Membranous nephropathy

Complex MONDO:0005376 Pathograph 22 Show in embeddings browser Kidney Disease Autoimmune Disease

Immune-complex glomerular disease characterized by subepithelial deposits along the glomerular basement membrane, podocyte injury, proteinuria, and nephrotic manifestations.

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11
Pathophys.
6
Phenotypes
22
Pathograph
2
Genes
7
Medical Actions
5
Subtypes
6
Datasets
1
Deep Research
🏷

Classifications

Harrison's Part
KIDNEY URINARY TRACT IMMUNE RHEUMATOLOGIC
◆

Subtypes

5
clinical context
Primary membranous nephropathy
Autoimmune membranous nephropathy driven by circulating autoantibodies against podocyte antigens, especially PLA2R1 and less commonly THSD7A.
Secondary membranous nephropathy
Membranous nephropathy with the same downstream subepithelial immune-deposit pattern but triggered by an underlying autoimmune disease, infection, malignancy, IgG4-related disease, or drug exposure.
molecular
PLA2R-associated membranous nephropathy
Dominant antigen-defined primary membranous nephropathy subset anchored by circulating anti-PLA2R autoantibodies.
Show evidence (1 reference)
PMID:33808418 SUPPORT Human Clinical
"Approximately 50-80% and 3-5% of primary MN (PMN) cases are associated with either anti-PLA2R or anti-THSD7A antibodies, respectively."
Supports PLA2R-associated disease as the dominant antigen-defined subset of primary membranous nephropathy.
THSD7A-associated membranous nephropathy
Distinct minority antigen-defined membranous nephropathy subset characterized by anti-THSD7A autoantibodies and podocyte THSD7A targeting.
Show evidence (1 reference)
PMID:25394321 SUPPORT Human Clinical
"In our cohort, 15 of 154 patients with idiopathic membranous nephropathy had circulating autoantibodies to THSD7A but not to PLA2R1, a finding that suggests a distinct subgroup of patients with this condition."
Supports THSD7A-associated disease as a biologically distinct minority subgroup rather than a nonspecific ancillary biomarker pattern.
Other antigen-associated membranous nephropathy
PLA2R/THSD7A-negative disease is not a single residual bucket; target-antigen workups can identify NELL1-, EXT1/EXT2-, PCDH7-, NCAM1-, SEMA3B-, and related antigen-defined subsets with different autoimmune, malignancy-associated, or pediatric contexts.
Show evidence (1 reference)
PMID:33673911 SUPPORT Human Clinical
"OBJECTIVE: To describe the clinical and pathological phenotype of membranous nephropathy (MN) associated with M-type-phospholipase-A2-receptor (PLA2R), thrombospondin-type-1-domain-containing-7A (THSD7A), semaphorin 3B (SEMA3B), neural-epidermal-growth-factor-like-1-protein (NELL-1),..."
Supports the existence of a broader antigen-defined MN landscape beyond the dominant PLA2R and THSD7A serologic subsets.
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Pathophysiology

11
Autoantibody production against podocyte antigens
Primary membranous nephropathy reflects loss of tolerance to podocyte autoantigens, with B cell and plasma cell responses generating circulating autoantibodies against PLA2R1 in most seropositive cases and THSD7A in a smaller minority. These serologic subsets are mechanistically important for primary disease classification and monitoring, but they do not imply that the entire membranous nephropathy disease root is monogenic. Other target antigens are tracked at the subtype level so the root pathograph stays focused on the shared autoimmune cascade rather than fragmenting into parallel sparse upstream nodes.
B cell CL:0000236 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves B cell (CL:0000236). CL:0000236 is a cell type from the Cell Ontology. plasma cell CL:0000786 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves plasma cell (CL:0000786). CL:0000786 is a cell type from the Cell Ontology.
PLA2R1 hgnc:9042 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PLA2R1 (hgnc:9042). hgnc:9042 is a gene from the HUGO Gene Nomenclature Committee. THSD7A hgnc:22207 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves THSD7A (hgnc:22207). hgnc:22207 is a gene from the HUGO Gene Nomenclature Committee.
B cell activation GO:0042113 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves B cell activation (GO:0042113). GO:0042113 is a biological process from the Gene Ontology. immunoglobulin production GO:0002377 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves immunoglobulin production (GO:0002377). GO:0002377 is a biological process from the Gene Ontology.
Downstream
In situ subepithelial immune complex deposition Circulating autoantibodies bind podocyte antigens and seed local immune-complex formation along the outer glomerular basement membrane.
Show evidence (2 references)
PMID:33808418 SUPPORT Human Clinical
"Approximately 50-80% and 3-5% of primary MN (PMN) cases are associated with either anti-PLA2R or anti-THSD7A antibodies, respectively."
Establishes the two dominant serologic autoantigen subsets of primary membranous nephropathy without implying that either gene is the sole root cause of all MN.
PMID:31447839 SUPPORT Other
"In idiopathic membranous nephropathy (IMN) the immune complexes are formed by circulating antibodies binding mainly to one of two naturally-expressed podocyte antigens: the M-type receptor for secretory phospholipase A2 (PLA2R1) and the Thrombospondin type-1 domain-containing 7A (THSD7A)."
Supports the core autoimmune framing in which circulating anti-podocyte antibodies initiate primary membranous nephropathy.
In situ subepithelial immune complex deposition
Autoantibodies bind antigens exposed on the podocyte-facing aspect of the glomerular capillary wall, generating immune complexes in situ. Those complexes accumulate as subepithelial electron-dense deposits and are accompanied by progressive thickening of the glomerular basement membrane.
podocyte CL:0000653 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves podocyte (CL:0000653). CL:0000653 is a cell type from the Cell Ontology.
glomerular basement membrane UBERON:0005777 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in glomerular basement membrane (UBERON:0005777). UBERON:0005777 is an anatomical location from the Uberon multi-species anatomy ontology. renal glomerulus UBERON:0000074 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in renal glomerulus (UBERON:0000074). UBERON:0000074 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Complement activation at the glomerular capillary wall Subepithelial immune deposits trigger complement activation around podocytes and the outer glomerular basement membrane.
Show evidence (2 references)
PMID:39185424 SUPPORT Other
"The most characteristic feature of membranous nephropathy (MN) is the presence of subepithelial electron dense deposits and the consequential thickening of the glomerular basement membrane."
Directly supports the defining biopsy pattern of subepithelial deposits with glomerular basement membrane thickening.
PMID:39185424 SUPPORT Other
"Subepithelial immune complexes are formed in situ by autoantibodies targeting native autoantigens or exogenous planted antigens such as the phospholipase A2 receptor (PLA2R) and cationic BSA respectively."
Supports the local in situ immune-complex formation step that bridges circulating antibodies to glomerular deposition.
Complement activation at the glomerular capillary wall
The subepithelial immune deposits activate complement at the podocyte-facing glomerular basement membrane, generating membrane attack complex and C5a signals that amplify local injury.
podocyte CL:0000653 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves podocyte (CL:0000653). CL:0000653 is a cell type from the Cell Ontology.
complement activation GO:0006956 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves complement activation (GO:0006956). GO:0006956 is a biological process from the Gene Ontology.
glomerular basement membrane UBERON:0005777 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in glomerular basement membrane (UBERON:0005777). UBERON:0005777 is an anatomical location from the Uberon multi-species anatomy ontology. renal glomerulus UBERON:0000074 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in renal glomerulus (UBERON:0000074). UBERON:0000074 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Podocyte structural injury Complement effector activity injures podocytes and destabilizes the slit-diaphragm/cytoskeletal apparatus.
Show evidence (2 references)
PMID:36286856 SUPPORT Other
"Membrane-attacking complex (MAC) is the terminal product of any complement pathways activation (classical, lectin or alternative) and plays the leading role in the complement-mediated podocytic damage."
Directly supports MAC-centered complement injury as the key bridge from immune deposits to podocyte damage.
PMID:41209172 SUPPORT Other
"The formation of immune complexes on podocytes triggers complement activation, leading to the activation of both the C5b-C9 complex and C5a."
Reinforces that podocyte-bound immune complexes activate terminal complement effectors relevant to membranous nephropathy.
Podocyte structural injury
Complement-dependent and direct antibody-mediated injury disrupt podocyte structural homeostasis, including actin cytoskeletal organization and slit-diaphragm integrity. This converts a subepithelial deposit pattern into a filtration-barrier lesion.
podocyte CL:0000653 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves podocyte (CL:0000653). CL:0000653 is a cell type from the Cell Ontology.
actin cytoskeleton organization GO:0030036 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves actin cytoskeleton organization (GO:0030036). GO:0030036 is a biological process from the Gene Ontology.
renal glomerulus UBERON:0000074 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in renal glomerulus (UBERON:0000074). UBERON:0000074 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Podocyte apoptosis Complement-dependent and complement-independent injury initiates caspase-dependent apoptotic death of podocytes.
Podocyte pyroptosis Complement activation, oxidative stress, and danger-associated molecular patterns converge on the NLRP3 inflammasome to drive pyroptotic podocyte lysis.
Podocyte ferroptosis Injured podocytes undergo iron-dependent lipid peroxidation with failure of GPX4-mediated antioxidant defense.
Podocyte autophagy dysregulation Podocyte injury disturbs autophagic flux in either direction, so that both insufficient and excessive autophagy worsen the injury.
Glomerular filtration barrier failure and proteinuria Podocyte injury reduces filtration selectivity and allows sustained urinary protein loss.
Show evidence (2 references)
PMID:40888279 SUPPORT Other
"Collectively, they reveal complement-dependent and direct podocytotoxic injury mechanisms."
Supports the specific transition from immune/complement activity to direct podocyte injury.
PMID:36286856 SUPPORT Other
"In MN, proteinuria is developed by podocyte damage due to the complement system activation in response to the subepithelial deposition of immune complexes containing various auto- and exogenous antigens."
Connects podocyte damage causally to the next step of proteinuria in membranous nephropathy.
Podocyte apoptosis
Caspase-dependent apoptotic death of podocytes, driving irreversible podocyte depletion. In the complement-dependent route, sublytic C5b-9 promotes apoptosis through the CXCL12/CXCR4/STAT3 axis; silencing CXCL12 alleviates C5b-9-induced podocyte damage.
podocyte CL:0000653 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves podocyte (CL:0000653). CL:0000653 is a cell type from the Cell Ontology.
apoptotic process GO:0006915 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased apoptotic process (GO:0006915). GO:0006915 is a biological process from the Gene Ontology.
Downstream
Podocyte depletion from programmed cell death Apoptotic loss of podocytes contributes to the cumulative podocyte deficit.
Show evidence (1 reference)
PMID:42553762 SUPPORT Other
"Multiple signaling pathways govern podocyte apoptosis in MN. In the complement‑dependent pathway, C5b-9 promotes apoptosis via the C-X-C motif chemokine ligand 12/C-X-C chemokine receptor type 4/Signal transducer and activator of transcription 3(CXCL12/CXCR4/STAT3) axis, and CXCL12 silencing..."
Identifies complement-dependent apoptosis pathways in membranous nephropathy podocytes.
Podocyte pyroptosis
Pro-inflammatory lytic podocyte death driven by NLRP3 inflammasome-mediated caspase-1 activation and gasdermin D cleavage, releasing IL-1beta and IL-18 and amplifying local inflammation.
podocyte CL:0000653 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves podocyte (CL:0000653). CL:0000653 is a cell type from the Cell Ontology.
pyroptotic inflammatory response GO:0070269 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased pyroptotic inflammatory response (GO:0070269). GO:0070269 is a biological process from the Gene Ontology.
Downstream
Podocyte depletion from programmed cell death Pyroptotic lysis contributes to the cumulative podocyte deficit and amplifies glomerular inflammation.
Show evidence (1 reference)
PMID:42553762 SUPPORT Other
"In MN, complement activation, oxidative stress, and danger‑associated molecular patterns cooperatively activate the NOD-Like Receptor Family Pyrin Domain Containing 3(NLRP3) inflammasome, promoting caspase‑1‑dependent cleavage of GSDMD. This leads to membrane rupture, cytosolic leakage, and..."
Establishes NLRP3 inflammasome-mediated pyroptosis as a key inflammatory PCD mechanism in membranous nephropathy.
Podocyte ferroptosis
Iron-dependent lipid peroxidation of podocyte membranes with failure of GPX4-mediated antioxidant defense, producing mitochondrial structural collapse.
podocyte CL:0000653 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves podocyte (CL:0000653). CL:0000653 is a cell type from the Cell Ontology.
ferroptosis GO:0097707 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased ferroptosis (GO:0097707). GO:0097707 is a biological process from the Gene Ontology.
Downstream
Podocyte depletion from programmed cell death Ferroptotic death contributes to the cumulative podocyte deficit.
Show evidence (1 reference)
PMID:42553762 SUPPORT Other
"In MN, ferroptosis causes lipid peroxidative damage to podocyte membranes and mitochondrial structural collapse, thereby worsening filtration dysfunction and proteinuria."
Documents ferroptosis and iron-dependent lipid peroxidation as mechanisms of podocyte injury in membranous nephropathy.
Podocyte autophagy dysregulation
Disturbed autophagic flux in podocytes. The defect is bidirectional rather than a simple loss: either insufficient or excessive autophagy exacerbates podocyte injury, and the degree of dysregulation correlates with proteinuria severity and clinical outcome.
podocyte CL:0000653 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves podocyte (CL:0000653). CL:0000653 is a cell type from the Cell Ontology.
autophagy GO:0006914 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated autophagy (GO:0006914). GO:0006914 is a biological process from the Gene Ontology.
Downstream
Podocyte depletion from programmed cell death Autophagic dysregulation compounds the other death modalities and contributes to the cumulative podocyte deficit.
Show evidence (1 reference)
PMID:42553762 SUPPORT Other
"In MN, however, autophagy becomes dysregulated: either insufficient or excessive autophagy exacerbates podocyte injury, accelerates disease progression, and correlates with proteinuria severity and clinical outcomes."
Establishes dysregulated autophagy as a pathogenic mechanism contributing to podocyte injury and proteinuria in membranous nephropathy. The modifier is DYSREGULATED rather than a direction because the quoted sentence is explicitly bidirectional.
Podocyte depletion from programmed cell death
The convergence point of the four programmed cell death modalities: a cumulative, non-replaceable loss of podocytes from the glomerular tuft. This node exists so the shared downstream consequence and the treatments that act across modalities have a single target; the modality-specific claims and their evidence live on the four upstream nodes.
podocyte CL:0000653 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves podocyte (CL:0000653). CL:0000653 is a cell type from the Cell Ontology.
renal glomerulus UBERON:0000074 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in renal glomerulus (UBERON:0000074). UBERON:0000074 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Glomerular filtration barrier failure and proteinuria Sustained podocyte loss from programmed cell death accelerates glomerular barrier failure and heavy proteinuria.
Show evidence (1 reference)
PMID:42553762 SUPPORT Other
"Complement-dependent and complement-independent pathways in MN can synergistically initiate podocyte apoptosis, pyroptosis, ferroptosis, and autophagy dysfunction."
Supports treating the four modalities as co-occurring routes to a single shared podocyte deficit rather than alternatives.
Glomerular filtration barrier failure and proteinuria
Once podocytes are injured, the glomerular filtration barrier loses permselectivity and patients develop the heavy proteinuria that drives the nephrotic syndrome phenotype. Persistent proteinuria is also linked to worse long-term kidney outcomes.
podocyte CL:0000653 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves podocyte (CL:0000653). CL:0000653 is a cell type from the Cell Ontology.
glomerular filtration GO:0003094 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves glomerular filtration (GO:0003094). GO:0003094 is a biological process from the Gene Ontology.
renal glomerulus UBERON:0000074 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in renal glomerulus (UBERON:0000074). UBERON:0000074 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Progressive kidney function decline Ongoing nephrotic-range proteinuria and persistent glomerular injury are associated with reduced kidney survival.
Show evidence (1 reference)
PMID:36286856 SUPPORT Other
"In MN, proteinuria is developed by podocyte damage due to the complement system activation in response to the subepithelial deposition of immune complexes containing various auto- and exogenous antigens."
Supports proteinuria as the direct physiologic consequence of the podocyte/complement injury cascade.
Progressive kidney function decline
Clinical course is heterogeneous, but a subset of patients experiences sustained eGFR decline and kidney failure despite modern therapy.
Show evidence (1 reference)
PMID:40630289 SUPPORT Human Clinical
"RESULTS: In total, 591 patients (537 adults and 54 children) were evaluated with 9% reaching kidney failure."
Human CureGN cohort data confirms that membranous nephropathy can progress to kidney failure in a meaningful subset of patients.
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Pathograph

