronic scarring/CKD, and kidney failure—not as a universal numbered GN staging system. The critical intervention window is before crescents and interstitial fibrosis become irreversible.

For LN, a 2024 consensus defines target renal response as stable/improved kidney function plus proteinuria reduction of 25% by 3 months, 50% by 6 months, and to <0.8 g/day by 12 months. (reisneto2024iibraziliansociety pages 1-2)

9. Inheritance and population epidemiology

There is no reliable global incidence for aggregate GN because biopsy policies, coding, age structure, infection burden, and subtype distribution differ. In one US Medicare cohort, up to 1.2% had GN; GN accounted for 18.7% of CKD in Germany and 30–36% of ESKD among US children/adolescents in the epidemiologic synthesis cited by Anders and colleagues. African American, Hispanic, Asian, and First Nations populations bear disproportionate burdens. (anders2023glomerulonephritisimmunopathogenesisand pages 1-2)

An African meta-analysis of 17 studies, 6,494 biopsy patients, and eight countries found pooled distributions of FSGS 26.1%, minimal-change disease 22.4%, membranous nephropathy 8.4%, MPGN 6.4%, mesangioproliferative GN 6.4%, post-infectious GN 2.6%, IgAN 2.6%, and crescentic GN 1.4%. Only four studies used the full light-microscopy/immunofluorescence/electron-microscopy combination, illustrating ascertainment bias. (ekrikpo2023prevalenceanddistribution pages 1-3)

LN affects approximately 40% of patients with SLE in a 2024 review and is more prevalent among Hispanic, African, and Asian than White populations. A separate 2024 consensus reports up to 50% of adult and 80% of juvenile-onset SLE patients. These differences reflect population and definition, not necessarily contradiction. (roveta2024lupusnephritisfrom pages 1-2, reisneto2024iibraziliansociety pages 1-2)

Most GN is multifactorial. Monogenic inheritance, penetrance, founder effect, consanguinity, carrier frequency, and cascade testing should be recorded only for a confirmed genetic subtype.

10. Diagnostics

Clinical work-up

Confirm glomerular injury: urinalysis and microscopy for dysmorphic erythrocytes/RBC casts; urine albumin- or protein-to-creatinine ratio; serum creatinine/eGFR, albumin, electrolytes, CBC, and blood pressure.
Define mechanism: C3/C4; ANA, anti-dsDNA; ANCA with PR3/MPO specificity; anti-GBM; hepatitis B/C and HIV testing; cultures when infection is possible; ASO/anti-DNase B when indicated; serum/urine electrophoresis, immunofixation, and free light chains; cryoglobulins; anti-PLA2R for membranous nephropathy.
Kidney biopsy: light microscopy, immunofluorescence, and electron microscopy. IF is essential for immunoglobulin, complement, light-chain, and linear-versus-granular pattern recognition. Clinical signs alone cannot reliably distinguish subtypes. (anders2023glomerulonephritisimmunopathogenesisand pages 1-2)
Imaging: renal ultrasound mainly assesses size, obstruction, anatomy, and biopsy safety; CT/MRI/PET are not primary GN diagnostic tests.

The 2024 biomarker review concludes that noninvasive biomarkers are increasingly useful, but biopsy still cannot generally be replaced. Anti-PLA2R is a real-world biomarker success; other urinary biomarkers and multi-analyte algorithms remain investigational. (davies2024thecurrentuse pages 13-15)

Histologic patterns and differential diagnosis

Distinguish immune-complex proliferative GN, pauci-immune necrotizing/crescentic GN, linear anti-GBM disease, C3-dominant GN, membranous disease, and monoclonal deposits. Important mimics include acute tubular injury, interstitial nephritis, diabetic kidney disease, hypertensive nephrosclerosis, thrombotic microangiopathy, hereditary Alport/COL4 disease, and podocytopathy.

Genetic testing

Use a phenotype-driven complement or glomerulopathy panel, escalating to WES/WGS when onset is pediatric/young, familial, syndromic, steroid-resistant, recurrent after transplant, or biopsy/serology suggests complement dysregulation. WGS is particularly useful for CFHR structural variants not captured by routine exome sequencing. CMA, karyotype, FISH, mtDNA, and repeat-expansion tests are not routine unless another phenotype indicates them.

Population screening is not recommended. Screen high-risk people with urinalysis, albuminuria, blood pressure, and creatinine; use cascade genetic testing only after a familial pathogenic variant is established.

