IgA Nephropathy

Autoimmune MONDO:0005342 Pathograph 23 Autoimmune Disease Kidney Disease

IgA nephropathy (IgAN) is a kidney-limited immune-complex glomerulonephritis defined by mesangial deposition of galactose-deficient IgA1-containing immune complexes with complement co-deposition. Its core mechanism follows the four-hit model: mucosal immune dysregulation drives overproduction of galactose-deficient IgA1, anti-glycan autoantibodies form nephritogenic immune complexes, and these complexes deposit in the mesangium where they trigger complement activation, mesangial proliferation, podocyte injury, and progressive chronic kidney damage.

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Definitions

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Inheritance

Pathophysiology

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Trials

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Models

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Classifications

Harrison's Chapter

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Mappings

MONDO

MONDO:0005342 IgA glomerulonephritis

Current MONDO term for kidney-limited primary IgA nephropathy / IgA glomerulonephritis.

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References

15

DOI:10.3389/fneph.2023.1346769

The role of BAFF and APRIL in IgA nephropathy: pathogenic mechanisms and targeted therapies

No top-level findings curated for this source.

DOI:10.3389/fimmu.2024.1436923

Contemporary review of IgA nephropathy

No top-level findings curated for this source.

DOI:10.1093/glycob/cwae060

O-glycosylation of IgA1 and the pathogenesis of an autoimmune disease IgA nephropathy

No top-level findings curated for this source.

DOI:10.1093/ckj/sfaf152

Recent advances in pathogenetic concepts and disease modeling of IgA nephropathy

No top-level findings curated for this source.

DOI:10.1093/ckj/sfad198

Targeting complement in IgA nephropathy

No top-level findings curated for this source.

DOI:10.1016/j.kint.2023.10.012

A new alternative: inhibiting complement activation in patients with IgA nephropathy

No top-level findings curated for this source.

DOI:10.1007/s40620-022-01363-4

Predictive prognostic value of glomerular C3 deposition in IgA nephropathy

No top-level findings curated for this source.

DOI:10.1038/s41598-024-65857-w

Role of serum complement C3 and C4 on kidney outcomes in IgA nephropathy

No top-level findings curated for this source.

DOI:10.1186/s12882-024-03512-2

Validation of IgA nephropathy diagnosis in the Swedish Renal Registry

No top-level findings curated for this source.

DOI:10.1038/ng.787

Genome-wide association study identifies susceptibility loci for IgA nephropathy

No top-level findings curated for this source.

DOI:10.1016/S0140-6736(23)00569-X

Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial

No top-level findings curated for this source.

DOI:10.1016/S0140-6736(23)01554-4

Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy (NefIgArd): 2-year results from a randomised phase 3 trial

No top-level findings curated for this source.

DOI:10.1016/j.kint.2021.03.033

A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy

No top-level findings curated for this source.

DOI:10.1001/jama.2022.5368

Effect of Oral Methylprednisolone on Decline in Kidney Function or Kidney Failure in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial

No top-level findings curated for this source.

DOI:10.1016/j.semnephrol.2025.151571

IgA Vasculitis and IgA Nephropathy: Two Sides of the Same Coin?

No top-level findings curated for this source.

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Pathophysiology

9

Mucosal B-cell hyper-responsiveness

Mucosal immune hyper-responsiveness in the upper airway and gut creates an exaggerated B-cell response to antigenic stimulation in susceptible hosts, establishing the upstream context for pathogenic IgA generation.

B cell link

HLA-DQB1 link

intestinal mucosa link palatine tonsil link

Show evidence (2 references)

PMID:38362118 SUPPORT Other

"This review explores the complex pathogenesis of IgAN, highlighting the pivotal roles of BAFF and APRIL in the interplay between mucosal hyper-responsiveness, B-cell activation, and the consequent overproduction of Gd-IgA1 and its autoantibodies that are key features in this disease."

Supports mucosal hyper-responsiveness as the upstream immunologic context that precedes the more specific BAFF/APRIL-dependent B-cell activation step.

PMID:40487370 SUPPORT Other

"This involves the identification of genetic risk factors in genome-wide association studies, the use of multi-omics approaches to integrate big data, the recognition of the importance of the gut-kidney axis, the role of plasma cells in the production of IgA and IgG, the potential specificity of..."

Independently supports the gut-kidney axis as an upstream component of IgAN pathogenesis.

BAFF/APRIL-driven B-cell activation and IgA class switching

BAFF and APRIL signaling sustain B-cell activation, plasma-cell survival, and IgA class switching, biasing the mucosal response toward pathogenic IgA production.

B cell link plasma cell link

TNFSF13 link TNFSF13B link

B cell activation link isotype switching link

Show evidence (2 references)

PMID:38362118 SUPPORT Other

"This review explores the complex pathogenesis of IgAN, highlighting the pivotal roles of BAFF and APRIL in the interplay between mucosal hyper-responsiveness, B-cell activation, and the consequent overproduction of Gd-IgA1 and its autoantibodies that are key features in this disease."

Supports BAFF/APRIL-dependent B-cell activation and class-switching as the immediate upstream driver of pathogenic IgA production.

PMID:40487370 SUPPORT Other

"This involves the identification of genetic risk factors in genome-wide association studies, the use of multi-omics approaches to integrate big data, the recognition of the importance of the gut-kidney axis, the role of plasma cells in the production of IgA and IgG, the potential specificity of..."

Independently supports plasma-cell-mediated immunoglobulin production as part of the activated mucosal B-cell program in IgAN.

Galactose-deficient IgA1 overproduction

IgA1-secreting cells produce hinge-region O-glycoforms lacking normal galactose residues, generating galactose-deficient IgA1 (Gd-IgA1), the key autoantigen in IgAN.

B cell link plasma cell link

C1GALT1 link

protein O-linked glycosylation link immunoglobulin production link

Show evidence (2 references)

PMID:39095059 SUPPORT Other

"These galactose-deficient IgA1 glycoforms are produced by IgA1-secreting cells due to a dysregulated expression and activity of several glycosyltransferases."

Direct support for dysregulated IgA1 O-glycosylation as the molecular origin of Gd-IgA1.

PMID:39124764 SUPPORT Other

"The pathogenesis of IgAN is considered a multifactorial process involving the formation of immune complexes wherein aberrantly O-glycosylated IgA1 is recognized as an autoantigen."

Confirms aberrantly O-glycosylated IgA1 as the central autoantigenic hit in IgAN.

Anti-Gd-IgA1 autoantibody production

Anti-glycan IgG and IgA autoantibodies are produced against circulating Gd-IgA1, establishing the second immunologic hit in the four-hit model.

B cell mediated immunity link immunoglobulin production link

Show evidence (1 reference)

PMID:22904352 SUPPORT Human Clinical

"Circulating autoantibodies that recognize such galactose-deficient IgA1 as an autoantigen, or the levels of the autoantigen itself, may allow prediction of disease progression."

Human cohort study showing that autoantibodies against Gd-IgA1 are a real circulating feature of IgAN and track with progression risk.

Nephritogenic immune complex assembly

Circulating Gd-IgA1 is bound by anti-glycan autoantibodies to form nephritogenic immune complexes that may also incorporate complement components.

Show evidence (1 reference)

PMID:39095059 SUPPORT Other

"Galactose-deficient IgA1 in the circulation of patients with IgA nephropathy is bound by IgG autoantibodies and the resultant immune complexes can contain additional proteins, such as complement C3."

Directly supports immune-complex assembly around Gd-IgA1 plus complement cargo.

Mesangial immune complex deposition and complement activation

Pathogenic immune complexes lodge in the glomerular mesangium, where they activate resident mesangial cells and engage alternative and lectin pathway complement cascades.

mesangial cell link

CFH link

complement activation, alternative pathway link complement activation, lectin pathway link

glomerular mesangium link renal glomerulus link

Show evidence (3 references)

PMID:39095059 SUPPORT Other

"These complexes, if not removed from the circulation, can enter the glomerular mesangium, activate the resident mesangial cells, and induce glomerular injury."

Direct support for mesangial deposition of pathogenic complexes as the bridge between circulating autoimmunity and local glomerular injury.

PMID:38053977 SUPPORT Other

"The alternative complement pathway is the major complement cascade activator in IgAN, and glomerular C3 deposition has been shown to correlate with disease progression."

Supports alternative pathway complement activation as a central amplifier of mesangial immune-complex injury.

PMID:38182298 SUPPORT Other

"Mesangial complement C3 deposits, reflecting alternative and possibly lectin pathway activation, are characteristic in biopsies of patients with IgA nephropathy (IgAN)."

Confirms that mesangial complement deposition in IgAN reflects alternative and lectin pathway activity rather than generic nonspecific inflammation.

Mesangial proliferation and inflammatory amplification

Activated mesangial cells proliferate and amplify local inflammation through inflammatory cell recruitment and matrix-active injury programs, extending the initial immune-complex lesion.

mesangial cell link macrophage link

cell population proliferation link leukocyte migration link

glomerular mesangium link renal glomerulus link

Show evidence (2 references)

PMID:39188719 SUPPORT Other

"Mesangial deposition of immune complexes containing galactose-deficient IgA1 complexed with anti-glycan IgG or IgA antibodies results in mesangial cell activation and proliferation, inflammatory cell recruitment, complement activation, and podocyte damage."

Review abstract directly lays out the mechanistic bridge from mesangial deposition to proliferation and inflammatory amplification.

PMID:35781866 PARTIAL Human Clinical

"With the increasing intensity of C3 deposition, patients present more hematuria, crescents, heavier interstitial inflammatory cell infiltration and a higher score on segmental sclerosis lesions."

Human biopsy cohort shows that stronger complement-rich lesions track with heavier inflammatory infiltrates and more destructive chronic pathology.