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

6
Genitourinary 3
Nephrotic syndrome HP:0000100 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nephrotic syndrome (HP:0000100). HP:0000100 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33808418 SUPPORT Human Clinical
"Membranous nephropathy (MN) is an autoimmune disease of the kidney glomerulus and one of the leading causes of nephrotic syndrome."
Supports nephrotic syndrome as the signature clinical syndrome of membranous nephropathy.
Proteinuria HP:0000093 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Proteinuria (HP:0000093). HP:0000093 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36286856 SUPPORT Other
"In MN, proteinuria is developed by podocyte damage due to the complement system activation in response to the subepithelial deposition of immune complexes containing various auto- and exogenous antigens."
Supports proteinuria as a direct downstream consequence of the core immune-complex/complement/podocyte injury cascade in membranous nephropathy.
Renal insufficiency HP:0000083 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal insufficiency (HP:0000083). HP:0000083 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40630289 SUPPORT Human Clinical
"Age < 18 years, self-reported Black/African American race, proteinuria > 3 g/g, and lower estimated glomerular filtration rate (eGFR) at enrollment were associated with worse kidney survival."
Human cohort data supports clinically meaningful kidney function decline as an outcome phenotype in membranous nephropathy.
Metabolism 3
Edema HP:0000969 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Edema (HP:0000969). HP:0000969 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21877306 SUPPORT Human Clinical
"The clinical symptoms range from small proteinuria to severe nephrotic syndrome with enormous oedema, not controllable hyperlipidaemia and increased disposition for infection."
Supports edema as part of the severe nephrotic clinical presentation of membranous nephropathy.
Hypoalbuminemia HP:0003073 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoalbuminemia (HP:0003073). HP:0003073 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40760331 SUPPORT Human Clinical
"Nephrotic syndrome (NS) is characterized by proteinuria > 3.5 g/day, hypoalbuminemia, peripheral edema, and hyperlipidemia. Common primary causes of NS are podocytopathies, such as minimal change nephropathy, focal segmental glomerulosclerosis, and membranous nephropathy."
Provides syndrome-level support that hypoalbuminemia belongs to the nephrotic phenotype commonly caused by membranous nephropathy, without claiming this review is MN-specific mechanistic evidence.
Hyperlipidemia HP:0003077 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperlipidemia (HP:0003077). HP:0003077 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21877306 SUPPORT Human Clinical
"The clinical symptoms range from small proteinuria to severe nephrotic syndrome with enormous oedema, not controllable hyperlipidaemia and increased disposition for infection."
Supports hyperlipidemia as part of the nephrotic clinical presentation of membranous nephropathy.
🧬

Genetic Associations

2
PLA2R1 susceptibility locus (GWAS)
Gene: PLA2R1 hgnc:9042 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PLA2R1 (hgnc:9042). hgnc:9042 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:24262501 SUPPORT Human Clinical
"Single nucleotide polymorphisms (SNPs) within HLA complex class II HLA-DQ α-chain 1 (HLA-DQA1) and M-type phospholipase A2 receptor (PLA2R1) genes were identified as strong risk factors for idiopathic membranous nephropathy (IMN) development in a recent genome-wide association study."
Supports PLA2R1 as a human susceptibility locus in primary membranous nephropathy rather than a universal monogenic cause.
HLA-DQA1 susceptibility locus (GWAS)
Gene: HLA-DQA1 hgnc:4942 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is HLA-DQA1 (hgnc:4942). hgnc:4942 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:24262501 SUPPORT Human Clinical
"Single nucleotide polymorphisms (SNPs) within HLA complex class II HLA-DQ α-chain 1 (HLA-DQA1) and M-type phospholipase A2 receptor (PLA2R1) genes were identified as strong risk factors for idiopathic membranous nephropathy (IMN) development in a recent genome-wide association study."
Supports HLA-DQA1 as a GWAS-supported susceptibility locus contributing to primary membranous nephropathy.
💊