11. Outcomes and prognosis

Outcome ranges from complete recovery to relapsing disease, CKD, ESKD, cardiovascular events, serious infection, and death. Prognosis is driven by baseline eGFR/creatinine, proteinuria, hypertension, age, speed of treatment, normal-glomerulus fraction, crescents/necrosis, and chronicity/interstitial fibrosis.

In a 2024 ANCA-GN cohort of 152 adults, median age was 63.8 years and follow-up 46.9 months; 59 (38.8%) reached ESKD/eGFR <15 and 20 died. Hypertension, creatinine, and percentage of normal glomeruli independently predicted ESKD; Renal Risk Score and Mayo Chronicity Score remained independently predictive. (engesser2024immuneprofilingbasedtargeting pages 1-2)

For LN, one 2024 consensus estimates that 30% progress to ESKD within 15 years, underscoring the importance of early proteinuria response and prevention of flares. (reisneto2024iibraziliansociety pages 1-2)

Nephrotic overlap adds thromboembolism, infection, malnutrition, dyslipidemia, and cardiovascular risk; membranous nephropathy has particularly high thrombosis risk. (wendt2024anupdatedcomprehensive pages 1-2)

No syndrome-wide 5- or 10-year survival estimate is meaningful. Quality-of-life and mortality analyses should be stratified by subtype, CKD stage, dialysis/transplant status, age, and immunosuppressive exposure.

12. Treatment and real-world implementation

General strategy

Treat the cause rather than the biopsy label alone.
Control blood pressure and proteinuria with ACE inhibitor/ARB where tolerated; consider SGLT2 inhibition in proteinuric CKD according to kidney function and indication.
Restrict excess sodium, manage edema with diuretics, avoid nephrotoxins, treat dyslipidemia and cardiovascular risk, and adjust drug doses to GFR.
Use glucocorticoids and immunosuppression only when mechanism and activity justify infection/toxicity risk.

Subtype-directed therapy

Infection-related GN: eradicate infection and provide supportive care; indiscriminate immunosuppression can be harmful.
ANCA-GN: glucocorticoid-sparing induction with rituximab or cyclophosphamide; avacopan targets C5a receptor biology; maintenance commonly uses rituximab or other guideline-directed therapy.
Anti-GBM: urgent plasma exchange plus glucocorticoid and cyclophosphamide-based immunosuppression when recovery is plausible.
LN class III/IV ± V: MMF, cyclophosphamide, MMF+tacrolimus, or MMF+belimumab for induction; MMF or azathioprine for maintenance; rituximab for refractory disease. Voclosporin and belimumab are major recent additions. (roveta2024lupusnephritisfrom pages 1-2, reisneto2024iibraziliansociety pages 1-2)
IgAN: optimized supportive care; selected high-risk patients may receive targeted-release budesonide or carefully selected glucocorticoid therapy. Emerging targets include APRIL/BAFF, complement, endothelin, and B/plasma cells.
C3 glomerulopathy: supportive therapy and complement-pathway-directed therapy/trials after excluding infection and monoclonal gammopathy.
Monoclonal gammopathy-related GN: B-cell- or plasma-cell clone-directed therapy.

Suggested NCIt intervention concepts include corticosteroid therapy, immunosuppressive therapy, rituximab therapy, cyclophosphamide therapy, mycophenolate therapy, plasma exchange, complement-inhibitor therapy, dialysis, and kidney transplantation. Chemical annotations may include glucocorticoids, cyclophosphamide, mycophenolate mofetil, rituximab, belimumab, voclosporin, avacopan, ACE inhibitors, ARBs, and SGLT2 inhibitors; exact CHEBI identifiers should be resolved against the current ontology release.

Experimental and precision therapies

A 2024 proof-of-concept study used spatial/single-cell data to nominate ustekinumab. Four relapsing ANCA-GN patients received 90 mg subcutaneously at weeks 0, 4, 12, and 24 with low-dose cyclophosphamide/steroids; all improved clinically over 26 weeks. This is promising but uncontrolled and far too small to establish efficacy. (engesser2024immuneprofilingbasedtargeting pages 1-2)

Current-development examples include NCT06277427 (BCMA CAR-T in refractory ANCA vasculitis/LN; recruiting, n=24), NCT06419205 (phase 2 ADX-097 in IgAN/LN/C3G; recruiting, n=30), NCT05732402 (povetacicept in autoantibody-associated glomerular disease; phase 1/2, n=72), and NCT05083364 (ARO-C3; completed phase 1/2, n=62). Trial availability and status should be verified at https://clinicaltrials.gov before use.

No established syndrome-wide pharmacogenomic dosing guideline exists. Genotype primarily informs disease mechanism and transplant recurrence risk rather than routine drug metabolism.