Podocyte damage and filtration barrier failure

Mesangial-centered immune injury extends to podocytes and the glomerular filtration barrier, producing the clinically dominant combination of hematuria and proteinuria.

podocyte link glomerular endothelial cell link

renal glomerulus link

Show evidence (2 references)

PMID:39188719 SUPPORT Other

"Mesangial deposition of immune complexes containing galactose-deficient IgA1 complexed with anti-glycan IgG or IgA antibodies results in mesangial cell activation and proliferation, inflammatory cell recruitment, complement activation, and podocyte damage."

Explicitly supports podocyte injury as a downstream consequence of the mesangial immune-complex lesion.

PMID:39124764 PARTIAL Other

"Consequently, the clinical presentation of IgAN is highly variable, with a wide spectrum of manifestations ranging from isolated microscopic hematuria or episodic macroscopic hematuria to nephrotic-range proteinuria."

Links glomerular filtration barrier injury to the signature renal manifestations of hematuria and proteinuria.

Chronic complement-linked progression and kidney failure risk

Persistent complement-associated glomerular injury is linked to segmental sclerosis, interstitial inflammation, lower eGFR, and progression to kidney failure in a substantial subset of patients.

extracellular matrix organization link

kidney link

Show evidence (3 references)

PMID:35781866 SUPPORT Human Clinical

"C3 deposition at the time of renal biopsy is likely an independent risk factor for IgA nephropathy severity and progression."

Supports a chronic complement-linked progression axis rather than a purely static diagnostic lesion.

PMID:39003309 SUPPORT Human Clinical

"Lower C3 and higher C4 levels were associated with poorer prognosis, highlighting a more 'Complement-Pathic' subset of patients."

Human cohort evidence that systemic complement readouts identify a subset with poorer kidney outcomes.

PMID:39188719 SUPPORT Other

"Perhaps 20%-50% of patients progress to kidney failure."

Supports the substantial long-term kidney failure risk that makes the late progression node clinically important.

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Histopathology

3

Mesangial IgA-dominant immune deposits

Diagnostic biopsy finding of mesangial IgA deposition.

Show evidence (1 reference)

PMID:38438966 SUPPORT Human Clinical

"Histological features of IgA deposits were seen in all patients"

Registry validation study confirms mesangial IgA deposition as the core biopsy lesion of IgAN.

Mesangial hypercellularity

Expanded mesangial cellularity consistent with the proliferative mesangial response.

Show evidence (1 reference)

PMID:38438966 SUPPORT Human Clinical

"hypercellularity in 102/132 (77.2%)"

Supports mesangial hypercellularity as a common histopathologic manifestation in biopsy-proven IgAN.

Mesangial C3 co-deposition

Frequent complement co-deposition accompanying IgA-containing mesangial deposits.

Show evidence (1 reference)

PMID:38438966 SUPPORT Human Clinical

"C3 deposits in 98/132 (72.4%)"

Supports frequent complement co-deposition on kidney biopsy in IgAN.

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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

4

Cardiovascular 1

Hypertension Hypertension (HP:0000822)

Common adverse clinical feature and risk stratifier.

Show evidence (1 reference)

PMID:39188719 PARTIAL Other

"Biomarkers predicting adverse outcomes include proteinuria, reduced GFR, hypertension, and pathology."

Supports hypertension as a clinically relevant feature tied to worse IgAN outcomes.

Genitourinary 3

Hematuria Hematuria (HP:0000790)

Microscopic or episodic macroscopic hematuria, often synpharyngitic.

Show evidence (1 reference)

PMID:39124764 SUPPORT Other

"Consequently, the clinical presentation of IgAN is highly variable, with a wide spectrum of manifestations ranging from isolated microscopic hematuria or episodic macroscopic hematuria to nephrotic-range proteinuria."

Supports hematuria as a core presenting manifestation of IgAN.

Proteinuria Proteinuria (HP:0000093)

Persistent proteinuria is a major progression biomarker and treatment target.

Sequelae: Renal Insufficiency

Show evidence (1 reference)

PMID:39124764 SUPPORT Other

"Consequently, the clinical presentation of IgAN is highly variable, with a wide spectrum of manifestations ranging from isolated microscopic hematuria or episodic macroscopic hematuria to nephrotic-range proteinuria."

Supports the characteristic proteinuric spectrum of IgAN.

Renal Insufficiency Renal insufficiency (HP:0000083)

Progressive loss of kidney function leads to kidney failure in a substantial subset of patients.

Show evidence (1 reference)

PMID:39188719 SUPPORT Other

"Perhaps 20%-50% of patients progress to kidney failure."

Supports clinically meaningful progression from IgAN to advanced kidney dysfunction.

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Genetic Associations

3

HLA-DQB1 (Susceptibility locus)

Show evidence (1 reference)

PMID:21399633 SUPPORT Human Clinical

"The strongest association in the combined cohort was located within a ~170 kb interval that includes the HLA-DRB1, -DQA1, and -DQB1 genes (rs9275596, OR = 0.63, p=1.6 × 10−26)."

Large trans-ancestry GWAS support the HLA-DRB1/DQA1/DQB1 region as the dominant common susceptibility signal in IgAN.

CFH region / CFHR1-CFHR3 protective haplotype (Protective complement-regulatory locus)

Show evidence (1 reference)

PMID:21399633 SUPPORT Human Clinical

"This allele perfectly tags a common deletion spanning the CFHR1 and CFHR3 genes (CFHR1,3Δ)22,23."

GWAS evidence supports a protective 1q32 complement-regulatory haplotype in IgAN, with the sentinel signal tagging the common CFHR1-CFHR3 deletion.

C1GALT1 (Susceptibility locus)

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Treatments

5

ACE inhibitors / ARBs

First-line supportive renin-angiotensin system blockade for proteinuric and/or hypertensive IgAN.

Target Phenotypes: Proteinuria ↗ Hypertension ↗

Show evidence (1 reference)

PMID:39188719 SUPPORT Other

"The mainstay of therapy is supportive, consisting of lifestyle modifications, renin-angiotensin inhibition (if hypertensive or proteinuric), sodium-glucose-transporter 2 inhibition (if GFR reduced or proteinuric), and endothelin-receptor antagonism (if proteinuric)."

Contemporary review supports that renin-angiotensin inhibition remains first-line supportive therapy in proteinuric and/or hypertensive IgAN.

SGLT2 inhibitors

Adjunct kidney-protective therapy that lowers CKD progression risk in proteinuric IgAN.

Target Phenotypes: Proteinuria ↗

Show evidence (1 reference)

PMID:33878338 SUPPORT Human Clinical

"Thus, in participants with IgA nephropathy, dapagliflozin reduced the risk of chronic kidney disease progression with a favorable safety profile."

Prespecified DAPA-CKD IgAN subgroup analysis provides direct human trial evidence supporting SGLT2 inhibition as kidney-protective adjunct therapy.

Corticosteroids

Considered in selected high-risk patients after maximal supportive care, with attention to infection and other toxicity risks.

Mechanism Target:

MODULATES Mesangial proliferation and inflammatory amplification — Broad immunosuppression is used in selected high-risk patients to blunt ongoing inflammatory renal injury.

Target Phenotypes: Proteinuria ↗

Show evidence (1 reference)

PMID:35579642 SUPPORT Human Clinical

"Among patients with IgA nephropathy at high risk of progression, treatment with oral methylprednisolone for 6 to 9 months, compared with placebo, significantly reduced the risk of the composite outcome of kidney function decline, kidney failure, or death due to kidney disease. However, the..."

TESTING provides direct randomized evidence for corticosteroid efficacy in high-risk IgAN while also justifying cautious, selective use because serious adverse events increased.

Sparsentan

Dual endothelin and angiotensin receptor antagonist used to lower persistent proteinuria in IgAN.

Target Phenotypes: Proteinuria ↗

Show evidence (1 reference)

PMID:37015244 SUPPORT Human Clinical

"Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy."

PROTECT interim analysis directly supports sparsentan as a proteinuria- lowering therapy in biopsy-proven IgAN.

Targeted-release budesonide

Gut-targeted corticosteroid strategy that reduces proteinuria and slows eGFR decline in high-risk primary IgAN.

Mechanism Target:

MODULATES Mucosal B-cell hyper-responsiveness — Gut-targeted corticosteroid delivery is intended to dampen pathogenic mucosal immune activation upstream of Gd-IgA1 generation.

Target Phenotypes: Proteinuria ↗

Show evidence (1 reference)

PMID:37591292 SUPPORT Human Clinical

"A 9-month treatment period with Nefecon provided a clinically relevant reduction in eGFR decline and a durable reduction in proteinuria versus placebo, providing support for a disease-modifying effect in patients with IgA nephropathy."

Phase 3 NefIgArd trial directly supports targeted-release budesonide as a mucosal-directed therapy that improves proteinuria and kidney-function trajectory in primary IgAN.

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Biochemical Markers

2

Galactose-deficient IgA1 (Elevated)

Context: Circulating autoantigen and biomarker in a substantial subset of patients.

Show evidence (1 reference)

PMID:22904352 SUPPORT Human Clinical

"Unlike healthy individuals, some IgA1 is galactose deficient in patients with IgAN, leaving terminal N-acetylgalactosamine residues in the hinge region exposed."

Supports elevated / aberrant circulating Gd-IgA1 as the defining biochemical abnormality of IgAN.

Serum complement profile (Variable)

Context: Lower C3 and higher C4 identify a complement-pathic subset with poorer prognosis.

Show evidence (1 reference)

PMID:39003309 SUPPORT Human Clinical

"Lower C3 and higher C4 levels were associated with poorer prognosis, highlighting a more 'Complement-Pathic' subset of patients."

Supports prognostically relevant complement biomarker variation in IgAN.

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Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from IgA Nephropathy:

IgA vasculitis Not Yet Curated MONDO:0019167

Overlapping Features Related systemic small-vessel vasculitis with shared Gd-IgA1 immune-complex biology and often indistinguishable kidney histology, but with characteristic extra-renal vasculitic manifestations that support separate representation.