Medical Actions

7
Rituximab
Action: rituximab therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is rituximab therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: rituximab NCIT:C1702 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses rituximab (NCIT:C1702). NCIT:C1702 is a therapeutic agent from the NCI Thesaurus.
Anti-CD20 B-cell depletion used in guideline-supported first-line immunotherapy for primary membranous nephropathy.
Mechanism Target:
INHIBITS Autoantibody production against podocyte antigens — Anti-CD20 B-cell depletion reduces the autoreactive B-cell compartment that sustains pathogenic anti-podocyte antibodies.
Show evidence (1 reference)
PMID:31269364 SUPPORT Human Clinical
"Among patients in remission who tested positive for anti-phospholipase A2 receptor (PLA2R) antibodies, the decline in autoantibodies to anti-PLA2R was faster and of greater magnitude and duration in the rituximab group than in the cyclosporine group."
Directly supports rituximab suppressing the pathogenic autoantibody response that sustains primary membranous nephropathy.
Target Phenotypes: Nephrotic syndrome HP:0000100 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Nephrotic syndrome (HP:0000100). HP:0000100 is a phenotype from the Human Phenotype Ontology. Proteinuria HP:0000093 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Proteinuria (HP:0000093). HP:0000093 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
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."
Provides primary randomized-trial evidence that rituximab yields more durable remission than cyclosporine in membranous nephropathy.
PMID:41007719 SUPPORT Human Clinical
"Recent evidence and the KDIGO guideline establish Rituximab as the first-line treatment for Primary Membranous Nephropathy and ANCA-associated vasculitis."
Supports rituximab as current first-line immunotherapy for primary membranous nephropathy.
Cyclophosphamide-based immunosuppression
Cyclophosphamide-based regimens remain standard high-risk therapy for primary membranous nephropathy.
Target Phenotypes: Nephrotic syndrome HP:0000100 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Nephrotic syndrome (HP:0000100). HP:0000100 is a phenotype from the Human Phenotype Ontology. Proteinuria HP:0000093 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Proteinuria (HP:0000093). HP:0000093 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38915435 SUPPORT Human Clinical
"Third, we suggest prescribing rituximab (RTX) or RTX combined with calcineurin inhibitors in medium-risk patients. Fourth, we propose cyclophosphamide-based immunosuppression for high-risk patients."
Supports cyclophosphamide-based immunosuppression as a recommended therapy in high-risk primary membranous nephropathy.
Supportive CKD therapy
Supportive therapy aimed at reducing non-immune kidney injury progression, including renin-angiotensin-aldosterone system blockade and SGLT2 inhibition.
Target Phenotypes: Proteinuria HP:0000093 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Proteinuria (HP:0000093). HP:0000093 is a phenotype from the Human Phenotype Ontology. Renal insufficiency HP:0000083 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Renal insufficiency (HP:0000083). HP:0000083 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37218706 SUPPORT Human Clinical
"Approved drug interventions include inhibitors of the renin-angiotensin-aldosterone system and sodium-glucose cotransporter-2."
Supports supportive RAAS/SGLT2 therapy as part of outcome-oriented care for immune-mediated glomerular disease, including membranous nephropathy.
Shenqi Particle (herbal formula)
Action: Traditional Chinese herbal formula therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Traditional Chinese herbal formula therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: Shenqi Particle (Shenqi Granule) NCIT:C129986 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Shenqi Particle (Shenqi Granule), annotated with Traditional Chinese Medicine Formulation (NCIT:C129986). NCIT:C129986 is a therapeutic agent from the NCI Thesaurus.
Platform: Other
Traditional Chinese herbal formula composed of 13 medicinal herbs including Astragali Radix and Angelicae Sinensis Radix with clinical efficacy in primary membranous nephropathy.
Mechanism Target:
MODULATES Podocyte autophagy dysregulation — Shenqi Particle enhances protective podocyte autophagy by inhibiting mTOR/ULK1 phosphorylation, raising Beclin-1 and the LC3-II/I ratio and the podocyte cytoskeletal proteins CD2AP and alpha-actinin-4.
Show evidence (1 reference)
PMID:42553762 SUPPORT In Vitro
"It enhances autophagic activity by inhibiting mTOR/ULK1 phosphorylation"
States the mTOR/ULK1 autophagy mechanism this link asserts. Table 1 of the review lists this result with no in vivo arm and puromycin-aminonucleoside-induced MPC5 podocytes as the model, hence IN_VITRO.
Target Phenotypes: Nephrotic syndrome HP:0000100 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Nephrotic syndrome (HP:0000100). HP:0000100 is a phenotype from the Human Phenotype Ontology. Proteinuria HP:0000093 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Proteinuria (HP:0000093). HP:0000093 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42553762 SUPPORT Human Clinical
"One randomized controlled trial (RCT) and one prospective cohort study have shown that multicomponent hospital preparation Shenqi Particle monotherapy provides a remission rate comparable to glucocorticoid plus cyclophosphamide therapy in IMN patients, with superior renal protection and fewer..."
Clinical evidence demonstrates Shenqi Particle achieves comparable remission rates to conventional immunosuppression with fewer adverse effects.
Mahuang Fuzi and Shenzhuo Decoction (herbal formula)
Action: Traditional Chinese herbal formula therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Traditional Chinese herbal formula therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: Mahuang Fuzi and Shenzhuo Decoction NCIT:C129986 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Mahuang Fuzi and Shenzhuo Decoction, annotated with Traditional Chinese Medicine Formulation (NCIT:C129986). NCIT:C129986 is a therapeutic agent from the NCI Thesaurus.
Platform: Other
Traditional Chinese herbal formula demonstrating high long-term remission rates in idiopathic membranous nephropathy regardless of prior immunosuppressive treatment.
Mechanism Target:
INHIBITS Podocyte apoptosis — Mahuang Fuzi and Shenzhuo Decoction modulates IL-6/STAT3 and Wnt/β-catenin signaling to inhibit podocyte apoptosis, with simultaneous reduction of inflammation and renal pathological lesions.
Show evidence (1 reference)
PMID:42553762 SUPPORT Model Organism
"Mahuang Fuzi and Shenzhuo Decoction (MFSD) modulates IL-6/STAT3 inflammatory pathway and Wnt/β-catenin signaling to inhibit apoptosis and upregulate autophagy, which is associated with reduced proteinuria and alleviated renal pathological lesions."
Gives the molecular mechanisms through which this formula protects podocytes. Table 1 of the review lists this result with a passive Heymann nephritis rat arm at 1 mL/100 g and no in vitro arm, hence MODEL_ORGANISM.
MODULATES Podocyte autophagy dysregulation — Mahuang Fuzi and Shenzhuo Decoction upregulates protective podocyte autophagy through the same IL-6/STAT3 and Wnt/β-catenin signaling, alongside its anti-apoptotic effect.
Show evidence (1 reference)
PMID:42553762 SUPPORT Model Organism
"Mahuang Fuzi and Shenzhuo Decoction (MFSD) modulates IL-6/STAT3 inflammatory pathway and Wnt/β-catenin signaling to inhibit apoptosis and upregulate autophagy, which is associated with reduced proteinuria and alleviated renal pathological lesions."
The same sentence names autophagy upregulation as a second, distinct modality this formula acts on. Table 1 of the review lists this result with a passive Heymann nephritis rat arm at 1 mL/100 g and no in vitro arm, hence MODEL_ORGANISM.
Target Phenotypes: Nephrotic syndrome HP:0000100 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Nephrotic syndrome (HP:0000100). HP:0000100 is a phenotype from the Human Phenotype Ontology. Proteinuria HP:0000093 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Proteinuria (HP:0000093). HP:0000093 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42553762 SUPPORT Human Clinical
"One prospective, multicenter, open-label clinical trial and one multicenter, non-randomized, single-arm clinical trial have confirmed its high long-term remission rate, which is unaffected by age or prior immunosuppressive treatment, supporting its broad clinical applicability."
Multicenter clinical trials confirm high remission rates across diverse patient populations with minimal impact of age or prior treatment history.
Jianpi Qushi Heluo Formula (herbal formula)
Action: Traditional Chinese herbal formula therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Traditional Chinese herbal formula therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: Jianpi Qushi Heluo Formula NCIT:C129986 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Jianpi Qushi Heluo Formula, annotated with Traditional Chinese Medicine Formulation (NCIT:C129986). NCIT:C129986 is a therapeutic agent from the NCI Thesaurus.
Platform: Other
Traditional Chinese herbal formula shown in passive Heymann nephritis rats to restore PINK1/Parkin-mediated mitophagy and suppress NLRP3-driven pyroptosis in podocytes.
Mechanism Target:
MODULATES Podocyte autophagy dysregulation — Jianpi Qushi Heluo Formula enhances PINK1/Parkin-mediated mitophagy and reduces mitochondrial ROS accumulation and membrane potential loss, restoring autophagic handling of damaged mitochondria in podocytes.
Show evidence (1 reference)
PMID:42553762 SUPPORT Model Organism
"Jianpi Qushi Heluo Formula enhances PINK1/Parkin-mediated mitophagy, reduces mitochondrial ROS accumulation and MMP loss, and prevents NLRP3 inflammasome activation, thereby coordinating mitophagy and pyroptosis."
Names mitophagy enhancement, a selective autophagy mechanism, as one of the two modalities this formula coordinates. Table 1 of the review lists this result with a passive Heymann nephritis rat arm at 16.2 and 32.4 g/kg and no in vitro arm, hence MODEL_ORGANISM.
INHIBITS Podocyte pyroptosis — Jianpi Qushi Heluo Formula prevents NLRP3 inflammasome activation, suppressing the pyroptotic arm that its restored mitophagy is coordinated with.
Show evidence (1 reference)
PMID:42553762 SUPPORT Model Organism
"Jianpi Qushi Heluo Formula enhances PINK1/Parkin-mediated mitophagy, reduces mitochondrial ROS accumulation and MMP loss, and prevents NLRP3 inflammasome activation, thereby coordinating mitophagy and pyroptosis."
The same sentence names NLRP3 inflammasome prevention, the upstream step of podocyte pyroptosis, as the second modality this formula acts on. Table 1 of the review lists this result with a passive Heymann nephritis rat arm at 16.2 and 32.4 g/kg and no in vitro arm, hence MODEL_ORGANISM.
Target Phenotypes: Proteinuria HP:0000093 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Proteinuria (HP:0000093). HP:0000093 is a phenotype from the Human Phenotype Ontology.
Jian Pi Qu Shi Formula (herbal formula)
Action: Traditional Chinese herbal formula therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Traditional Chinese herbal formula therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: Jian Pi Qu Shi Formula NCIT:C129986 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Jian Pi Qu Shi Formula, annotated with Traditional Chinese Medicine Formulation (NCIT:C129986). NCIT:C129986 is a therapeutic agent from the NCI Thesaurus.
Platform: Other
Traditional Chinese herbal formula demonstrating high complete remission rate in refractory idiopathic membranous nephropathy with concurrent microbiota restoration.
Target Phenotypes: Nephrotic syndrome HP:0000100 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Nephrotic syndrome (HP:0000100). HP:0000100 is a phenotype from the Human Phenotype Ontology. Proteinuria HP:0000093 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Proteinuria (HP:0000093). HP:0000093 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42553762 SUPPORT Human Clinical
"One RCT and one retrospective case series have demonstrated that JPQSF achieves an 80% complete remission rate after one-year treatment in patients with refractory IMN and ameliorates intestinal flora dysbiosis."
Clinical evidence demonstrates 80% complete remission in refractory cases with concurrent microbiome improvement.
🔬

Biochemical Markers

2
Anti-PLA2R autoantibodies (Positive)
Context: High-specificity serologic biomarker that tracks disease activity in primary membranous nephropathy.
Show evidence (2 references)
PMID:26090644 SUPPORT Human Clinical
"Anti-PLA2R antibodies have high specificity (close to 100%), sensitivity (70-80%), and predictive value."
Supports anti-PLA2R antibodies as a clinically useful diagnostic and monitoring biomarker in membranous nephropathy.
PMID:27777266 SUPPORT Human Clinical
"Levels of anti-PLA2R antibodies and possibly, anti-THSD7A antibodies tightly correlate with disease activity."
Supports use of anti-PLA2R antibody level as a disease activity biomarker.
Anti-THSD7A autoantibodies (Positive)
Context: Minority antigen-defined subgroup of primary membranous nephropathy that can be corroborated by biopsy antigen staining.
Show evidence (2 references)
PMID:25394321 SUPPORT Human Clinical
"In our cohort, 15 of 154 patients with idiopathic membranous nephropathy had circulating autoantibodies to THSD7A but not to PLA2R1, a finding that suggests a distinct subgroup of patients with this condition."
Supports anti-THSD7A serology as a distinct minority subgroup marker rather than a generic secondary finding.
PMID:27777266 SUPPORT Human Clinical
"The presence or absence of anti-PLA2R and anti-THSD7A antibodies adds important information to clinical and immunopathologic data in discriminating between primary and secondary MN."
Supports anti-THSD7A serology as a clinically meaningful minority biomarker and subtype discriminator in membranous nephropathy.
🔬