13. Prevention

Primary: vaccination; sanitation and infection control; prompt treatment of streptococcal/endovascular infections; avoidance of cocaine/levamisole and causative drugs; smoking cessation; healthy weight and blood-pressure control. Vaccination does not prevent autoimmune GN generally but reduces infection triggers and treatment complications.
Secondary: urinalysis, albuminuria, creatinine/eGFR, and blood pressure in SLE, systemic vasculitis, chronic infection, monoclonal gammopathy, or genetically at-risk relatives. All SLE patients should undergo creatinine and urinalysis screening for renal involvement. (reisneto2024iibraziliansociety pages 1-2)
Tertiary: proteinuria/BP control, relapse monitoring, vaccination before immunosuppression where possible, Pneumocystis prophylaxis when indicated, bone and gastric protection, fertility preservation counseling, thrombosis-risk assessment, and CKD cardiovascular care.
Genetic counseling: appropriate for confirmed complement or other monogenic disease; discuss incomplete penetrance, variable expressivity, donor selection, recurrence after transplantation, and reproductive options.

There is no population newborn-screening program or prophylactic medication appropriate for GN as a whole.

14. Other species and natural disease

Naturally occurring immune-complex and infectious GN occurs in dogs, cats, horses, livestock, and wildlife, but veterinary nomenclature and prevalence are species- and cause-specific. Dogs develop immune-complex GN associated with chronic infection, neoplasia, and systemic inflammatory disease; breed-associated hereditary glomerulopathies more often model structural GBM or podocyte disorders than aggregate human GN. No single VBO breed term or cross-species transmission model applies.

GN itself is not zoonotically transmitted. A zoonotic or vector-borne pathogen can infect humans and animals and independently trigger immune renal injury, but the glomerular lesion is a host response rather than a transmissible phenotype. Orthologs of complement, immunoglobulin, cytokine, and GBM genes are highly conserved across mammals.

15. Model organisms and experimental systems

Nephrotoxic-serum/nephrotoxic-nephritis mice: rapid antibody-mediated crescentic GN; useful for complement, neutrophil, macrophage, Th1/Th17, crescent, and fibrosis studies. Limitation: artificial immunization and compressed time course.
Lupus-prone mice: MRL/lpr, NZB/W F1, and related strains reproduce autoantibodies, immune-complex GN, proteinuria, and aspects of systemic autoimmunity. Strain-specific biology and treatment responses limit direct translation.
IgAN models: grouped ddY, humanized/transgenic and immunization models reproduce parts of aberrant IgA production, immune-complex deposition, and mesangial injury. Only primates produce the human IgA1 subclass, so no mouse model captures the entire human multi-hit pathway.
Anti-GBM/ANCA models: antibody-transfer and antigen-immunization models isolate autoantibody, neutrophil, and complement effects but incompletely reproduce spontaneous human loss of tolerance.
In vitro systems: cultured podocytes, glomerular endothelial and mesangial cells, kidney organoids, glomerulus-on-chip systems, and patient-derived cells support mechanistic and drug studies but lack complete circulation and immunity.

A recent model review emphasizes that rodents remain dominant because genetically modified strains are available, while organoids, kidney-on-chip, zebrafish, and larger animals are emerging. Model selection must match the mechanistic question; there is no universally faithful “GN model.”

Evidence interpretation and key authoritative conclusions

The strongest current expert position is that histology remains indispensable but should be integrated with mechanism. Anders and colleagues argue that lesion patterns “do not align well with their diverse pathological mechanisms” and propose treatment according to immunopathogenesis. (anders2023glomerulonephritisimmunopathogenesisand pages 1-2)

Recent technologies support this transition but are not yet replacements for conventional care. The 2024 biomarker literature concludes that biopsy “still cannot be replaced by non-invasive strategies,” while the proteomic/metabolomic review found promising markers but emphasized the need for larger validation studies. (davies2024thecurrentuse pages 1-2, davies2024thecurrentuse pages 13-15)