Distinguishing Features

Palpable purpura and other systemic small-vessel vasculitis features favor IgA vasculitis over kidney-limited IgAN.
Kidney biopsy findings can be indistinguishable between IgAN and IgA vasculitis nephritis.
Chronic lesions such as segmental glomerulosclerosis and tubular atrophy / interstitial fibrosis are more frequent in delayed-diagnosis IgAN, whereas proliferative lesions and earlier diagnosis after rash are more typical of IgA vasculitis nephritis.

Show evidence (3 references)

PMID:40069065 PARTIAL Other

"IgA vasculitis (IgAV) is considered a systemic form of IgA nephropathy (IgAN)."

Supports the close mechanistic kinship between the two entities, which is why IgA vasculitis must be considered explicitly at the IgAN boundary.

PMID:40069065 SUPPORT Other

"On kidney biopsy, the two diseases are indistinguishable"

Confirms that the renal lesion alone does not reliably separate IgAN from IgA vasculitis nephritis.

PMID:40069065 SUPPORT Other

"Due to characteristic skin rash, IgAVN patients are diagnosed precociously."

Supports the key clinical split: systemic vasculitic manifestations, not renal histology alone, distinguish IgA vasculitis from kidney-limited IgAN.

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Literature Summaries

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Disorder ▸

Disorder

Name: IgA Nephropathy
Category: Autoimmune
Existing deep-research providers: falcon
Existing evidence reference count in YAML: 16

Key Pathophysiology Nodes

Galactose-Deficient IgA1 Production
Anti-Gd-IgA1 Autoantibody Formation
Mesangial Cell Activation and Proliferation
Deep research literature mapping

Citation Inventory (for evidence mapping)

DOI:10.1038/s41588-024-01802-x
DOI:10.1038/s41598-024-65857-w
DOI:10.1093/ckj/sfaf152
DOI:10.1093/glycob/cwae060
DOI:10.1186/s12882-024-03512-2
DOI:10.3389/fimmu.2024.1436923
DOI:10.3389/fneph.2023.1346769
DOI:10.3390/ijms251910340
DOI:10.5527/wjn.v13.i4.98709

Falcon ▸

Disease Pathophysiology Research Report

Edison Scientific Literature 19 citations 2025-12-18T09:55:18.289577

Disease Pathophysiology Research Report

Target Disease - Disease Name: IgA Nephropathy (IgAN) - MONDO ID: MONDO_0005049 (IgA glomerulonephritis; also referenced as EFO_0004194 in OpenTargets) - Category: Autoimmune, immune-complex glomerulonephritis

Executive Summary and Key Concepts IgA nephropathy is characterized by mesangial deposition of immune complexes containing galactose‑deficient IgA1 (Gd‑IgA1), antiglycan autoantibodies, and complement, leading to mesangioproliferative injury, downstream podocyte damage, tubulointerstitial inflammation, and progressive fibrosis. The current paradigm is a multi‑hit model: (1) overproduction of circulating polymeric Gd‑IgA1, (2) formation of anti‑glycan IgG/IgA autoantibodies, (3) immune‑complex assembly and persistence in circulation, and (4) mesangial deposition with glomerular cell activation and complement engagement, predominantly via the alternative and lectin pathways (quotes and synthesis from 2023–2024 reviews) (filippone2024contemporaryreviewof pages 1-2, novak2024oglycosylationofiga1 pages 1-2, cheung2024theroleof pages 2-3, salvadori2024whatisnew pages 2-3).

Direct quote supporting the multi‑hit model and Gd‑IgA1: “Galactose‑deficient IgA1 in the circulation of patients with IgA nephropathy is bound by IgG autoantibodies… These complexes… can enter the glomerular mesangium, activate the resident mesangial cells, and induce glomerular injury.” (Glycobiology 2024; DOI: 10.1093/glycob/cwae060; URL: https://doi.org/10.1093/glycob/cwae060) (novak2024oglycosylationofiga1 pages 1-2).

1) Core Pathophysiology - Multi‑hit pathogenesis: Elevated polymeric Gd‑IgA1 (Hit 1), antiglycan autoantibodies (Hit 2), circulating immune complexes (Hit 3), mesangial deposition and activation (Hit 4) (Nature Reviews Disease Primers 2023; Frontiers Immunology 2024; Frontiers Nephrology 2024) (filippone2024contemporaryreviewof pages 1-2, cheung2024theroleof pages 2-3, salvadori2024whatisnew pages 2-3). - Dysregulated glycosylation: Aberrant O‑glycosylation in the IgA1 hinge due to dysregulated glycosyltransferases produces Gd‑IgA1 that self‑aggregates, binds IgG, and is nephritogenic (Glycobiology 2024) (novak2024oglycosylationofiga1 pages 1-2). - Mucosal immunity and microbiome: MALT (GALT/NALT) plasma cells and BAFF/APRIL signaling promote excessive mucosal IgA and Gd‑IgA1; dysbiosis and TLR activation contribute to mucosal hyper‑responsiveness (Frontiers Nephrology 2024; BMC Nephrol 2024 review and studies) (cheung2024theroleof pages 1-2, salvadori2024whatisnew pages 2-3). - Complement activation: C3 co‑localizes with IgA in most biopsies; alternative and lectin pathways are implicated, with complement deposition correlating with disease activity and prognosis (Frontiers Immunology 2024; World J Nephrol 2024; Scientific Reports 2024) (filippone2024contemporaryreviewof pages 1-2, salvadori2024whatisnew pages 2-3). - Intrarenal cellular responses: Mesangial proliferation, matrix expansion, and cytokine secretion; downstream podocyte injury with proteinuria; emerging single‑cell/spatial studies implicate early endothelial activation and complex immune cell interactions in glomeruli (Nat Genet 2024 multi‑omic atlas; contextual reviews) (filippone2024contemporaryreviewof pages 1-2, dreher2025recentadvancesin pages 8-9).

2) Key Molecular Players - Genes/Proteins (HGNC): - TNFSF13 (APRIL) and TNFSF13B (BAFF): B‑cell/plasma‑cell survival factors driving overproduction of Gd‑IgA1 and autoantibodies; therapeutic targets (Frontiers Nephrol 2024; IJMS 2024) (cheung2024theroleof pages 1-2, muto2024newinsightsand pages 1-2). - C1GALT1, ST6GAL1: Glycosyltransferases linked to IgA1 O‑glycosylation; dysregulation leads to Gd‑IgA1 (Glycobiology 2024) (novak2024oglycosylationofiga1 pages 1-2). - Complement components: C3; regulators CFH/CFHR (genetic risk) that modulate alternative pathway activation (reviews 2023–2024) (salvadori2024whatisnew pages 2-3, filippone2024contemporaryreviewof pages 1-2). - Chemical Entities (CHEBI): Galactose; N‑acetylgalactosamine (GalNAc) defining IgA1 O‑glycans (Glycobiology 2024) (novak2024oglycosylationofiga1 pages 1-2). - Cell Types (CL): Mesangial cells (deposition/activation), glomerular endothelial cells (early inflammatory activation), podocytes (injury/proteinuria), plasma cells/B cells (mucosal/systemic IgA1; autoantibodies), T follicular helper cells (mucosal germinal centers) (Frontiers Immunology 2024; Nat Genet 2024) (filippone2024contemporaryreviewof pages 1-2, dreher2025recentadvancesin pages 8-9). - Anatomical Locations (UBERON): Kidney/glomerulus/mesangium (injury site); palatine tonsil (NALT) and Peyer’s patches (GALT) as sources of mucosal IgA (Primers 2023; IJMS 2024) (filippone2024contemporaryreviewof pages 1-2, muto2024newinsightsand pages 1-2).

3) Biological Processes (GO) Disrupted - Protein O‑linked glycosylation (IgA1 hinge region) (novak2024oglycosylationofiga1 pages 1-2). - B‑cell activation and class‑switch recombination to IgA (BAFF/APRIL‑mediated) (cheung2024theroleof pages 1-2, muto2024newinsightsand pages 1-2). - Complement activation—alternative and lectin pathways—intraglomerular inflammation (filippone2024contemporaryreviewof pages 1-2, salvadori2024whatisnew pages 2-3). - Mesangial cell proliferation, extracellular matrix organization; podocyte injury responses (filippone2024contemporaryreviewof pages 1-2).

4) Cellular Components (GO-CC) - Extracellular region/space (immune complexes, complement factors), mesangial matrix; cell membrane receptors on mesangial/endothelial/podocyte cells; germinal center structures in tonsil/Peyer’s patches (filippone2024contemporaryreviewof pages 1-2, novak2024oglycosylationofiga1 pages 1-2, muto2024newinsightsand pages 1-2).

5) Disease Progression - Sequence of events: Mucosal dysregulation → overproduction of Gd‑IgA1 and autoantibodies → circulating immune complexes → mesangial deposition → mesangial activation and cytokine release → complement activation (AP/LP) → podocyte injury and proteinuria → tubulointerstitial inflammation/fibrosis → progressive eGFR decline (Primers 2023; Frontiers 2024) (filippone2024contemporaryreviewof pages 1-2, cheung2024theroleof pages 2-3). - Distinct phases: Subclinical deposition and episodic synpharyngitic hematuria; persistent proteinuria phase with histologic activity (MEST‑C), and progressive fibrosis with declining GFR (filippone2024contemporaryreviewof pages 1-2).

6) Phenotypic Manifestations - Clinical phenotypes: Microscopic/macroscopic hematuria (often synpharyngitic), proteinuria, hypertension; progressive CKD with variable course (filippone2024contemporaryreviewof pages 1-2). - Pathology: Mesangial IgA (IgA1) and C3 deposits; mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental sclerosis (S), tubular atrophy/interstitial fibrosis (T), and crescents (C) — the Oxford MEST‑C classification (filippone2024contemporaryreviewof pages 1-2). - Prognostic biomarkers: Persistent proteinuria and lower eGFR are strongly prognostic; circulating and histologic complement (C3/C4) add incremental risk information (Scientific Reports 2024) (filippone2024contemporaryreviewof pages 1-2).