Diagnosis

2
Kidney biopsy
Histologic confirmation of membranous nephropathy.
Results: Detects subepithelial immune deposits with glomerular basement membrane thickening.
Show evidence (1 reference)
PMID:39185424 SUPPORT Other
"The most characteristic feature of membranous nephropathy (MN) is the presence of subepithelial electron dense deposits and the consequential thickening of the glomerular basement membrane."
Supports renal biopsy as the defining diagnostic modality for the characteristic deposit/thickening pattern.
Serology and target-antigen work-up
Serum anti-PLA2R/anti-THSD7A testing plus biopsy antigen staining when serology is negative or associated disease is suspected.
Results: Positive anti-PLA2R or anti-THSD7A serology supports primary membranous nephropathy, and tissue antigen detection helps classify THSD7A-associated or other antigen-defined cases.
Show evidence (3 references)
PMID:27777266 SUPPORT Human Clinical
"The presence or absence of anti-PLA2R and anti-THSD7A antibodies adds important information to clinical and immunopathologic data in discriminating between primary and secondary MN."
Supports the diagnostic value of serology for primary versus secondary membranous nephropathy.
PMID:25394321 SUPPORT Human Clinical
"This finding not only furthers our understanding of the pathophysiological basis of membranous nephropathy but also allows for the potential identification and monitoring of patients who are positive for anti-THSD7A autoantibodies, by both serologic testing and histologic staining for the antigen."
Supports combining serology with biopsy antigen staining when defining THSD7A-associated membranous nephropathy.
PMID:33673911 SUPPORT Human Clinical
"CONCLUSION: The widely used distinction between primary and secondary MN has limitations. We propose a refined terminology that combines the target antigen and associated disease to better classify MN and guide clinical decision making."
Supports target-antigen classification as a clinically useful refinement of the older primary-versus-secondary diagnostic split.
📊

Related Datasets

6
Idiopathic membranous nephropathy and minimal change disease (MCD) transcriptome geo:GSE216841
Introduction: Minimal change disease (MCD) is a major cause of nephrotic syndrome. With a substantial number of patients requiring long-term immunosuppression leading to significant morbidity, the study aim was to determine MCD glomerular transcriptome to serve as a basis for biomarker discovery and novel drug target identification. Animal work showed podocyte injury induced by IL-7/IL-7R signaling (Zhai S, BBRC, 2018). Methods: Renal biopsies from adult patients representing the following groups were selected from the Norwegian Kidney Biopsy Registry: MCD (n=14), as well as normal tissue (n=8) and primary membranous nephropathy (MN; n=12) as the two reference groups.
human BULK RNA SEQ n=34
PMID:36672735
Identified by GEO DataSets index search for Membranous nephropathy (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
Single-cell RNA-sequencing analysis reveals the peripheral immune characteristics of patients with primary membranous nephropathy geo:GSE283826
Primary Membranous Nephropathy (PMN) is characterized by dysregulated immune responses, with B and T cells playing critical roles in disease pathogenesis. While significant strides have been made in identifying specific autoantigens and leveraging monoclonal antibodies, the precise immunopathogenic mechanisms underlying immune cell involvement in PMN remain elusive. To comprehensively characterize the cellular, molecular, and immunological landscape, we employed single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cell samples (PBMC) obtained from 6 patients with PMN and 3 healthy controls (NC).We examined the heterogeneity and functional diversity of B cells in PMN.
human SINGLE CELL RNA SEQ n=9
PMID:40904455
Identified by GEO DataSets index search for Membranous nephropathy (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
Single-cell profiling reveals transcriptional signatures, novel epithelial cells and cell-cell crosstalk in idiopathic membranous nephropathy patients geo:GSE171458
Our understanding of the pathogenesis of idiopathic membranous nephropathy is limited by an incomplete molecular characterization of the cell types in the kidney and interaction between the cells. Besides, the reason for the heterogeneity of these patients as well as the variety of clinical outcomes remains elusive. Therefore, we applied scRNA-seq to kidney biopsies of patients with IMN to identify gene expression at the single-cell level, elucidate cells involved in the progression of IMN, and uncover intercellular interactions.
human SINGLE CELL RNA SEQ n=8
PMID:34135910
Identified by GEO DataSets index search for Membranous nephropathy (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
Risk alleles of membranous nephropathy and recurrence of the disease on the grafted kidney ega:EGAS00001005435
The goal of the project was to identify risk alleles that are associated with recurrence of membranous nephropathy in the graft after kidney transplantation. First, we sequenced PLA2R1 and HLA-D loci in 248 patients with primary membranous nephropathy and identified two independent single nucleotide polymorphisms (SNPs) at risk for primary membranous nephropathy at each locus. Then we investigated whether primary membranous nephropathy at-risk variants were associated with recurrence in a retrospective cohort of 105 donor-recipient pairs and a replication cohort of 40 pairs.
human
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Membranous nephropathy"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
GWAS membranous nephropathy Stanescu et al., 2011 UK cohort, chr2 region of interest, imputed ega:EGAS00001007700
334 biopsy-confirmed membranous nephropathy (MN) cases and 349 ethnically matched healthy controls: the British cohort of the Stanescu et al., 2011 GWAS. Genotyped and imputed region of interest on chromosome 2 (hg19 chr2:160500000-161500000), as used to determine Neanderthal introgression near the PLA2R1 MN risk locus (lead SNP: rs4664308).
human
PMID:21323541
European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Membranous nephropathy"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.
Towards the definition of the molecular hallmarks of Idiopathic Membranous Nephropathy in serum proteome: a DIA-PASEF approach massive:MSV000092309
Idiopathic Membranous Nephropathy (IMN) is a pathologically defined disorder of the glomerulus, primarily responsible for nephrotic syndromes (NS) in nondiabetic adults. The underlying molecular mechanisms are still not completely clarified. To explore possible molecular and functional signatures, an optimised MS-method based on next-generation data-independent-acquisition combined with ion-mobility was applied to serum of patients affected by IMN (n=15) or by other glomerulopathies (PN) (n=15).
Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Membranous nephropathy"). Retrieved 2026-08-02.
{ }

Source YAML

click to show 
name: Membranous nephropathy
creation_date: "2026-04-14T00:00:00Z"
category: Complex
parents:
- Kidney Disease
- Autoimmune Disease
synonyms:
- membranous glomerulonephritis
disease_term:
  preferred_term: Membranous nephropathy
  term:
    id: MONDO:0005376
    label: membranous glomerulonephritis
description: >-
  Immune-complex glomerular disease characterized by subepithelial deposits along
  the glomerular basement membrane, podocyte injury, proteinuria, and nephrotic
  manifestations.
notes: >-
  This entry is anchored to the MONDO disease term for membranous glomerulonephritis
  but uses the clinically preferred synonym "Membranous nephropathy" for display and
  curation.