Selected recent sources

Anders H-J et al. Glomerulonephritis: immunopathogenesis and immunotherapy. Nature Reviews Immunology. Published January 2023. DOI/URL: https://doi.org/10.1038/s41577-022-00816-y. (anders2023glomerulonephritisimmunopathogenesisand pages 1-2)
Park S et al. Glomerular spatial transcriptomics of IgA nephropathy according to mesangial proliferation. Scientific Reports. Published January 2024. https://doi.org/10.1038/s41598-024-52581-8. (park2024glomerularspatialtranscriptomics pages 1-2)
Davies E et al. The current use of proteomics and metabolomics in glomerulonephritis. Journal of Nephrology. Published April 2024. https://doi.org/10.1007/s40620-024-01923-w. (davies2024thecurrentuse pages 1-2)
Engesser J et al. Immune profiling-based targeting of pathogenic T cells with ustekinumab in ANCA-associated GN. Nature Communications. Published September 2024. https://doi.org/10.1038/s41467-024-52525-w. (engesser2024immuneprofilingbasedtargeting pages 1-2)
dos Reis-Neto ET et al. II Brazilian Society of Rheumatology consensus for lupus nephritis. Advances in Rheumatology. Published June 2024. https://doi.org/10.1186/s42358-024-00386-8. (reisneto2024iibraziliansociety pages 1-2)
Roveta A et al. Lupus nephritis from pathogenesis to new therapies. International Journal of Molecular Sciences. Published August 2024. https://doi.org/10.3390/ijms25168981. (roveta2024lupusnephritisfrom pages 1-2)
Ekrikpo UE et al. Primary glomerular diseases in Africa: systematic review and meta-analysis. Pan African Medical Journal. Published August 2023. https://doi.org/10.11604/pamj.2023.45.153.40741. (ekrikpo2023prevalenceanddistribution pages 1-3)

Knowledge-base recommendation: represent “glomerulonephritis” as a parent syndrome and attach genes, variants, epidemiology, biomarkers, prognosis, treatments, inheritance, and models to mechanistically and histopathologically defined child entities. This avoids false syndrome-wide assertions and reflects current expert understanding.