Recent Developments and Latest Research (2023–2024 priority) - Glycosylation and immune complexes: 2024 Glycobiology review consolidates the enzymology and structural basis of Gd‑IgA1 pathogenicity and immune complex formation, with explicit mechanistic statements (Novak et al. 2024, DOI above) (novak2024oglycosylationofiga1 pages 1-2). - BAFF/APRIL biology: 2024 reviews highlight elevated serum BAFF/APRIL correlating with disease severity and therapeutic potential of APRIL antagonists (e.g., reductions in proteinuria and Gd‑IgA1 in early studies) (cheung2024theroleof pages 1-2, muto2024newinsightsand pages 1-2). - Complement and prognostication: Contemporary reviews and cohort analyses underscore alternative/lectin pathway involvement; lower serum C3 and higher C4 at diagnosis improved prediction beyond standard risk tools (Sci Rep 2024; doi:10.1038/s41598-024-65857-w; https://doi.org/10.1038/s41598-024-65857-w) (filippone2024contemporaryreviewof pages 1-2). - Single‑cell and spatial kidney atlases: Multi‑omic human kidney maps implicate endothelial activation and fibroinflammatory microenvironments in progression, complementing mesangial‑centric models (Nat Genet 2024; doi:10.1038/s41588-024-01802-x; https://doi.org/10.1038/s41588-024-01802-x) (dreher2025recentadvancesin pages 8-9).

Current Applications and Real‑world Implementations - Supportive care: RAAS blockade; SGLT2 inhibitors now broadly used in proteinuric CKD including IgAN, reducing proteinuria and slowing eGFR decline (summarized in 2024 reviews) (filippone2024contemporaryreviewof pages 1-2). - Targeted‑release budesonide (Nefecon/TARPEYO): Mucosal‑targeted corticosteroid that reduces proteinuria and slows eGFR loss in IgAN; integrated in contemporary management (dreher2025recentadvancesin pages 8-9, filippone2024contemporaryreviewof pages 1-2). - Endothelin/angiotensin blockade: Sparsentan (dual ERA/ARB) used to reduce proteinuria as part of supportive strategy (filippone2024contemporaryreviewof pages 1-2). - Complement inhibitors in trials: Agents targeting alternative (factor B) and lectin (MASP‑2) pathways and terminal components are under active investigation and selective use (e.g., ravulizumab study NCT06291376; iptacopan biopsy‑impact study NCT06797518) (filippone2024contemporaryreviewof pages 1-2). - BAFF/APRIL inhibitors in trials: Atacicept/telitacicept/zigakibart targeting BAFF/APRIL axes are being tested with signals on Gd‑IgA1 reduction and proteinuria (cheung2024theroleof pages 1-2, muto2024newinsightsand pages 1-2).

Expert Opinions and Authoritative Analyses - Nature Reviews Disease Primers (2023) and contemporary 2024 reviews converge on the multi‑hit framework and emphasize mucosal immune dysregulation and complement as central pathogenic drivers translating to targeted therapy development (filippone2024contemporaryreviewof pages 1-2, cheung2024theroleof pages 2-3, salvadori2024whatisnew pages 2-3). - Direct quote highlighting complement’s role (integrated across sources): co‑localization of C3 with IgA is present in the vast majority of biopsies, implicating alternative/lectin pathways in glomerular injury (summarized in Filippone 2024 and Muto 2024) (filippone2024contemporaryreviewof pages 1-2, muto2024newinsightsand pages 1-2).

Relevant Statistics and Data (recent studies) - Registry‑validated biopsy diagnosis PPV 95% (95% CI 90–98%) with frequent C3 deposition (72.4%) in a Swedish cohort (2015–2019) (BMC Nephrol 2024; doi:10.1186/s12882-024-03512-2; https://doi.org/10.1186/s12882-024-03512-2) (filippone2024contemporaryreviewof pages 1-2). - Serum complement prognostication: Low baseline C3 associated with higher incidence of 50% eGFR decline/kidney failure; adding C3/C4 improved model discrimination (Sci Rep 2024; doi above) (filippone2024contemporaryreviewof pages 1-2).

Ontology‑ready Annotations - Genes/Proteins (HGNC): TNFSF13 (APRIL); TNFSF13B (BAFF); C1GALT1; ST6GAL1; CFH; C3 (novak2024oglycosylationofiga1 pages 1-2, cheung2024theroleof pages 1-2, muto2024newinsightsand pages 1-2, salvadori2024whatisnew pages 2-3). - Biological Processes (GO): Protein O‑linked glycosylation; B cell activation; class switch recombination to IgA; complement activation (alternative/lectin) (novak2024oglycosylationofiga1 pages 1-2, cheung2024theroleof pages 1-2, salvadori2024whatisnew pages 2-3, filippone2024contemporaryreviewof pages 1-2). - Cellular Components (GO-CC): Extracellular region; mesangial matrix; cell membrane receptor complexes; germinal center (novak2024oglycosylationofiga1 pages 1-2, filippone2024contemporaryreviewof pages 1-2). - Cell Types (CL): Mesangial cell; glomerular endothelial cell; podocyte; plasma cell; B cell; T follicular helper cell (filippone2024contemporaryreviewof pages 1-2, dreher2025recentadvancesin pages 8-9, cheung2024theroleof pages 1-2). - Anatomical Locations (UBERON): Kidney; glomerulus; mesangium; palatine tonsil; small intestine/Peyer’s patch (filippone2024contemporaryreviewof pages 1-2, muto2024newinsightsand pages 1-2). - Chemical Entities (CHEBI): Galactose; N‑acetylgalactosamine; budesonide; dapagliflozin (novak2024oglycosylationofiga1 pages 1-2, dreher2025recentadvancesin pages 8-9).

Evidence items with PMIDs/DOIs and URLs (selected, 2023–2024 priority) - Novak J, et al. O‑glycosylation of IgA1 and the pathogenesis of IgAN. Glycobiology. 2024. DOI: 10.1093/glycob/cwae060. URL: https://doi.org/10.1093/glycob/cwae060 (novak2024oglycosylationofiga1 pages 1-2). - Filippone EJ, et al. Contemporary review of IgAN. Front Immunol. 2024. DOI: 10.3389/fimmu.2024.1436923. URL: https://doi.org/10.3389/fimmu.2024.1436923 (filippone2024contemporaryreviewof pages 1-2). - Cheung CK, et al. BAFF/APRIL in IgAN. Front Nephrol. 2024. DOI: 10.3389/fneph.2023.1346769. URL: https://doi.org/10.3389/fneph.2023.1346769 (cheung2024theroleof pages 1-2, cheung2024theroleof pages 2-3). - Muto M, et al. APRIL in IgAN. Int J Mol Sci. 2024. DOI: 10.3390/ijms251910340. URL: https://doi.org/10.3390/ijms251910340 (muto2024newinsightsand pages 1-2). - Tringali E, et al. Serum C3 and C4 prognostic value. Sci Rep. 2024. DOI: 10.1038/s41598-024-65857-w. URL: https://doi.org/10.1038/s41598-024-65857-w (filippone2024contemporaryreviewof pages 1-2). - Abedini A, et al. Single‑cell multi‑omics kidney atlas. Nat Genet. 2024. DOI: 10.1038/s41588-024-01802-x. URL: https://doi.org/10.1038/s41588-024-01802-x (dreher2025recentadvancesin pages 8-9). - Rehnberg J, et al. Registry validation of IgAN biopsies; C3 deposits common. BMC Nephrol. 2024. DOI: 10.1186/s12882-024-03512-2. URL: https://doi.org/10.1186/s12882-024-03512-2 (filippone2024contemporaryreviewof pages 1-2).

Cellular and Molecular Mechanisms narrative (for knowledge base) - Pathophysiology description: IgAN is an immune‑complex glomerulonephritis in which aberrantly O‑glycosylated polymeric IgA1 (Gd‑IgA1) and antiglycan autoantibodies form circulating immune complexes that deposit in the mesangium, triggering mesangial proliferation, cytokine release, and complement activation (primarily alternative and lectin pathways). Downstream podocyte injury drives proteinuria; chronic inflammation leads to tubulointerstitial fibrosis and progressive CKD (novak2024oglycosylationofiga1 pages 1-2, filippone2024contemporaryreviewof pages 1-2, cheung2024theroleof pages 2-3). - Gene/protein annotations with ontology terms: TNFSF13/APRIL (HGNC: TNFSF13); TNFSF13B/BAFF (HGNC: TNFSF13B); C1GALT1 (HGNC); ST6GAL1 (HGNC); CFH (HGNC); C3 (HGNC) (novak2024oglycosylationofiga1 pages 1-2, cheung2024theroleof pages 1-2, salvadori2024whatisnew pages 2-3). - Phenotype associations (HP terms): Hematuria (HP:0000790), Proteinuria (HP:0000093), Hypertension (HP:0000822), Decreased eGFR/CKD (HP:0000083) supported by biopsy MEST‑C features (filippone2024contemporaryreviewof pages 1-2). - Cell type involvement (CL terms): Mesangial cell (CL); Glomerular endothelial cell (CL); Podocyte (CL); Plasma cell (CL); B cell (CL); Tfh cell (CL) (filippone2024contemporaryreviewof pages 1-2, dreher2025recentadvancesin pages 8-9, cheung2024theroleof pages 1-2). - Anatomical locations (UBERON terms): Kidney (UBERON:0002113), Glomerulus (UBERON:0000074), Mesangium (UBERON:0000075), Palatine tonsil (UBERON:0002372), Peyer’s patch (UBERON:0002114) (filippone2024contemporaryreviewof pages 1-2, muto2024newinsightsand pages 1-2). - Chemical entities (CHEBI): Galactose (CHEBI:28260), N‑acetylgalactosamine (CHEBI:18066), Budesonide (CHEBI:3215), Dapagliflozin (CHEBI:79307) (novak2024oglycosylationofiga1 pages 1-2, dreher2025recentadvancesin pages 8-9).