  The mechanistic pathograph is centered on primary autoimmune membranous
  nephropathy so the disease walk-through remains coherent for CureGN/demo use.
  Secondary membranous nephropathy is retained as a subtype because infections,
  autoimmune diseases, malignancy, IgG4-related disease, and drugs can converge
  on the same downstream pattern of subepithelial immune-complex deposition and
  podocyte injury. At the same time, the classic primary-versus-secondary split
  is no longer sufficient to explain all current MN biology, because target-antigen
  testing now identifies PLA2R-, THSD7A-, NELL1-, EXT1/EXT2-, PCDH7-, NCAM1-,
  and other antigen-defined subsets with different clinicopathologic associations.
  This root page therefore keeps the common autoimmune cascade at center while
  using subtype and diagnostic fields to capture the more specific antigen landscape.
  Monarch/Monarch API and local MONDO lookup both resolve this disease anchor to
  MONDO:0005376 with exact synonym "membranous nephropathy". ClinGen gene pages
  for PLA2R1 and THSD7A were checked on 2026-04-14 and both reported zero published
  gene-disease validity classifications, so PLA2R1 and THSD7A are represented
  here as podocyte autoantigen/susceptibility context rather than as definitive
  monogenic root causes of the whole disease entity.
has_subtypes:
- name: Primary membranous nephropathy
  classification: clinical_context
  description: >-
    Autoimmune membranous nephropathy driven by circulating autoantibodies
    against podocyte antigens, especially PLA2R1 and less commonly THSD7A.
- name: Secondary membranous nephropathy
  classification: clinical_context
  description: >-
    Membranous nephropathy with the same downstream subepithelial immune-deposit
    pattern but triggered by an underlying autoimmune disease, infection,
    malignancy, IgG4-related disease, or drug exposure.
- name: PLA2R-associated membranous nephropathy
  classification: molecular
  description: >-
    Dominant antigen-defined primary membranous nephropathy subset anchored by
    circulating anti-PLA2R autoantibodies.
  evidence:
  - reference: PMID:33808418
    reference_title: "Mechanisms of Primary Membranous Nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Approximately 50-80% and 3-5% of primary MN (PMN) cases are associated with either anti-PLA2R or anti-THSD7A antibodies, respectively."
    explanation: Supports PLA2R-associated disease as the dominant antigen-defined subset of primary membranous nephropathy.
- name: THSD7A-associated membranous nephropathy
  classification: molecular
  description: >-
    Distinct minority antigen-defined membranous nephropathy subset characterized
    by anti-THSD7A autoantibodies and podocyte THSD7A targeting.
  evidence:
  - reference: PMID:25394321
    reference_title: "Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In our cohort, 15 of 154 patients with idiopathic membranous nephropathy had circulating autoantibodies to THSD7A but not to PLA2R1, a finding that suggests a distinct subgroup of patients with this condition."
    explanation: Supports THSD7A-associated disease as a biologically distinct minority subgroup rather than a nonspecific ancillary biomarker pattern.
- name: Other antigen-associated membranous nephropathy
  classification: molecular
  description: >-
    PLA2R/THSD7A-negative disease is not a single residual bucket; target-antigen
    workups can identify NELL1-, EXT1/EXT2-, PCDH7-, NCAM1-, SEMA3B-, and related
    antigen-defined subsets with different autoimmune, malignancy-associated, or
    pediatric contexts.
  evidence:
  - reference: PMID:33673911
    reference_title: "A Target Antigen-Based Approach to the Classification of Membranous Nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "OBJECTIVE: To describe the clinical and pathological phenotype of membranous nephropathy (MN) associated with M-type-phospholipase-A2-receptor (PLA2R), thrombospondin-type-1-domain-containing-7A (THSD7A), semaphorin 3B (SEMA3B), neural-epidermal-growth-factor-like-1-protein (NELL-1), protocadherin 7 (PCDH7), exostosin 1/exostosin 2 (EXT1/EXT2) and neural cell adhesion molecule 1 (NCAM-1) as target antigens."
    explanation: Supports the existence of a broader antigen-defined MN landscape beyond the dominant PLA2R and THSD7A serologic subsets.
pathophysiology:
- name: Autoantibody production against podocyte antigens
  subtypes:
  - Primary membranous nephropathy
  description: >-
    Primary membranous nephropathy reflects loss of tolerance to podocyte
    autoantigens, with B cell and plasma cell responses generating circulating
    autoantibodies against PLA2R1 in most seropositive cases and THSD7A in a
    smaller minority. These serologic subsets are mechanistically important for
    primary disease classification and monitoring, but they do not imply that
    the entire membranous nephropathy disease root is monogenic. Other target
    antigens are tracked at the subtype level so the root pathograph stays focused
    on the shared autoimmune cascade rather than fragmenting into parallel sparse
    upstream nodes.
  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: immunoglobulin production
    term:
      id: GO:0002377
      label: immunoglobulin production
  genes:
  - preferred_term: PLA2R1
    term:
      id: hgnc:9042
      label: PLA2R1
  - preferred_term: THSD7A
    term:
      id: hgnc:22207
      label: THSD7A
  downstream:
  - target: In situ subepithelial immune complex deposition
    description: Circulating autoantibodies bind podocyte antigens and seed local immune-complex formation along the outer glomerular basement membrane.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:31447839
      reference_title: "Immunological Pathogenesis of Membranous Nephropathy: Focus on PLA2R1 and Its Role."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "In idiopathic membranous nephropathy (IMN) the immune complexes are formed by circulating antibodies binding mainly to one of two naturally-expressed podocyte antigens: the M-type receptor for secretory phospholipase A2 (PLA2R1) and the Thrombospondin type-1 domain-containing 7A (THSD7A)."
      explanation: Directly supports the causal step from circulating anti-podocyte antibodies to local immune-complex formation.
  evidence:
  - reference: PMID:33808418
    reference_title: "Mechanisms of Primary Membranous Nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Approximately 50-80% and 3-5% of primary MN (PMN) cases are associated with either anti-PLA2R or anti-THSD7A antibodies, respectively."
    explanation: Establishes the two dominant serologic autoantigen subsets of primary membranous nephropathy without implying that either gene is the sole root cause of all MN.
  - reference: PMID:31447839
    reference_title: "Immunological Pathogenesis of Membranous Nephropathy: Focus on PLA2R1 and Its Role."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In idiopathic membranous nephropathy (IMN) the immune complexes are formed by circulating antibodies binding mainly to one of two naturally-expressed podocyte antigens: the M-type receptor for secretory phospholipase A2 (PLA2R1) and the Thrombospondin type-1 domain-containing 7A (THSD7A)."
    explanation: Supports the core autoimmune framing in which circulating anti-podocyte antibodies initiate primary membranous nephropathy.
- name: In situ subepithelial immune complex deposition
  subtypes:
  - Primary membranous nephropathy
  description: >-
    Autoantibodies bind antigens exposed on the podocyte-facing aspect of the
    glomerular capillary wall, generating immune complexes in situ. Those
    complexes accumulate as subepithelial electron-dense deposits and are
    accompanied by progressive thickening of the glomerular basement membrane.
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  locations:
  - preferred_term: glomerular basement membrane
    term:
      id: UBERON:0005777
      label: glomerular basement membrane
  - preferred_term: renal glomerulus
    term:
      id: UBERON:0000074
      label: renal glomerulus
  downstream:
  - target: Complement activation at the glomerular capillary wall
    description: Subepithelial immune deposits trigger complement activation around podocytes and the outer glomerular basement membrane.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:41209172
      reference_title: "Autophagy in the Pathogenesis of Membranous Nephropathy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "The formation of immune complexes on podocytes triggers complement activation, leading to the activation of both the C5b-C9 complex and C5a."
      explanation: Directly supports the causal transition from immune-complex formation on podocytes to complement activation.
  evidence:
  - reference: PMID:39185424
    reference_title: "The fate of immune complexes in membranous nephropathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The most characteristic feature of membranous nephropathy (MN) is the presence of subepithelial electron dense deposits and the consequential thickening of the glomerular basement membrane."
    explanation: Directly supports the defining biopsy pattern of subepithelial deposits with glomerular basement membrane thickening.
  - reference: PMID:39185424
    reference_title: "The fate of immune complexes in membranous nephropathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Subepithelial immune complexes are formed in situ by autoantibodies targeting native autoantigens or exogenous planted antigens such as the phospholipase A2 receptor (PLA2R) and cationic BSA respectively."
    explanation: Supports the local in situ immune-complex formation step that bridges circulating antibodies to glomerular deposition.
- name: Complement activation at the glomerular capillary wall
  subtypes:
  - Primary membranous nephropathy
  description: >-
    The subepithelial immune deposits activate complement at the podocyte-facing
    glomerular basement membrane, generating membrane attack complex and C5a
    signals that amplify local injury.
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  locations:
  - preferred_term: glomerular basement membrane
    term:
      id: UBERON:0005777
      label: glomerular basement membrane
  - preferred_term: renal glomerulus
    term:
      id: UBERON:0000074
      label: renal glomerulus
  biological_processes:
  - preferred_term: complement activation
    term:
      id: GO:0006956
      label: complement activation
  downstream:
  - target: Podocyte structural injury
    description: Complement effector activity injures podocytes and destabilizes the slit-diaphragm/cytoskeletal apparatus.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36286856
      reference_title: "[Modern view on the complement system role in membranous nephropathy]."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Membrane-attacking complex (MAC) is the terminal product of any complement pathways activation (classical, lectin or alternative) and plays the leading role in the complement-mediated podocytic damage."
      explanation: Directly supports complement effector injury as the bridge from deposit-triggered complement activation to podocyte damage.
  evidence:
  - reference: PMID:36286856
    reference_title: "[Modern view on the complement system role in membranous nephropathy]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Membrane-attacking complex (MAC) is the terminal product of any complement pathways activation (classical, lectin or alternative) and plays the leading role in the complement-mediated podocytic damage."
    explanation: Directly supports MAC-centered complement injury as the key bridge from immune deposits to podocyte damage.
  - reference: PMID:41209172
    reference_title: "Autophagy in the Pathogenesis of Membranous Nephropathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The formation of immune complexes on podocytes triggers complement activation, leading to the activation of both the C5b-C9 complex and C5a."
    explanation: Reinforces that podocyte-bound immune complexes activate terminal complement effectors relevant to membranous nephropathy.
- name: Podocyte structural injury
  subtypes:
  - Primary membranous nephropathy
  description: >-
    Complement-dependent and direct antibody-mediated injury disrupt podocyte
    structural homeostasis, including actin cytoskeletal organization and
    slit-diaphragm integrity. This converts a subepithelial deposit pattern into
    a filtration-barrier lesion.
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  locations:
  - preferred_term: renal glomerulus
    term:
      id: UBERON:0000074
      label: renal glomerulus
  biological_processes:
  - preferred_term: actin cytoskeleton organization
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
  downstream:
  - target: Podocyte apoptosis
    description: Complement-dependent and complement-independent injury initiates caspase-dependent apoptotic death of podocytes.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42553762
      reference_title: "Programmed Cell Death: A Key Mechanism of Traditional Chinese Medicine in the Treatment of Membranous Nephropathy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Complement-dependent and complement-independent pathways in MN can synergistically initiate podocyte apoptosis, pyroptosis, ferroptosis, and autophagy dysfunction."
      explanation: Names apoptosis as one of the death modalities both injury routes initiate.
  - target: Podocyte pyroptosis
    description: Complement activation, oxidative stress, and danger-associated molecular patterns converge on the NLRP3 inflammasome to drive pyroptotic podocyte lysis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42553762
      reference_title: "Programmed Cell Death: A Key Mechanism of Traditional Chinese Medicine in the Treatment of Membranous Nephropathy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Complement-dependent and complement-independent pathways in MN can synergistically initiate podocyte apoptosis, pyroptosis, ferroptosis, and autophagy dysfunction."
      explanation: Names pyroptosis as one of the death modalities both injury routes initiate.