References

(anders2023glomerulonephritisimmunopathogenesisand pages 1-2): Hans-Joachim Anders, A. Richard Kitching, Nelson Leung, and Paola Romagnani. Glomerulonephritis: immunopathogenesis and immunotherapy. Nature Reviews. Immunology, 23:1-19, Jan 2023. URL: https://doi.org/10.1038/s41577-022-00816-y, doi:10.1038/s41577-022-00816-y. This article has 247 citations.
(casuscelli2023autoimmunityandinfection pages 1-2): Chiara Casuscelli, Elisa Longhitano, Veronica Maressa, Silvia Di Carlo, Luigi Peritore, Simone Di Lorenzo, Vincenzo Calabrese, Valeria Cernaro, and Domenico Santoro. Autoimmunity and infection in glomerular disease. Microorganisms, 11:2227, Sep 2023. URL: https://doi.org/10.3390/microorganisms11092227, doi:10.3390/microorganisms11092227. This article has 14 citations.
(park2024glomerularspatialtranscriptomics pages 1-2): Sehoon Park, Minji Kang, Yong Chul Kim, Dong Ki Kim, Kook-Hwan Oh, Kwon Wook Joo, Yon Su Kim, Hyun Je Kim, Kyung Chul Moon, and Hajeong Lee. Glomerular spatial transcriptomics of iga nephropathy according to the presence of mesangial proliferation. Scientific Reports, Jan 2024. URL: https://doi.org/10.1038/s41598-024-52581-8, doi:10.1038/s41598-024-52581-8. This article has 12 citations and is from a peer-reviewed journal.
(davies2024thecurrentuse pages 1-2): Elin Davies, Andrew Chetwynd, Garry McDowell, Anirudh Rao, and Louise Oni. The current use of proteomics and metabolomics in glomerulonephritis: a systematic literature review. Journal of Nephrology, 37:1209-1225, Apr 2024. URL: https://doi.org/10.1007/s40620-024-01923-w, doi:10.1007/s40620-024-01923-w. This article has 12 citations and is from a peer-reviewed journal.
(roveta2024lupusnephritisfrom pages 1-2): Annalisa Roveta, Emanuele Luigi Parodi, Brigida Brezzi, Francesca Tunesi, Valentina Zanetti, Guido Merlotti, Alessia Francese, Antonio G. Maconi, and Marco Quaglia. Lupus nephritis from pathogenesis to new therapies: an update. International Journal of Molecular Sciences, 25:8981, Aug 2024. URL: https://doi.org/10.3390/ijms25168981, doi:10.3390/ijms25168981. This article has 103 citations.
(reisneto2024iibraziliansociety pages 1-2): Edgard Torres dos Reis-Neto, Luciana Parente Costa Seguro, Emília Inoue Sato, Eduardo Ferreira Borba, Evandro Mendes Klumb, Lilian Tereza Lavras Costallat, Marta Maria das Chagas Medeiros, Eloisa Bonfá, Nafice Costa Araújo, Simone Appenzeller, Ana Carolina de Oliveira e Silva Montandon, Emily Figueiredo Neves Yuki, Roberto Cordeiro de Andrade Teixeira, Rosa Weiss Telles, Danielle Christinne Soares do Egypto, Francinne Machado Ribeiro, Andrese Aline Gasparin, Antonio Silaide de Araujo Junior, Cláudia Lopes Santoro Neiva, Debora Cerqueira Calderaro, and Odirlei Andre Monticielo. Ii brazilian society of rheumatology consensus for lupus nephritis diagnosis and treatment. Advances in Rheumatology, 64:1-25, Jun 2024. URL: https://doi.org/10.1186/s42358-024-00386-8, doi:10.1186/s42358-024-00386-8. This article has 22 citations.
(lichtnekert2022lupusnephritiscurrent pages 14-15): Julia Lichtnekert, Hans-Joachim Anders, and Maciej Lech. Lupus nephritis: current perspectives and moving forward. Journal of Inflammation Research, 15:6533-6552, Dec 2022. URL: https://doi.org/10.2147/jir.s363722, doi:10.2147/jir.s363722. This article has 32 citations and is from a peer-reviewed journal.
(engesser2024immuneprofilingbasedtargeting pages 1-2): Jonas Engesser, Robin Khatri, Darius Schaub, Yu Zhao, Hans-Joachim Paust, Zeba Sultana, Nariaki Asada, Jan-Hendrik Riedel, Varshi Sivayoganathan, Anett Peters, Anna Kaffke, Saskia-Larissa Jauch-Speer, Thiago Goldbeck-Strieder, Victor G. Puelles, Ulrich O. Wenzel, Oliver M. Steinmetz, Elion Hoxha, Jan-Eric Turner, Hans-Willi Mittrücker, Thorsten Wiech, Tobias B. Huber, Stefan Bonn, Christian F. Krebs, and Ulf Panzer. Immune profiling-based targeting of pathogenic t cells with ustekinumab in anca-associated glomerulonephritis. Nature Communications, Sep 2024. URL: https://doi.org/10.1038/s41467-024-52525-w, doi:10.1038/s41467-024-52525-w. This article has 50 citations and is from a highest quality peer-reviewed journal.
(OpenTargets Search: glomerulonephritis): Open Targets Query (glomerulonephritis, 26 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(ekrikpo2023prevalenceanddistribution pages 1-3): Udeme Ekpenyong Ekrikpo, Patience Ngozi Obiagwu, Aniema Isaac Udo, Ijezie Innocent Chukwuonye, Jean Jacques Noubiap, Ugochi Sophia Okpechi-Samuel, Udeme-Abasi Nelson Udoudo, Elliot Korateng Tannor, Stanley Chidozie Ngoka, Ikechukwu Okeke Mbah, Aminu Kasarawa Bello, and Ikechi Gareth Okpechi. Prevalence and distribution of primary glomerular diseases in africa: a systematic review and meta-analysis of observational studies. The Pan African Medical Journal, Aug 2023. URL: https://doi.org/10.11604/pamj.2023.45.153.40741, doi:10.11604/pamj.2023.45.153.40741. This article has 10 citations.
(linke2022pathogenictcellresponses pages 21-22): Alexandra Linke, Gisa Tiegs, and Katrin Neumann. Pathogenic t-cell responses in immune-mediated glomerulonephritis. Cells, 11:1625, May 2022. URL: https://doi.org/10.3390/cells11101625, doi:10.3390/cells11101625. This article has 53 citations.
(davies2024thecurrentuse pages 13-15): Elin Davies, Andrew Chetwynd, Garry McDowell, Anirudh Rao, and Louise Oni. The current use of proteomics and metabolomics in glomerulonephritis: a systematic literature review. Journal of Nephrology, 37:1209-1225, Apr 2024. URL: https://doi.org/10.1007/s40620-024-01923-w, doi:10.1007/s40620-024-01923-w. This article has 12 citations and is from a peer-reviewed journal.
(wendt2024anupdatedcomprehensive pages 1-2): R. Wendt, Alina Sobhani, P. Diefenhardt, Moritz Trappe, and Linus Alexander Völker. An updated comprehensive review on diseases associated with nephrotic syndromes. Biomedicines, Oct 2024. URL: https://doi.org/10.3390/biomedicines12102259, doi:10.3390/biomedicines12102259. This article has 25 citations.

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Glomerulonephritis: comprehensive disease-characteristics report

Executive summary and scope

1. Disease information

Definition and identifiers

2. Etiology, risks, protective factors, and gene–environment interaction

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Environmental and host risk factors

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4. Genetic, molecular, and epigenetic information

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7. Anatomical structures affected

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