Current Trials and Implementations (examples with NCT IDs) - Complement inhibitors: Ravulizumab (C5) in IgAN—NCT06291376 (recruiting). Iptacopan (factor B) biopsy‑impact—NCT06797518 (recruiting) (filippone2024contemporaryreviewof pages 1-2). - BAFF/APRIL inhibitors: Atacicept—NCT07020923; Telitacicept—NCT06654596; Zigakibart—NCT06858319 (extensions) (cheung2024theroleof pages 1-2). - Mucosal steroid: Extended TARPEYO (nefecon) beyond 9 months—NCT06712407 (filippone2024contemporaryreviewof pages 1-2).

Embedded artifact (ontology‑mapped key players) | Category | Entity | Ontology (prefix term) | Role in IgAN | Evidence (citation id) | |---|---|---|---|---| | Gene / Protein | TNFSF13 (APRIL) | HGNC: TNFSF13 | Plasma-cell survival factor; promotes Gd-IgA1 production | (cheung2024theroleof pages 1-2, muto2024newinsightsand pages 1-2) | | Gene / Protein | TNFSF13B (BAFF) | HGNC: TNFSF13B | B-cell survival/activation; supports IgA class switching and Gd-IgA1 production | (cheung2024theroleof pages 1-2, salvadori2024whatisnew pages 2-3) | | Gene / Protein | C1GALT1 | HGNC: C1GALT1 | Core O-glycosyltransferase implicated in IgA1 hinge galactosylation | (novak2024oglycosylationofiga1 pages 1-2, salvadori2024whatisnew pages 2-3) | | Gene / Protein | ST6GAL1 | HGNC: ST6GAL1 | Glycosyltransferase linked to Ig glycome/glycosylation patterns | (novak2024oglycosylationofiga1 pages 1-2, dreher2025recentadvancesin pages 8-9) | | Gene / Protein | CFH (complement factor H) | HGNC: CFH | Regulator of alternative complement pathway; genetic loci modulate complement-driven injury | (salvadori2024whatisnew pages 2-3, filippone2024contemporaryreviewof pages 1-2) | | Gene / Protein | C3 | HGNC: C3 | Central complement component; co-localizes with IgA in glomeruli | (novak2024oglycosylationofiga1 pages 1-2, filippone2024contemporaryreviewof pages 1-2) | | Cell type | Mesangial cell | CL: mesangial cell | Principal deposition site of IgA-containing immune complexes; proliferates and secretes ECM/cytokines | (filippone2024contemporaryreviewof pages 1-2, novak2024oglycosylationofiga1 pages 1-2) | | Cell type | Glomerular endothelial cell | CL: glomerular endothelial cell | Early inflammatory activation, contributes to glomerular injury (scRNA/spatial evidence) | (dreher2025recentadvancesin pages 8-9, filippone2024contemporaryreviewof pages 1-2) | | Cell type | Podocyte | CL: podocyte | Injury leads to proteinuria and filtration barrier disruption downstream of mesangial injury | (filippone2024contemporaryreviewof pages 1-2) | | Cell type | Plasma cell | CL: plasma cell | Source of (mucosal/systemic) IgA1 including pathogenic Gd-IgA1 | (cheung2024theroleof pages 1-2, muto2024newinsightsand pages 1-2) | | Cell type | B cell | CL: B cell | Generates antiglycan autoantibodies and undergoes class-switching to IgA | (cheung2024theroleof pages 1-2, muto2024newinsightsand pages 1-2) | | Cell type | T follicular helper cell (Tfh) | CL: T follicular helper cell | Provides help for B-cell affinity maturation and IgA class switching in mucosa/tonsils | (filippone2024contemporaryreviewof pages 1-2, muto2024newinsightsand pages 1-2) | | Anatomical site | Kidney | UBERON: kidney | Organ affected; site of immune-complex deposition and progressive fibrosis | (filippone2024contemporaryreviewof pages 1-2) | | Anatomical site | Glomerulus | UBERON: glomerulus | Microanatomic site of mesangial immune-deposits and complement activation | (filippone2024contemporaryreviewof pages 1-2) | | Anatomical site | Mesangium | UBERON: mesangium | Mesangial cell expansion and matrix accumulation drive glomerular dysfunction | (novak2024oglycosylationofiga1 pages 1-2, filippone2024contemporaryreviewof pages 1-2) | | Anatomical site | Palatine tonsil | UBERON: palatine tonsil | Mucosal site (NALT) implicated as source of pathogenic mucosal IgA in some patients | (salvadori2024whatisnew pages 2-3, muto2024newinsightsand pages 1-2) | | Anatomical site | Small intestine / Peyer's patch | UBERON: small intestine; UBERON: Peyer's patch | GALT sites of IgA induction and mucosal immune responses influencing Gd-IgA1 | (filippone2024contemporaryreviewof pages 1-2, muto2024newinsightsand pages 1-2) | | Chemical entity | Galactose | CHEBI: galactose | Sugar missing from Gd-IgA1 O-glycans; central to the aberrant glycoform definition | (novak2024oglycosylationofiga1 pages 1-2) | | Chemical entity | N-acetylgalactosamine (GalNAc) | CHEBI: N-acetylgalactosamine | Core residue of IgA1 O-glycans; site of aberrant galactosylation | (novak2024oglycosylationofiga1 pages 1-2) | | Chemical entity | Budesonide (targeted-release) | CHEBI: budesonide | Mucosal-targeted steroid (Nefecon) that reduces proteinuria by modulating mucosal IgA responses | (dreher2025recentadvancesin pages 8-9, filippone2024contemporaryreviewof pages 1-2) | | Chemical entity | Dapagliflozin (SGLT2 inhibitor) | CHEBI: dapagliflozin | Supportive therapy that reduces proteinuria and slows CKD progression in IgAN cohorts | (filippone2024contemporaryreviewof pages 1-2, dreher2025recentadvancesin pages 8-9) | | Pathway / Process | Complement activation | GO: complement activation | Key mediator of glomerular inflammation in IgAN; involves alternative and lectin pathways | (filippone2024contemporaryreviewof pages 1-2, salvadori2024whatisnew pages 2-3) | | Pathway / Process | Alternative complement pathway | GO: alternative complement activation | Frequently implicated route of complement-mediated glomerular damage in IgAN | (salvadori2024whatisnew pages 2-3, dreher2025recentadvancesin pages 8-9) | | Pathway / Process | Lectin complement pathway | GO: lectin complement activation | Contributes to complement deposition and injury in many patients | (salvadori2024whatisnew pages 2-3) | | Pathway / Process | O-linked glycosylation (IgA1 hinge) | GO: protein O-linked glycosylation | Aberrant O-glycosylation (Gd-IgA1) is the initiating molecular abnormality (Hit 1) | (novak2024oglycosylationofiga1 pages 1-2) | | Pathway / Process | B cell activation | GO: B cell activation | Drives autoantibody formation and expansion of IgA-producing clones | (cheung2024theroleof pages 1-2) | | Pathway / Process | Class switch recombination to IgA | GO: class switch recombination | Mechanism for generation of mucosal IgA; dysregulated in IgAN mucosal sites | (cheung2024theroleof pages 1-2, muto2024newinsightsand pages 1-2) |

Table: Compact mapping of key genes/proteins, cell types, anatomical sites, chemicals, and pathways in IgA nephropathy with ontology prefixes and supporting evidence citations for rapid reference.

Limitations - While multi‑hit pathogenic mechanisms are well supported, inter‑patient heterogeneity remains; causality for specific microbiome taxa and exact antigenic drivers continue to be clarified. Some single‑cell/spatial findings are from broader CKD atlases rather than IgAN‑only cohorts.

References (by context id) - Core contemporary and mechanistic reviews and studies: (novak2024oglycosylationofiga1 pages 1-2, filippone2024contemporaryreviewof pages 1-2, cheung2024theroleof pages 1-2, cheung2024theroleof pages 2-3, salvadori2024whatisnew pages 2-3, dreher2025recentadvancesin pages 8-9).

References

(filippone2024contemporaryreviewof pages 1-2): Edward J. Filippone, Rakesh Gulati, and John L. Farber. Contemporary review of iga nephropathy. Frontiers in Immunology, Aug 2024. URL: https://doi.org/10.3389/fimmu.2024.1436923, doi:10.3389/fimmu.2024.1436923. This article has 29 citations and is from a peer-reviewed journal.
(novak2024oglycosylationofiga1 pages 1-2): Jan Novak, R Glenn King, Janet Yother, Matthew B Renfrow, and Todd J Green. O-glycosylation of iga1 and the pathogenesis of an autoimmune disease iga nephropathy. Glycobiology, Aug 2024. URL: https://doi.org/10.1093/glycob/cwae060, doi:10.1093/glycob/cwae060. This article has 7 citations and is from a peer-reviewed journal.
(cheung2024theroleof pages 2-3): Chee Kay Cheung, Jonathan Barratt, Adrian Liew, Hong Zhang, Vladimir Tesar, and Richard Lafayette. The role of baff and april in iga nephropathy: pathogenic mechanisms and targeted therapies. Frontiers in Nephrology, Feb 2024. URL: https://doi.org/10.3389/fneph.2023.1346769, doi:10.3389/fneph.2023.1346769. This article has 59 citations and is from a poor quality or predatory journal.
(salvadori2024whatisnew pages 2-3): Maurizio Salvadori and Giuseppina Rosso. What is new in the pathogenesis and treatment of iga glomerulonephritis. World Journal of Nephrology, Dec 2024. URL: https://doi.org/10.5527/wjn.v13.i4.98709, doi:10.5527/wjn.v13.i4.98709. This article has 4 citations.
(cheung2024theroleof pages 1-2): Chee Kay Cheung, Jonathan Barratt, Adrian Liew, Hong Zhang, Vladimir Tesar, and Richard Lafayette. The role of baff and april in iga nephropathy: pathogenic mechanisms and targeted therapies. Frontiers in Nephrology, Feb 2024. URL: https://doi.org/10.3389/fneph.2023.1346769, doi:10.3389/fneph.2023.1346769. This article has 59 citations and is from a poor quality or predatory journal.
(dreher2025recentadvancesin pages 8-9): Leonie Dreher, Lars Nilges, Thorsten Wiech, Markus M Rinschen, and Nicola M Tomas. Recent advances in pathogenetic concepts and disease modeling of iga nephropathy. Clinical Kidney Journal, May 2025. URL: https://doi.org/10.1093/ckj/sfaf152, doi:10.1093/ckj/sfaf152. This article has 0 citations and is from a peer-reviewed journal.
(muto2024newinsightsand pages 1-2): Masahiro Muto, Hitoshi Suzuki, and Yusuke Suzuki. New insights and future perspectives of april in iga nephropathy. International Journal of Molecular Sciences, 25:10340, Sep 2024. URL: https://doi.org/10.3390/ijms251910340, doi:10.3390/ijms251910340. This article has 10 citations and is from a poor quality or predatory journal.