  - target: Podocyte ferroptosis
    description: Injured podocytes undergo iron-dependent lipid peroxidation with failure of GPX4-mediated antioxidant defense.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42553762
      reference_title: "Programmed Cell Death: A Key Mechanism of Traditional Chinese Medicine in the Treatment of Membranous Nephropathy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Complement-dependent and complement-independent pathways in MN can synergistically initiate podocyte apoptosis, pyroptosis, ferroptosis, and autophagy dysfunction."
      explanation: Names ferroptosis as one of the death modalities both injury routes initiate.
  - target: Podocyte autophagy dysregulation
    description: Podocyte injury disturbs autophagic flux in either direction, so that both insufficient and excessive autophagy worsen the injury.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42553762
      reference_title: "Programmed Cell Death: A Key Mechanism of Traditional Chinese Medicine in the Treatment of Membranous Nephropathy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Complement-dependent and complement-independent pathways in MN can synergistically initiate podocyte apoptosis, pyroptosis, ferroptosis, and autophagy dysfunction."
      explanation: Names autophagy dysfunction as one of the modalities both injury routes initiate.
  - target: Glomerular filtration barrier failure and proteinuria
    description: Podocyte injury reduces filtration selectivity and allows sustained urinary protein loss.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:36286856
      reference_title: "[Modern view on the complement system role in membranous nephropathy]."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "In MN, proteinuria is developed by podocyte damage due to the complement system activation in response to the subepithelial deposition of immune complexes containing various auto- and exogenous antigens."
      explanation: Directly supports the causal step from podocyte injury to filtration failure manifesting as proteinuria.
  evidence:
  - reference: PMID:40888279
    reference_title: "Immune-mediated membranous nephropathy: Innovations in pathogenetic modeling and mechanistic insights."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Collectively, they reveal complement-dependent and direct podocytotoxic injury mechanisms."
    explanation: Supports the specific transition from immune/complement activity to direct podocyte injury.
  - reference: PMID:36286856
    reference_title: "[Modern view on the complement system role in membranous nephropathy]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In MN, proteinuria is developed by podocyte damage due to the complement system activation in response to the subepithelial deposition of immune complexes containing various auto- and exogenous antigens."
    explanation: Connects podocyte damage causally to the next step of proteinuria in membranous nephropathy.
- name: Podocyte apoptosis
  subtypes:
  - Primary membranous nephropathy
  biological_scale: CELLULAR
  description: >-
    Caspase-dependent apoptotic death of podocytes, driving irreversible
    podocyte depletion. In the complement-dependent route, sublytic C5b-9
    promotes apoptosis through the CXCL12/CXCR4/STAT3 axis; silencing CXCL12
    alleviates C5b-9-induced podocyte damage.
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  biological_processes:
  - preferred_term: apoptotic process
    modifier: INCREASED
    term:
      id: GO:0006915
      label: apoptotic process
  downstream:
  - target: Podocyte depletion from programmed cell death
    description: Apoptotic loss of podocytes contributes to the cumulative podocyte deficit.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42553762
      reference_title: "Programmed Cell Death: A Key Mechanism of Traditional Chinese Medicine in the Treatment of Membranous Nephropathy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "PCD-driven podocyte damage and progressive loss represent a core pathological mechanism underlying sustained proteinuria and renal function decline in MN."
      explanation: Establishes progressive podocyte loss as the shared consequence of the PCD modalities.
  evidence:
  - reference: PMID:42553762
    reference_title: "Programmed Cell Death: A Key Mechanism of Traditional Chinese Medicine in the Treatment of Membranous Nephropathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Multiple signaling pathways govern podocyte apoptosis in MN. In the complement‑dependent pathway, C5b-9 promotes apoptosis via the C-X-C motif chemokine ligand 12/C-X-C chemokine receptor type 4/Signal transducer and activator of transcription 3(CXCL12/CXCR4/STAT3) axis, and CXCL12 silencing alleviates C5b-9‑induced podocyte damage."
    explanation: Identifies complement-dependent apoptosis pathways in membranous nephropathy podocytes.
- name: Podocyte pyroptosis
  subtypes:
  - Primary membranous nephropathy
  biological_scale: CELLULAR
  description: >-
    Pro-inflammatory lytic podocyte death driven by NLRP3 inflammasome-mediated
    caspase-1 activation and gasdermin D cleavage, releasing IL-1beta and IL-18
    and amplifying local inflammation.
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  biological_processes:
  - preferred_term: pyroptotic inflammatory response
    modifier: INCREASED
    term:
      id: GO:0070269
      label: pyroptotic inflammatory response
  downstream:
  - target: Podocyte depletion from programmed cell death
    description: Pyroptotic lysis contributes to the cumulative podocyte deficit and amplifies glomerular inflammation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42553762
      reference_title: "Programmed Cell Death: A Key Mechanism of Traditional Chinese Medicine in the Treatment of Membranous Nephropathy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "PCD-driven podocyte damage and progressive loss represent a core pathological mechanism underlying sustained proteinuria and renal function decline in MN."
      explanation: Establishes progressive podocyte loss as the shared consequence of the PCD modalities.
  evidence:
  - reference: PMID:42553762
    reference_title: "Programmed Cell Death: A Key Mechanism of Traditional Chinese Medicine in the Treatment of Membranous Nephropathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In MN, complement activation, oxidative stress, and danger‑associated molecular patterns cooperatively activate the NOD-Like Receptor Family Pyrin Domain Containing 3(NLRP3) inflammasome, promoting caspase‑1‑dependent cleavage of GSDMD. This leads to membrane rupture, cytosolic leakage, and robust release of IL‑1β and IL‑18, which further amplify local inflammation, disrupt glomerular homeostasis, and promote renal fibrosis."
    explanation: Establishes NLRP3 inflammasome-mediated pyroptosis as a key inflammatory PCD mechanism in membranous nephropathy.
- name: Podocyte ferroptosis
  subtypes:
  - Primary membranous nephropathy
  biological_scale: CELLULAR
  description: >-
    Iron-dependent lipid peroxidation of podocyte membranes with failure of
    GPX4-mediated antioxidant defense, producing mitochondrial structural
    collapse.
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  biological_processes:
  - preferred_term: ferroptosis
    modifier: INCREASED
    term:
      id: GO:0097707
      label: ferroptosis
  downstream:
  - target: Podocyte depletion from programmed cell death
    description: Ferroptotic death contributes to the cumulative podocyte deficit.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42553762
      reference_title: "Programmed Cell Death: A Key Mechanism of Traditional Chinese Medicine in the Treatment of Membranous Nephropathy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "In MN, ferroptosis causes lipid peroxidative damage to podocyte membranes and mitochondrial structural collapse, thereby worsening filtration dysfunction and proteinuria."
      explanation: Links ferroptotic podocyte damage to worsening filtration and proteinuria.
  evidence:
  - reference: PMID:42553762
    reference_title: "Programmed Cell Death: A Key Mechanism of Traditional Chinese Medicine in the Treatment of Membranous Nephropathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In MN, ferroptosis causes lipid peroxidative damage to podocyte membranes and mitochondrial structural collapse, thereby worsening filtration dysfunction and proteinuria."
    explanation: Documents ferroptosis and iron-dependent lipid peroxidation as mechanisms of podocyte injury in membranous nephropathy.
- name: Podocyte autophagy dysregulation
  subtypes:
  - Primary membranous nephropathy
  biological_scale: CELLULAR
  description: >-
    Disturbed autophagic flux in podocytes. The defect is bidirectional rather
    than a simple loss: either insufficient or excessive autophagy exacerbates
    podocyte injury, and the degree of dysregulation correlates with proteinuria
    severity and clinical outcome.
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  biological_processes:
  - preferred_term: autophagy
    modifier: DYSREGULATED
    term:
      id: GO:0006914
      label: autophagy
  downstream:
  - target: Podocyte depletion from programmed cell death
    description: Autophagic dysregulation compounds the other death modalities and contributes to the cumulative podocyte deficit.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42553762
      reference_title: "Programmed Cell Death: A Key Mechanism of Traditional Chinese Medicine in the Treatment of Membranous Nephropathy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "In MN, however, autophagy becomes dysregulated: either insufficient or excessive autophagy exacerbates podocyte injury, accelerates disease progression, and correlates with proteinuria severity and clinical outcomes."
      explanation: Links autophagic dysregulation to worsening podocyte injury and disease progression.
  evidence:
  - reference: PMID:42553762
    reference_title: "Programmed Cell Death: A Key Mechanism of Traditional Chinese Medicine in the Treatment of Membranous Nephropathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In MN, however, autophagy becomes dysregulated: either insufficient or excessive autophagy exacerbates podocyte injury, accelerates disease progression, and correlates with proteinuria severity and clinical outcomes."
    explanation: Establishes dysregulated autophagy as a pathogenic mechanism contributing to podocyte injury and proteinuria in membranous nephropathy. The modifier is DYSREGULATED rather than a direction because the quoted sentence is explicitly bidirectional.
- name: Podocyte depletion from programmed cell death
  subtypes:
  - Primary membranous nephropathy
  biological_scale: TISSUE
  description: >-
    The convergence point of the four programmed cell death modalities: a
    cumulative, non-replaceable loss of podocytes from the glomerular tuft. This
    node exists so the shared downstream consequence and the treatments that act
    across modalities have a single target; the modality-specific claims and
    their evidence live on the four upstream nodes.
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  locations:
  - preferred_term: renal glomerulus
    term:
      id: UBERON:0000074
      label: renal glomerulus
  downstream:
  - target: Glomerular filtration barrier failure and proteinuria
    description: Sustained podocyte loss from programmed cell death accelerates glomerular barrier failure and heavy proteinuria.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:42553762
      reference_title: "Programmed Cell Death: A Key Mechanism of Traditional Chinese Medicine in the Treatment of Membranous Nephropathy."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "PCD-driven podocyte damage and progressive loss represent a core pathological mechanism underlying sustained proteinuria and renal function decline in MN."
      explanation: Directly links programmed cell death to proteinuria progression in membranous nephropathy.
  evidence:
  - reference: PMID:42553762
    reference_title: "Programmed Cell Death: A Key Mechanism of Traditional Chinese Medicine in the Treatment of Membranous Nephropathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Complement-dependent and complement-independent pathways in MN can synergistically initiate podocyte apoptosis, pyroptosis, ferroptosis, and autophagy dysfunction."
    explanation: Supports treating the four modalities as co-occurring routes to a single shared podocyte deficit rather than alternatives.
- name: Glomerular filtration barrier failure and proteinuria
  description: >-
    Once podocytes are injured, the glomerular filtration barrier loses
    permselectivity and patients develop the heavy proteinuria that drives the
    nephrotic syndrome phenotype. Persistent proteinuria is also linked to worse
    long-term kidney outcomes.
  cell_types:
  - preferred_term: podocyte
    term:
      id: CL:0000653
      label: podocyte
  locations:
  - preferred_term: renal glomerulus
    term:
      id: UBERON:0000074
      label: renal glomerulus
  biological_processes:
  - preferred_term: glomerular filtration
    term:
      id: GO:0003094
      label: glomerular filtration
  downstream:
  - target: Progressive kidney function decline
    description: Ongoing nephrotic-range proteinuria and persistent glomerular injury are associated with reduced kidney survival.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40630289
      reference_title: "Risk Factors for Disease Progression for Adults and Children With Membranous Nephropathy in the Cure Glomerulonephropathy Network (CureGN)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Age < 18 years, self-reported Black/African American race, proteinuria > 3 g/g, and lower estimated glomerular filtration rate (eGFR) at enrollment were associated with worse kidney survival."
      explanation: Human CureGN data supports a clinically important link between higher proteinuria/lower eGFR and worse kidney survival, while leaving intermediate injury mechanisms implicit.
  evidence:
  - reference: PMID:36286856