{ }

Source YAML

click to show

name: IgA Nephropathy
creation_date: '2025-12-19T01:12:52Z'
updated_date: '2026-04-15T04:43:47Z'
category: Autoimmune
parents:
- Autoimmune Disease
- Kidney Disease
disease_term:
  preferred_term: IgA nephropathy
  term:
    id: MONDO:0005342
    label: IgA glomerulonephritis
synonyms:
- Berger's disease
- primary IgA nephropathy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0005342
      label: IgA glomerulonephritis
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Current MONDO term for kidney-limited primary IgA nephropathy / IgA glomerulonephritis.
description: >-
  IgA nephropathy (IgAN) is a kidney-limited immune-complex glomerulonephritis
  defined by mesangial deposition of galactose-deficient IgA1-containing immune
  complexes with complement co-deposition. Its core mechanism follows the
  four-hit model: mucosal immune dysregulation drives overproduction of
  galactose-deficient IgA1, anti-glycan autoantibodies form nephritogenic immune
  complexes, and these complexes deposit in the mesangium where they trigger
  complement activation, mesangial proliferation, podocyte injury, and
  progressive chronic kidney damage.
notes: >-
  This entry models kidney-limited / primary IgA nephropathy. The core page
  deliberately includes only the shared kidney-relevant four-hit biology
  (mucosal dysregulation, galactose-deficient IgA1, anti-glycan
  autoantibodies, and mesangial immune-complex/complement injury) that also
  underlies IgA vasculitis nephritis. The systemic small-vessel vasculitis
  manifestations of IgA vasculitis, such as palpable purpura, arthritis, and
  gastrointestinal vasculitis, are kept in separate disease framing rather than
  collapsed into this kidney-limited IgAN page.
pathophysiology:
- name: Mucosal B-cell hyper-responsiveness
  description: >-
    Mucosal immune hyper-responsiveness in the upper airway and gut creates an
    exaggerated B-cell response to antigenic stimulation in susceptible hosts,
    establishing the upstream context for pathogenic IgA generation.
  genes:
  - preferred_term: HLA-DQB1
    term:
      id: hgnc:4944
      label: HLA-DQB1
  locations:
  - preferred_term: intestinal mucosa
    term:
      id: UBERON:0001242
      label: intestinal mucosa
  - preferred_term: palatine tonsil
    term:
      id: UBERON:0002373
      label: palatine tonsil
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  evidence:
  - reference: PMID:38362118
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This review explores the complex pathogenesis of IgAN, highlighting the
      pivotal roles of BAFF and APRIL in the interplay between mucosal
      hyper-responsiveness, B-cell activation, and the consequent overproduction
      of Gd-IgA1 and its autoantibodies that are key features in this disease.
    explanation: >-
      Supports mucosal hyper-responsiveness as the upstream immunologic context
      that precedes the more specific BAFF/APRIL-dependent B-cell activation
      step.
  - reference: PMID:40487370
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This involves the identification of genetic risk factors in genome-wide
      association studies, the use of multi-omics approaches to integrate big
      data, the recognition of the importance of the gut-kidney axis, the role
      of plasma cells in the production of IgA and IgG, the potential
      specificity of circulating IgA for mesangial antigens, and the activation
      of the complement system with subsequent damage to glomerular cells.
    explanation: >-
      Independently supports the gut-kidney axis as an upstream component of
      IgAN pathogenesis.
  downstream:
  - target: BAFF/APRIL-driven B-cell activation and IgA class switching
    description: Mucosal immune hyper-responsiveness feeds into BAFF/APRIL-dependent B-cell activation and pathogenic IgA class switching.

- name: BAFF/APRIL-driven B-cell activation and IgA class switching
  description: >-
    BAFF and APRIL signaling sustain B-cell activation, plasma-cell survival,
    and IgA class switching, biasing the mucosal response toward pathogenic IgA
    production.
  genes:
  - preferred_term: TNFSF13
    term:
      id: hgnc:11928
      label: TNFSF13
  - preferred_term: TNFSF13B
    term:
      id: hgnc:11929
      label: TNFSF13B
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  biological_processes:
  - preferred_term: B cell activation
    term:
      id: GO:0042113
      label: B cell activation
  - preferred_term: isotype switching
    term:
      id: GO:0045190
      label: isotype switching
  evidence:
  - reference: PMID:38362118
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This review explores the complex pathogenesis of IgAN, highlighting the
      pivotal roles of BAFF and APRIL in the interplay between mucosal
      hyper-responsiveness, B-cell activation, and the consequent overproduction
      of Gd-IgA1 and its autoantibodies that are key features in this disease.
    explanation: >-
      Supports BAFF/APRIL-dependent B-cell activation and class-switching as the
      immediate upstream driver of pathogenic IgA production.
  - reference: PMID:40487370
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This involves the identification of genetic risk factors in genome-wide
      association studies, the use of multi-omics approaches to integrate big
      data, the recognition of the importance of the gut-kidney axis, the role
      of plasma cells in the production of IgA and IgG, the potential
      specificity of circulating IgA for mesangial antigens, and the activation
      of the complement system with subsequent damage to glomerular cells.
    explanation: >-
      Independently supports plasma-cell-mediated immunoglobulin production as
      part of the activated mucosal B-cell program in IgAN.
  downstream:
  - target: Galactose-deficient IgA1 overproduction
    description: BAFF/APRIL-supported mucosal B-cell and plasma-cell responses increase production of nephritogenic IgA1 glycoforms.

- name: Galactose-deficient IgA1 overproduction
  description: >-
    IgA1-secreting cells produce hinge-region O-glycoforms lacking normal
    galactose residues, generating galactose-deficient IgA1 (Gd-IgA1), the key
    autoantigen in IgAN.
  genes:
  - preferred_term: C1GALT1
    term:
      id: hgnc:24337
      label: C1GALT1
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  biological_processes:
  - preferred_term: protein O-linked glycosylation
    term:
      id: GO:0006493
      label: protein O-linked glycosylation
  - preferred_term: immunoglobulin production
    term:
      id: GO:0002377
      label: immunoglobulin production
  evidence:
  - reference: PMID:39095059
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These galactose-deficient IgA1 glycoforms are produced by IgA1-secreting
      cells due to a dysregulated expression and activity of several
      glycosyltransferases.
    explanation: >-
      Direct support for dysregulated IgA1 O-glycosylation as the molecular
      origin of Gd-IgA1.
  - reference: PMID:39124764
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The pathogenesis of IgAN is considered a multifactorial process involving
      the formation of immune complexes wherein aberrantly O-glycosylated IgA1
      is recognized as an autoantigen.
    explanation: >-
      Confirms aberrantly O-glycosylated IgA1 as the central autoantigenic hit
      in IgAN.
  downstream:
  - target: Galactose-deficient IgA1
    description: Excess production of aberrantly glycosylated IgA1 creates the characteristic circulating biochemical abnormality measured in IgAN.
  - target: Anti-Gd-IgA1 autoantibody production
    description: Galactose-deficient IgA1 exposes neoepitopes that trigger anti-glycan autoantibody production.

- name: Anti-Gd-IgA1 autoantibody production
  description: >-
    Anti-glycan IgG and IgA autoantibodies are produced against circulating
    Gd-IgA1, establishing the second immunologic hit in the four-hit model.
  biological_processes:
  - preferred_term: B cell mediated immunity
    term:
      id: GO:0019724
      label: B cell mediated immunity
  - preferred_term: immunoglobulin production
    term:
      id: GO:0002377
      label: immunoglobulin production
  evidence:
  - reference: PMID:22904352
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Circulating autoantibodies that recognize such galactose-deficient IgA1 as
      an autoantigen, or the levels of the autoantigen itself, may allow
      prediction of disease progression.
    explanation: >-
      Human cohort study showing that autoantibodies against Gd-IgA1 are a real
      circulating feature of IgAN and track with progression risk.
  downstream:
  - target: Nephritogenic immune complex assembly
    description: Anti-Gd-IgA1 autoantibodies bind circulating Gd-IgA1 to form nephritogenic immune complexes.

- name: Nephritogenic immune complex assembly
  description: >-
    Circulating Gd-IgA1 is bound by anti-glycan autoantibodies to form
    nephritogenic immune complexes that may also incorporate complement
    components.
  evidence:
  - reference: PMID:39095059
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Galactose-deficient IgA1 in the circulation of patients with IgA
      nephropathy is bound by IgG autoantibodies and the resultant immune
      complexes can contain additional proteins, such as complement C3.
    explanation: >-
      Directly supports immune-complex assembly around Gd-IgA1 plus complement
      cargo.
  downstream:
  - target: Mesangial immune complex deposition and complement activation
    description: Circulating Gd-IgA1 autoantibody complexes traffic to the glomerulus and initiate local complement-rich injury.

- name: Mesangial immune complex deposition and complement activation
  description: >-
    Pathogenic immune complexes lodge in the glomerular mesangium, where they
    activate resident mesangial cells and engage alternative and lectin pathway
    complement cascades.
  genes:
  - preferred_term: CFH
    term:
      id: hgnc:4883
      label: CFH
  locations:
  - preferred_term: glomerular mesangium
    term:
      id: UBERON:0002320
      label: glomerular mesangium
  - preferred_term: renal glomerulus
    term:
      id: UBERON:0000074
      label: renal glomerulus
  cell_types:
  - preferred_term: mesangial cell
    term:
      id: CL:0000650
      label: mesangial cell
  biological_processes:
  - preferred_term: complement activation, alternative pathway
    term:
      id: GO:0006957
      label: complement activation, alternative pathway
  - preferred_term: complement activation, lectin pathway
    term:
      id: GO:0001867
      label: complement activation, lectin pathway
  evidence:
  - reference: PMID:39095059
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These complexes, if not removed from the circulation, can enter the
      glomerular mesangium, activate the resident mesangial cells, and induce
      glomerular injury.
    explanation: >-
      Direct support for mesangial deposition of pathogenic complexes as the
      bridge between circulating autoimmunity and local glomerular injury.
  - reference: PMID:38053977
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The alternative complement pathway is the major complement cascade
      activator in IgAN, and glomerular C3 deposition has been shown to
      correlate with disease progression.
    explanation: >-
      Supports alternative pathway complement activation as a central amplifier
      of mesangial immune-complex injury.
  - reference: PMID:38182298
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mesangial complement C3 deposits, reflecting alternative and possibly
      lectin pathway activation, are characteristic in biopsies of patients with
      IgA nephropathy (IgAN).
    explanation: >-
      Confirms that mesangial complement deposition in IgAN reflects alternative
      and lectin pathway activity rather than generic nonspecific inflammation.
  downstream:
  - target: Mesangial proliferation and inflammatory amplification
    description: Mesangial complement-rich injury triggers local proliferation, inflammatory recruitment, and expansion of glomerular damage.

- name: Mesangial proliferation and inflammatory amplification
  description: >-
    Activated mesangial cells proliferate and amplify local inflammation through
    inflammatory cell recruitment and matrix-active injury programs, extending
    the initial immune-complex lesion.
  locations:
  - preferred_term: glomerular mesangium
    term:
      id: UBERON:0002320
      label: glomerular mesangium
  - preferred_term: renal glomerulus
    term:
      id: UBERON:0000074
      label: renal glomerulus
  cell_types:
  - preferred_term: mesangial cell
    term:
      id: CL:0000650
      label: mesangial cell
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: cell population proliferation
    term:
      id: GO:0008283
      label: cell population proliferation
  - preferred_term: leukocyte migration
    term:
      id: GO:0050900
      label: leukocyte migration
  evidence:
  - reference: PMID:39188719
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mesangial deposition of immune complexes containing galactose-deficient
      IgA1 complexed with anti-glycan IgG or IgA antibodies results in mesangial
      cell activation and proliferation, inflammatory cell recruitment,
      complement activation, and podocyte damage.
    explanation: >-
      Review abstract directly lays out the mechanistic bridge from mesangial
      deposition to proliferation and inflammatory amplification.
  - reference: PMID:35781866
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      With the increasing intensity of C3 deposition, patients present more
      hematuria, crescents, heavier interstitial inflammatory cell infiltration
      and a higher score on segmental sclerosis lesions.
    explanation: >-
      Human biopsy cohort shows that stronger complement-rich lesions track with
      heavier inflammatory infiltrates and more destructive chronic pathology.
  downstream:
  - target: Podocyte damage and filtration barrier failure
    description: Ongoing mesangial and complement-mediated glomerular injury secondarily compromises podocytes and the filtration barrier.

- name: Podocyte damage and filtration barrier failure
  description: >-
    Mesangial-centered immune injury extends to podocytes and the glomerular
    filtration barrier, producing the clinically dominant combination of
    hematuria and proteinuria.
  locations:
  - preferred_term: renal glomerulus
    term:
      id: UBERON:0000074
      label: renal glomerulus
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  - preferred_term: glomerular endothelial cell
    term:
      id: CL:0002188
      label: glomerular endothelial cell
  evidence:
  - reference: PMID:39188719
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mesangial deposition of immune complexes containing galactose-deficient
      IgA1 complexed with anti-glycan IgG or IgA antibodies results in mesangial
      cell activation and proliferation, inflammatory cell recruitment,
      complement activation, and podocyte damage.
    explanation: >-
      Explicitly supports podocyte injury as a downstream consequence of the
      mesangial immune-complex lesion.
  - reference: PMID:39124764
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      Consequently, the clinical presentation of IgAN is highly variable, with a
      wide spectrum of manifestations ranging from isolated microscopic hematuria
      or episodic macroscopic hematuria to nephrotic-range proteinuria.
    explanation: >-
      Links glomerular filtration barrier injury to the signature renal
      manifestations of hematuria and proteinuria.
  downstream:
  - target: Hematuria
    description: Filtration-barrier disruption produces the characteristic hematuric presentation of IgAN, often with synpharyngitic flares.
  - target: Proteinuria
    description: Podocyte and glomerular barrier injury drives persistent urinary protein loss.
  - target: Chronic complement-linked progression and kidney failure risk
    description: Persistent filtration-barrier injury and complement-rich chronic damage drive long-term loss of kidney function.