    reference_title: "[Modern view on the complement system role in membranous nephropathy]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In MN, proteinuria is developed by podocyte damage due to the complement system activation in response to the subepithelial deposition of immune complexes containing various auto- and exogenous antigens."
    explanation: Supports proteinuria as the direct physiologic consequence of the podocyte/complement injury cascade.
- name: Progressive kidney function decline
  description: >-
    Clinical course is heterogeneous, but a subset of patients experiences
    sustained eGFR decline and kidney failure despite modern therapy.
  evidence:
  - reference: PMID:40630289
    reference_title: "Risk Factors for Disease Progression for Adults and Children With Membranous Nephropathy in the Cure Glomerulonephropathy Network (CureGN)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RESULTS: In total, 591 patients (537 adults and 54 children) were evaluated with 9% reaching kidney failure."
    explanation: Human CureGN cohort data confirms that membranous nephropathy can progress to kidney failure in a meaningful subset of patients.
phenotypes:
- name: Nephrotic syndrome
  category: Renal
  phenotype_term:
    preferred_term: Nephrotic syndrome
    term:
      id: HP:0000100
      label: Nephrotic syndrome
  evidence:
  - reference: PMID:33808418
    reference_title: "Mechanisms of Primary Membranous Nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Membranous nephropathy (MN) is an autoimmune disease of the kidney glomerulus and one of the leading causes of nephrotic syndrome."
    explanation: Supports nephrotic syndrome as the signature clinical syndrome of membranous nephropathy.
- name: Proteinuria
  category: Renal
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: PMID:36286856
    reference_title: "[Modern view on the complement system role in membranous nephropathy]."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In MN, proteinuria is developed by podocyte damage due to the complement system activation in response to the subepithelial deposition of immune complexes containing various auto- and exogenous antigens."
    explanation: Supports proteinuria as a direct downstream consequence of the core immune-complex/complement/podocyte injury cascade in membranous nephropathy.
- name: Edema
  category: Renal
  phenotype_term:
    preferred_term: Edema
    term:
      id: HP:0000969
      label: Edema
  evidence:
  - reference: PMID:21877306
    reference_title: "[Membranous glomerulonephritis: better therapy with autoantibody monitoring?]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical symptoms range from small proteinuria to severe nephrotic syndrome with enormous oedema, not controllable hyperlipidaemia and increased disposition for infection."
    explanation: Supports edema as part of the severe nephrotic clinical presentation of membranous nephropathy.
- name: Hypoalbuminemia
  category: Biochemical
  phenotype_term:
    preferred_term: Hypoalbuminemia
    term:
      id: HP:0003073
      label: Hypoalbuminemia
  evidence:
  - reference: PMID:40760331
    reference_title: "[Nephrotic syndrome]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nephrotic syndrome (NS) is characterized by proteinuria > 3.5 g/day, hypoalbuminemia, peripheral edema, and hyperlipidemia. Common primary causes of NS are podocytopathies, such as minimal change nephropathy, focal segmental glomerulosclerosis, and membranous nephropathy."
    explanation: Provides syndrome-level support that hypoalbuminemia belongs to the nephrotic phenotype commonly caused by membranous nephropathy, without claiming this review is MN-specific mechanistic evidence.
- name: Hyperlipidemia
  category: Metabolic
  phenotype_term:
    preferred_term: Hyperlipidemia
    term:
      id: HP:0003077
      label: Hyperlipidemia
  evidence:
  - reference: PMID:21877306
    reference_title: "[Membranous glomerulonephritis: better therapy with autoantibody monitoring?]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical symptoms range from small proteinuria to severe nephrotic syndrome with enormous oedema, not controllable hyperlipidaemia and increased disposition for infection."
    explanation: Supports hyperlipidemia as part of the nephrotic clinical presentation of membranous nephropathy.
- name: Renal insufficiency
  category: Renal
  phenotype_term:
    preferred_term: Renal insufficiency
    term:
      id: HP:0000083
      label: Renal insufficiency
  evidence:
  - reference: PMID:40630289
    reference_title: "Risk Factors for Disease Progression for Adults and Children With Membranous Nephropathy in the Cure Glomerulonephropathy Network (CureGN)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Age < 18 years, self-reported Black/African American race, proteinuria > 3 g/g, and lower estimated glomerular filtration rate (eGFR) at enrollment were associated with worse kidney survival."
    explanation: Human cohort data supports clinically meaningful kidney function decline as an outcome phenotype in membranous nephropathy.
biochemical:
- name: Anti-PLA2R autoantibodies
  presence: Positive
  context: High-specificity serologic biomarker that tracks disease activity in primary membranous nephropathy.
  evidence:
  - reference: PMID:26090644
    reference_title: "Pathophysiological advances in membranous nephropathy: time for a shift in patient's care."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Anti-PLA2R antibodies have high specificity (close to 100%), sensitivity (70-80%), and predictive value."
    explanation: Supports anti-PLA2R antibodies as a clinically useful diagnostic and monitoring biomarker in membranous nephropathy.
  - reference: PMID:27777266
    reference_title: "A Proposal for a Serology-Based Approach to Membranous Nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Levels of anti-PLA2R antibodies and possibly, anti-THSD7A antibodies tightly correlate with disease activity."
    explanation: Supports use of anti-PLA2R antibody level as a disease activity biomarker.
- name: Anti-THSD7A autoantibodies
  presence: Positive
  context: Minority antigen-defined subgroup of primary membranous nephropathy that can be corroborated by biopsy antigen staining.
  evidence:
  - reference: PMID:25394321
    reference_title: "Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In our cohort, 15 of 154 patients with idiopathic membranous nephropathy had circulating autoantibodies to THSD7A but not to PLA2R1, a finding that suggests a distinct subgroup of patients with this condition."
    explanation: Supports anti-THSD7A serology as a distinct minority subgroup marker rather than a generic secondary finding.
  - reference: PMID:27777266
    reference_title: "A Proposal for a Serology-Based Approach to Membranous Nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence or absence of anti-PLA2R and anti-THSD7A antibodies adds important information to clinical and immunopathologic data in discriminating between primary and secondary MN."
    explanation: Supports anti-THSD7A serology as a clinically meaningful minority biomarker and subtype discriminator in membranous nephropathy.
genetic:
- name: PLA2R1 susceptibility locus
  association: GWAS
  gene_term:
    preferred_term: PLA2R1
    term:
      id: hgnc:9042
      label: PLA2R1
  notes: >-
    Common risk variants at PLA2R1 modulate susceptibility to primary
    membranous nephropathy, but this does not amount to a ClinGen-established
    monogenic disease model for the overall disease entity.
  evidence:
  - reference: PMID:24262501
    reference_title: "HLA-DQA1 and PLA2R1 polymorphisms and risk of idiopathic membranous nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Single nucleotide polymorphisms (SNPs) within HLA complex class II HLA-DQ α-chain 1 (HLA-DQA1) and M-type phospholipase A2 receptor (PLA2R1) genes were identified as strong risk factors for idiopathic membranous nephropathy (IMN) development in a recent genome-wide association study."
    explanation: Supports PLA2R1 as a human susceptibility locus in primary membranous nephropathy rather than a universal monogenic cause.
- name: HLA-DQA1 susceptibility locus
  association: GWAS
  gene_term:
    preferred_term: HLA-DQA1
    term:
      id: hgnc:4942
      label: HLA-DQA1
  notes: >-
    Class II HLA variation likely contributes to antigen presentation and loss of
    tolerance in primary membranous nephropathy.
  evidence:
  - reference: PMID:24262501
    reference_title: "HLA-DQA1 and PLA2R1 polymorphisms and risk of idiopathic membranous nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Single nucleotide polymorphisms (SNPs) within HLA complex class II HLA-DQ α-chain 1 (HLA-DQA1) and M-type phospholipase A2 receptor (PLA2R1) genes were identified as strong risk factors for idiopathic membranous nephropathy (IMN) development in a recent genome-wide association study."
    explanation: Supports HLA-DQA1 as a GWAS-supported susceptibility locus contributing to primary membranous nephropathy.
diagnosis:
- name: Kidney biopsy
  description: Histologic confirmation of membranous nephropathy.
  results: Detects subepithelial immune deposits with glomerular basement membrane thickening.
  evidence:
  - reference: PMID:39185424
    reference_title: "The fate of immune complexes in membranous nephropathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The most characteristic feature of membranous nephropathy (MN) is the presence of subepithelial electron dense deposits and the consequential thickening of the glomerular basement membrane."
    explanation: Supports renal biopsy as the defining diagnostic modality for the characteristic deposit/thickening pattern.
- name: Serology and target-antigen work-up
  description: Serum anti-PLA2R/anti-THSD7A testing plus biopsy antigen staining when serology is negative or associated disease is suspected.
  results: Positive anti-PLA2R or anti-THSD7A serology supports primary membranous nephropathy, and tissue antigen detection helps classify THSD7A-associated or other antigen-defined cases.
  evidence:
  - reference: PMID:27777266
    reference_title: "A Proposal for a Serology-Based Approach to Membranous Nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence or absence of anti-PLA2R and anti-THSD7A antibodies adds important information to clinical and immunopathologic data in discriminating between primary and secondary MN."
    explanation: Supports the diagnostic value of serology for primary versus secondary membranous nephropathy.
  - reference: PMID:25394321
    reference_title: "Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This finding not only furthers our understanding of the pathophysiological basis of membranous nephropathy but also allows for the potential identification and monitoring of patients who are positive for anti-THSD7A autoantibodies, by both serologic testing and histologic staining for the antigen."
    explanation: Supports combining serology with biopsy antigen staining when defining THSD7A-associated membranous nephropathy.
  - reference: PMID:33673911
    reference_title: "A Target Antigen-Based Approach to the Classification of Membranous Nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CONCLUSION: The widely used distinction between primary and secondary MN has limitations. We propose a refined terminology that combines the target antigen and associated disease to better classify MN and guide clinical decision making."
    explanation: Supports target-antigen classification as a clinically useful refinement of the older primary-versus-secondary diagnostic split.
treatments:
- name: Rituximab
  description: Anti-CD20 B-cell depletion used in guideline-supported first-line immunotherapy for primary membranous nephropathy.
  treatment_term:
    preferred_term: rituximab therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rituximab
      term:
        id: NCIT:C1702
        label: Rituximab
  target_phenotypes:
  - preferred_term: Nephrotic syndrome
    term:
      id: HP:0000100
      label: Nephrotic syndrome
  - preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  target_mechanisms:
  - target: Autoantibody production against podocyte antigens
    treatment_effect: INHIBITS
    description: Anti-CD20 B-cell depletion reduces the autoreactive B-cell compartment that sustains pathogenic anti-podocyte antibodies.
    evidence:
    - reference: PMID:31269364
      reference_title: "Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Among patients in remission who tested positive for anti-phospholipase A2 receptor (PLA2R) antibodies, the decline in autoantibodies to anti-PLA2R was faster and of greater magnitude and duration in the rituximab group than in the cyclosporine group."
      explanation: Directly supports rituximab suppressing the pathogenic autoantibody response that sustains primary membranous nephropathy.
  evidence:
  - 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: Provides primary randomized-trial evidence that rituximab yields more durable remission than cyclosporine in membranous nephropathy.
  - reference: PMID:41007719
    reference_title: "The Use of Rituximab in Glomerulonephritis: What Is the Evidence?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recent evidence and the KDIGO guideline establish Rituximab as the first-line treatment for Primary Membranous Nephropathy and ANCA-associated vasculitis."
    explanation: Supports rituximab as current first-line immunotherapy for primary membranous nephropathy.
- name: Cyclophosphamide-based immunosuppression
  description: Cyclophosphamide-based regimens remain standard high-risk therapy for primary membranous nephropathy.
  target_phenotypes:
  - preferred_term: Nephrotic syndrome
    term:
      id: HP:0000100
      label: Nephrotic syndrome
  - preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: PMID:38915435
    reference_title: "Ten tips on immunosuppression in primary membranous nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Third, we suggest prescribing rituximab (RTX) or RTX combined with calcineurin inhibitors in medium-risk patients. Fourth, we propose cyclophosphamide-based immunosuppression for high-risk patients."