- name: Chronic complement-linked progression and kidney failure risk
  description: >-
    Persistent complement-associated glomerular injury is linked to segmental
    sclerosis, interstitial inflammation, lower eGFR, and progression to kidney
    failure in a substantial subset of patients.
  locations:
  - preferred_term: kidney
    term:
      id: UBERON:0002113
      label: kidney
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
  evidence:
  - reference: PMID:35781866
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      C3 deposition at the time of renal biopsy is likely an independent risk
      factor for IgA nephropathy severity and progression.
    explanation: >-
      Supports a chronic complement-linked progression axis rather than a purely
      static diagnostic lesion.
  - reference: PMID:39003309
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lower C3 and higher C4 levels were associated with poorer prognosis,
      highlighting a more 'Complement-Pathic' subset of patients.
    explanation: >-
      Human cohort evidence that systemic complement readouts identify a subset
      with poorer kidney outcomes.
  - reference: PMID:39188719
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Perhaps 20%-50% of patients progress to kidney failure.
    explanation: >-
      Supports the substantial long-term kidney failure risk that makes the late
      progression node clinically important.
  downstream:
  - target: Serum complement profile
    description: Complement-active disease subsets can show prognostically informative circulating C3/C4 abnormalities.
  - target: Renal Insufficiency
    description: Chronic glomerular scarring and ongoing complement-linked injury reduce kidney function over time.
  - target: Hypertension
    description: Progressive chronic kidney injury is commonly accompanied by clinically relevant hypertension.
phenotypes:
- name: Hematuria
  category: Renal
  phenotype_term:
    preferred_term: Hematuria
    term:
      id: HP:0000790
      label: Hematuria
  notes: Microscopic or episodic macroscopic hematuria, often synpharyngitic.
  evidence:
  - reference: PMID:39124764
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Consequently, the clinical presentation of IgAN is highly variable, with a
      wide spectrum of manifestations ranging from isolated microscopic hematuria
      or episodic macroscopic hematuria to nephrotic-range proteinuria.
    explanation: Supports hematuria as a core presenting manifestation of IgAN.
- name: Proteinuria
  category: Renal
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  notes: Persistent proteinuria is a major progression biomarker and treatment target.
  sequelae:
  - target: Renal Insufficiency
    description: Sustained proteinuric injury tracks with and contributes to progressive kidney dysfunction.
  evidence:
  - reference: PMID:39124764
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Consequently, the clinical presentation of IgAN is highly variable, with a
      wide spectrum of manifestations ranging from isolated microscopic hematuria
      or episodic macroscopic hematuria to nephrotic-range proteinuria.
    explanation: Supports the characteristic proteinuric spectrum of IgAN.
- name: Hypertension
  category: Cardiovascular
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  notes: Common adverse clinical feature and risk stratifier.
  evidence:
  - reference: PMID:39188719
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      Biomarkers predicting adverse outcomes include proteinuria, reduced GFR,
      hypertension, and pathology.
    explanation: Supports hypertension as a clinically relevant feature tied to worse IgAN outcomes.
- name: Renal Insufficiency
  category: Renal
  phenotype_term:
    preferred_term: Renal insufficiency
    term:
      id: HP:0000083
      label: Renal insufficiency
  notes: Progressive loss of kidney function leads to kidney failure in a substantial subset of patients.
  evidence:
  - reference: PMID:39188719
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Perhaps 20%-50% of patients progress to kidney failure.
    explanation: Supports clinically meaningful progression from IgAN to advanced kidney dysfunction.
histopathology:
- name: Mesangial IgA-dominant immune deposits
  description: Diagnostic biopsy finding of mesangial IgA deposition.
  diagnostic: true
  evidence:
  - reference: PMID:38438966
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Histological features of IgA deposits were seen in all patients
    explanation: Registry validation study confirms mesangial IgA deposition as the core biopsy lesion of IgAN.
- name: Mesangial hypercellularity
  description: Expanded mesangial cellularity consistent with the proliferative mesangial response.
  evidence:
  - reference: PMID:38438966
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: hypercellularity in 102/132 (77.2%)
    explanation: Supports mesangial hypercellularity as a common histopathologic manifestation in biopsy-proven IgAN.
- name: Mesangial C3 co-deposition
  description: Frequent complement co-deposition accompanying IgA-containing mesangial deposits.
  evidence:
  - reference: PMID:38438966
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: C3 deposits in 98/132 (72.4%)
    explanation: Supports frequent complement co-deposition on kidney biopsy in IgAN.
biochemical:
- name: Galactose-deficient IgA1
  presence: Elevated
  context: Circulating autoantigen and biomarker in a substantial subset of patients.
  evidence:
  - reference: PMID:22904352
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Unlike healthy individuals, some IgA1 is galactose deficient in patients
      with IgAN, leaving terminal N-acetylgalactosamine residues in the hinge
      region exposed.
    explanation: Supports elevated / aberrant circulating Gd-IgA1 as the defining biochemical abnormality of IgAN.
- name: Serum complement profile
  presence: Variable
  context: Lower C3 and higher C4 identify a complement-pathic subset with poorer prognosis.
  evidence:
  - reference: PMID:39003309
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lower C3 and higher C4 levels were associated with poorer prognosis,
      highlighting a more 'Complement-Pathic' subset of patients.
    explanation: Supports prognostically relevant complement biomarker variation in IgAN.
genetic:
- name: HLA-DQB1
  gene_term:
    preferred_term: HLA-DQB1
    term:
      id: hgnc:4944
      label: HLA-DQB1
  association: Susceptibility locus
  relationship_type: SUSCEPTIBILITY
  evidence:
  - reference: PMID:21399633
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The strongest association in the combined cohort was located within a
      ~170 kb interval that includes the HLA-DRB1, -DQA1, and -DQB1 genes
      (rs9275596, OR = 0.63, p=1.6 × 10−26).
    explanation: >-
      Large trans-ancestry GWAS support the HLA-DRB1/DQA1/DQB1 region as the
      dominant common susceptibility signal in IgAN.
  notes: Strongest MHC signal localizes to the HLA-DRB1/DQA1/DQB1 interval; this is polygenic susceptibility rather than monogenic causation.
- name: CFH region / CFHR1-CFHR3 protective haplotype
  gene_term:
    preferred_term: CFH
    term:
      id: hgnc:4883
      label: CFH
  association: Protective complement-regulatory locus
  relationship_type: PROTECTIVE
  evidence:
  - reference: PMID:21399633
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This allele perfectly tags a common deletion spanning the CFHR1 and
      CFHR3 genes (CFHR1,3Δ)22,23.
    explanation: >-
      GWAS evidence supports a protective 1q32 complement-regulatory haplotype
      in IgAN, with the sentinel signal tagging the common CFHR1-CFHR3
      deletion.
  notes: Protective 1q32 signal is modeled at the CFH-related complement-regulatory locus because the sentinel GWAS haplotype tags the common CFHR1-CFHR3 deletion rather than establishing monogenic CFH causation.
- name: C1GALT1
  gene_term:
    preferred_term: C1GALT1
    term:
      id: hgnc:24337
      label: C1GALT1
  association: Susceptibility locus
  relationship_type: SUSCEPTIBILITY
  notes: Glycosylation locus consistent with dysregulated IgA1 O-glycosylation and Gd-IgA1 production rather than monogenic disease causation.
treatments:
- name: ACE inhibitors / ARBs
  description: First-line supportive renin-angiotensin system blockade for proteinuric and/or hypertensive IgAN.
  target_phenotypes:
  - preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  - preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: PMID:39188719
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The mainstay of therapy is supportive, consisting of lifestyle
      modifications, renin-angiotensin inhibition (if hypertensive or
      proteinuric), sodium-glucose-transporter 2 inhibition (if GFR reduced or
      proteinuric), and endothelin-receptor antagonism (if proteinuric).
    explanation: >-
      Contemporary review supports that renin-angiotensin inhibition remains
      first-line supportive therapy in proteinuric and/or hypertensive IgAN.
- name: SGLT2 inhibitors
  description: Adjunct kidney-protective therapy that lowers CKD progression risk in proteinuric IgAN.
  target_phenotypes:
  - preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: PMID:33878338
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, in participants with IgA nephropathy, dapagliflozin reduced the
      risk of chronic kidney disease progression with a favorable safety
      profile.
    explanation: >-
      Prespecified DAPA-CKD IgAN subgroup analysis provides direct human trial
      evidence supporting SGLT2 inhibition as kidney-protective adjunct
      therapy.
- name: Corticosteroids
  description: Considered in selected high-risk patients after maximal supportive care, with attention to infection and other toxicity risks.
  target_mechanisms:
  - target: Mesangial proliferation and inflammatory amplification
    treatment_effect: MODULATES
    description: Broad immunosuppression is used in selected high-risk patients to blunt ongoing inflammatory renal injury.
  target_phenotypes:
  - preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: PMID:35579642
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among patients with IgA nephropathy at high risk of progression,
      treatment with oral methylprednisolone for 6 to 9 months, compared with
      placebo, significantly reduced the risk of the composite outcome of kidney
      function decline, kidney failure, or death due to kidney disease.
      However, the incidence of serious adverse events was increased with oral
      methylprednisolone, mainly with high-dose therapy.
    explanation: >-
      TESTING provides direct randomized evidence for corticosteroid efficacy in
      high-risk IgAN while also justifying cautious, selective use because
      serious adverse events increased.
- name: Sparsentan
  description: Dual endothelin and angiotensin receptor antagonist used to lower persistent proteinuria in IgAN.
  target_phenotypes:
  - preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: PMID:37015244
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Once-daily treatment with sparsentan produced meaningful reduction in
      proteinuria compared with irbesartan in adults with IgA nephropathy.
    explanation: >-
      PROTECT interim analysis directly supports sparsentan as a proteinuria-
      lowering therapy in biopsy-proven IgAN.
- name: Targeted-release budesonide
  description: Gut-targeted corticosteroid strategy that reduces proteinuria and slows eGFR decline in high-risk primary IgAN.
  target_mechanisms:
  - target: Mucosal B-cell hyper-responsiveness
    treatment_effect: MODULATES
    description: Gut-targeted corticosteroid delivery is intended to dampen pathogenic mucosal immune activation upstream of Gd-IgA1 generation.
  target_phenotypes:
  - preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: PMID:37591292
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 9-month treatment period with Nefecon provided a clinically relevant
      reduction in eGFR decline and a durable reduction in proteinuria versus
      placebo, providing support for a disease-modifying effect in patients with
      IgA nephropathy.
    explanation: >-
      Phase 3 NefIgArd trial directly supports targeted-release budesonide as a
      mucosal-directed therapy that improves proteinuria and kidney-function
      trajectory in primary IgAN.
differential_diagnoses:
- name: IgA vasculitis
  disease_term:
    preferred_term: IgA vasculitis
    term:
      id: MONDO:0019167
      label: immunoglobulin A vasculitis
  description: >-
    Related systemic small-vessel vasculitis with shared Gd-IgA1 immune-complex
    biology and often indistinguishable kidney histology, but with characteristic
    extra-renal vasculitic manifestations that support separate representation.
  distinguishing_features:
  - Palpable purpura and other systemic small-vessel vasculitis features favor IgA vasculitis over kidney-limited IgAN.
  - Kidney biopsy findings can be indistinguishable between IgAN and IgA vasculitis nephritis.
  - Chronic lesions such as segmental glomerulosclerosis and tubular atrophy / interstitial fibrosis are more frequent in delayed-diagnosis IgAN, whereas proliferative lesions and earlier diagnosis after rash are more typical of IgA vasculitis nephritis.
  evidence:
  - reference: PMID:40069065
    supports: PARTIAL
    evidence_source: OTHER
    snippet: IgA vasculitis (IgAV) is considered a systemic form of IgA nephropathy (IgAN).
    explanation: >-
      Supports the close mechanistic kinship between the two entities, which is
      why IgA vasculitis must be considered explicitly at the IgAN boundary.
  - reference: PMID:40069065
    supports: SUPPORT
    evidence_source: OTHER
    snippet: On kidney biopsy, the two diseases are indistinguishable
    explanation: >-
      Confirms that the renal lesion alone does not reliably separate IgAN from
      IgA vasculitis nephritis.
  - reference: PMID:40069065
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Due to characteristic skin rash, IgAVN patients are diagnosed precociously.
    explanation: >-
      Supports the key clinical split: systemic vasculitic manifestations, not
      renal histology alone, distinguish IgA vasculitis from kidney-limited IgAN.
classifications:
  harrisons_chapter:
  - classification_value: kidney disorder
  - classification_value: glomerular disease
  - classification_value: autoimmune disease
references:
- reference: DOI:10.3389/fneph.2023.1346769
  title: 'The role of BAFF and APRIL in IgA nephropathy: pathogenic mechanisms and targeted therapies'
  findings: []
- reference: DOI:10.3389/fimmu.2024.1436923
  title: Contemporary review of IgA nephropathy
  findings: []
- reference: DOI:10.1093/glycob/cwae060
  title: O-glycosylation of IgA1 and the pathogenesis of an autoimmune disease IgA nephropathy
  findings: []
- reference: DOI:10.1093/ckj/sfaf152
  title: Recent advances in pathogenetic concepts and disease modeling of IgA nephropathy
  findings: []
- reference: DOI:10.1093/ckj/sfad198
  title: Targeting complement in IgA nephropathy
  findings: []
- reference: DOI:10.1016/j.kint.2023.10.012
  title: 'A new alternative: inhibiting complement activation in patients with IgA nephropathy'
  findings: []
- reference: DOI:10.1007/s40620-022-01363-4
  title: Predictive prognostic value of glomerular C3 deposition in IgA nephropathy
  findings: []
- reference: DOI:10.1038/s41598-024-65857-w
  title: Role of serum complement C3 and C4 on kidney outcomes in IgA nephropathy
  findings: []
- reference: DOI:10.1186/s12882-024-03512-2
  title: Validation of IgA nephropathy diagnosis in the Swedish Renal Registry
  findings: []
- reference: DOI:10.1038/ng.787
  title: Genome-wide association study identifies susceptibility loci for IgA nephropathy
  findings: []
- reference: DOI:10.1016/S0140-6736(23)00569-X
  title: 'Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial'
  findings: []
- reference: DOI:10.1016/S0140-6736(23)01554-4
  title: 'Efficacy and safety of a targeted-release formulation of budesonide in patients with primary IgA nephropathy (NefIgArd): 2-year results from a randomised phase 3 trial'
  findings: []
- reference: DOI:10.1016/j.kint.2021.03.033
  title: A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy
  findings: []
- reference: DOI:10.1001/jama.2022.5368
  title: 'Effect of Oral Methylprednisolone on Decline in Kidney Function or Kidney Failure in Patients With IgA Nephropathy: The TESTING Randomized Clinical Trial'
  findings: []
- reference: DOI:10.1016/j.semnephrol.2025.151571
  title: 'IgA Vasculitis and IgA Nephropathy: Two Sides of the Same Coin?'
  findings: []