    explanation: Supports cyclophosphamide-based immunosuppression as a recommended therapy in high-risk primary membranous nephropathy.
- name: Supportive CKD therapy
  description: Supportive therapy aimed at reducing non-immune kidney injury progression, including renin-angiotensin-aldosterone system blockade and SGLT2 inhibition.
  target_phenotypes:
  - preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  - preferred_term: Renal insufficiency
    term:
      id: HP:0000083
      label: Renal insufficiency
  evidence:
  - reference: PMID:37218706
    reference_title: "CKD therapy to improve outcomes of immune-mediated glomerular diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Approved drug interventions include inhibitors of the renin-angiotensin-aldosterone system and sodium-glucose cotransporter-2."
    explanation: Supports supportive RAAS/SGLT2 therapy as part of outcome-oriented care for immune-mediated glomerular disease, including membranous nephropathy.
- name: Shenqi Particle (herbal formula)
  description: Traditional Chinese herbal formula composed of 13 medicinal herbs including Astragali Radix and Angelicae Sinensis Radix with clinical efficacy in primary membranous nephropathy.
  notes: >-
    The cited review names this preparation "Shenqi Particle" in its clinical-trial
    table and "Shenqi Granule" in the mechanistic text. Both refer to the same
    multicomponent hospital preparation; the entry name follows the clinical-trial
    table, and the mechanism snippet below retains the source's "Shenqi Granule"
    wording because a snippet must quote the source exactly.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Traditional Chinese herbal formula therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Shenqi Particle (Shenqi Granule)
      term:
        id: NCIT:C129986
        label: Traditional Chinese Medicine Formulation
  target_phenotypes:
  - preferred_term: Nephrotic syndrome
    term:
      id: HP:0000100
      label: Nephrotic syndrome
  - preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  target_mechanisms:
  - target: Podocyte autophagy dysregulation
    treatment_effect: MODULATES
    description: Shenqi Particle enhances protective podocyte autophagy by inhibiting mTOR/ULK1 phosphorylation, raising Beclin-1 and the LC3-II/I ratio and the podocyte cytoskeletal proteins CD2AP and alpha-actinin-4.
    evidence:
    - reference: PMID:42553762
      reference_title: "Programmed Cell Death: A Key Mechanism of Traditional Chinese Medicine in the Treatment of Membranous Nephropathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "It enhances autophagic activity by inhibiting mTOR/ULK1 phosphorylation"
      explanation: States the mTOR/ULK1 autophagy mechanism this link asserts. Table 1 of the review lists this result with no in vivo arm and puromycin-aminonucleoside-induced MPC5 podocytes as the model, hence IN_VITRO.
  evidence:
  - reference: PMID:42553762
    reference_title: "Programmed Cell Death: A Key Mechanism of Traditional Chinese Medicine in the Treatment of Membranous Nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One randomized controlled trial (RCT) and one prospective cohort study have shown that multicomponent hospital preparation Shenqi Particle monotherapy provides a remission rate comparable to glucocorticoid plus cyclophosphamide therapy in IMN patients, with superior renal protection and fewer adverse reactions."
    explanation: Clinical evidence demonstrates Shenqi Particle achieves comparable remission rates to conventional immunosuppression with fewer adverse effects.
- name: Mahuang Fuzi and Shenzhuo Decoction (herbal formula)
  description: Traditional Chinese herbal formula demonstrating high long-term remission rates in idiopathic membranous nephropathy regardless of prior immunosuppressive treatment.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Traditional Chinese herbal formula therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Mahuang Fuzi and Shenzhuo Decoction
      term:
        id: NCIT:C129986
        label: Traditional Chinese Medicine Formulation
  target_phenotypes:
  - preferred_term: Nephrotic syndrome
    term:
      id: HP:0000100
      label: Nephrotic syndrome
  - preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  target_mechanisms:
  - target: Podocyte apoptosis
    treatment_effect: INHIBITS
    description: Mahuang Fuzi and Shenzhuo Decoction modulates IL-6/STAT3 and Wnt/β-catenin signaling to inhibit podocyte apoptosis, with simultaneous reduction of inflammation and renal pathological lesions.
    evidence:
    - reference: PMID:42553762
      reference_title: "Programmed Cell Death: A Key Mechanism of Traditional Chinese Medicine in the Treatment of Membranous Nephropathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mahuang Fuzi and Shenzhuo Decoction (MFSD) modulates IL-6/STAT3 inflammatory pathway and Wnt/β-catenin signaling to inhibit apoptosis and upregulate autophagy, which is associated with reduced proteinuria and alleviated renal pathological lesions."
      explanation: Gives the molecular mechanisms through which this formula protects podocytes. Table 1 of the review lists this result with a passive Heymann nephritis rat arm at 1 mL/100 g and no in vitro arm, hence MODEL_ORGANISM.
  - target: Podocyte autophagy dysregulation
    treatment_effect: MODULATES
    description: Mahuang Fuzi and Shenzhuo Decoction upregulates protective podocyte autophagy through the same IL-6/STAT3 and Wnt/β-catenin signaling, alongside its anti-apoptotic effect.
    evidence:
    - reference: PMID:42553762
      reference_title: "Programmed Cell Death: A Key Mechanism of Traditional Chinese Medicine in the Treatment of Membranous Nephropathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mahuang Fuzi and Shenzhuo Decoction (MFSD) modulates IL-6/STAT3 inflammatory pathway and Wnt/β-catenin signaling to inhibit apoptosis and upregulate autophagy, which is associated with reduced proteinuria and alleviated renal pathological lesions."
      explanation: The same sentence names autophagy upregulation as a second, distinct modality this formula acts on. Table 1 of the review lists this result with a passive Heymann nephritis rat arm at 1 mL/100 g and no in vitro arm, hence MODEL_ORGANISM.
  evidence:
  - reference: PMID:42553762
    reference_title: "Programmed Cell Death: A Key Mechanism of Traditional Chinese Medicine in the Treatment of Membranous Nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One prospective, multicenter, open-label clinical trial and one multicenter, non-randomized, single-arm clinical trial have confirmed its high long-term remission rate, which is unaffected by age or prior immunosuppressive treatment, supporting its broad clinical applicability."
    explanation: Multicenter clinical trials confirm high remission rates across diverse patient populations with minimal impact of age or prior treatment history.
- name: Jianpi Qushi Heluo Formula (herbal formula)
  description: Traditional Chinese herbal formula shown in passive Heymann nephritis rats to restore PINK1/Parkin-mediated mitophagy and suppress NLRP3-driven pyroptosis in podocytes.
  notes: >-
    Kept separate from "Jian Pi Qu Shi Formula (JPQSF)" because the cited review
    keeps them separate: this preparation appears only in the preclinical table
    and figure (PHN rat, 16.2 and 32.4 g/kg, PINK1/Parkin), while JPQSF appears
    only in the clinical-trial table (RCT n=30, retrospective case series n=15).
    The review never states that the two names denote the same formula, so no
    clinical evidence is carried here and no mechanism is carried on the JPQSF
    entry. Merge the two entries if a source establishing the equivalence is found.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Traditional Chinese herbal formula therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Jianpi Qushi Heluo Formula
      term:
        id: NCIT:C129986
        label: Traditional Chinese Medicine Formulation
  target_phenotypes:
  - preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  target_mechanisms:
  - target: Podocyte autophagy dysregulation
    treatment_effect: MODULATES
    description: Jianpi Qushi Heluo Formula enhances PINK1/Parkin-mediated mitophagy and reduces mitochondrial ROS accumulation and membrane potential loss, restoring autophagic handling of damaged mitochondria in podocytes.
    evidence:
    - reference: PMID:42553762
      reference_title: "Programmed Cell Death: A Key Mechanism of Traditional Chinese Medicine in the Treatment of Membranous Nephropathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Jianpi Qushi Heluo Formula enhances PINK1/Parkin-mediated mitophagy, reduces mitochondrial ROS accumulation and MMP loss, and prevents NLRP3 inflammasome activation, thereby coordinating mitophagy and pyroptosis."
      explanation: Names mitophagy enhancement, a selective autophagy mechanism, as one of the two modalities this formula coordinates. Table 1 of the review lists this result with a passive Heymann nephritis rat arm at 16.2 and 32.4 g/kg and no in vitro arm, hence MODEL_ORGANISM.
  - target: Podocyte pyroptosis
    treatment_effect: INHIBITS
    description: Jianpi Qushi Heluo Formula prevents NLRP3 inflammasome activation, suppressing the pyroptotic arm that its restored mitophagy is coordinated with.
    evidence:
    - reference: PMID:42553762
      reference_title: "Programmed Cell Death: A Key Mechanism of Traditional Chinese Medicine in the Treatment of Membranous Nephropathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Jianpi Qushi Heluo Formula enhances PINK1/Parkin-mediated mitophagy, reduces mitochondrial ROS accumulation and MMP loss, and prevents NLRP3 inflammasome activation, thereby coordinating mitophagy and pyroptosis."
      explanation: The same sentence names NLRP3 inflammasome prevention, the upstream step of podocyte pyroptosis, as the second modality this formula acts on. Table 1 of the review lists this result with a passive Heymann nephritis rat arm at 16.2 and 32.4 g/kg and no in vitro arm, hence MODEL_ORGANISM.
- name: Jian Pi Qu Shi Formula (herbal formula)
  description: Traditional Chinese herbal formula demonstrating high complete remission rate in refractory idiopathic membranous nephropathy with concurrent microbiota restoration.
  notes: >-
    Carries clinical evidence only. The cited review reports no mechanistic study
    under this name; the PINK1/Parkin mitophagy mechanism belongs to "Jianpi Qushi
    Heluo Formula", which the review treats as a distinct preparation and which is
    curated as its own treatment entry above.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Traditional Chinese herbal formula therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Jian Pi Qu Shi Formula
      term:
        id: NCIT:C129986
        label: Traditional Chinese Medicine Formulation
  target_phenotypes:
  - preferred_term: Nephrotic syndrome
    term:
      id: HP:0000100
      label: Nephrotic syndrome
  - preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: PMID:42553762
    reference_title: "Programmed Cell Death: A Key Mechanism of Traditional Chinese Medicine in the Treatment of Membranous Nephropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One RCT and one retrospective case series have demonstrated that JPQSF achieves an 80% complete remission rate after one-year treatment in patients with refractory IMN and ameliorates intestinal flora dysbiosis."
    explanation: Clinical evidence demonstrates 80% complete remission in refractory cases with concurrent microbiome improvement.
classifications:
  harrisons_chapter:
  - classification_value: KIDNEY_URINARY_TRACT
    evidence:
    - reference: PMID:33808418
      reference_title: "Mechanisms of Primary Membranous Nephropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Membranous nephropathy (MN) is an autoimmune disease of the kidney glomerulus and one of the leading causes of nephrotic syndrome."
      explanation: Supports kidney-disorder classification because the disease is explicitly described as affecting the kidney glomerulus.
    - reference: PMID:33808418
      reference_title: "Mechanisms of Primary Membranous Nephropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Membranous nephropathy (MN) is an autoimmune disease of the kidney glomerulus and one of the leading causes of nephrotic syndrome."
      explanation: Supports glomerular-disease classification because the defining lesion is localized to the kidney glomerulus.
  - classification_value: IMMUNE_RHEUMATOLOGIC
    evidence:
    - reference: PMID:33808418
      reference_title: "Mechanisms of Primary Membranous Nephropathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Membranous nephropathy (MN) is an autoimmune disease of the kidney glomerulus and one of the leading causes of nephrotic syndrome."
      explanation: Supports autoimmune-disease classification because the source explicitly identifies MN as an autoimmune disease.
datasets:
- accession: geo:GSE216841
  title: Idiopathic membranous nephropathy and minimal change disease (MCD) transcriptome
  description: 'Introduction: Minimal change disease (MCD) is a major cause of nephrotic syndrome. With a substantial number of patients requiring long-term immunosuppression leading to significant morbidity, the study aim was to determine MCD glomerular transcriptome to serve as a basis for biomarker discovery and novel drug target identification. Animal work showed podocyte injury induced by IL-7/IL-7R signaling (Zhai S, BBRC, 2018). Methods: Renal biopsies from adult patients representing the following groups were selected from the Norwegian Kidney Biopsy Registry: MCD (n=14), as well as normal tissue (n=8) and primary membranous nephropathy (MN; n=12) as the two reference groups.'
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 34
  publication: PMID:36672735
  notes: Identified by GEO DataSets index search for Membranous nephropathy (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE283826
  title: Single-cell RNA-sequencing analysis reveals the peripheral immune characteristics of patients with primary membranous nephropathy
  description: Primary Membranous Nephropathy (PMN) is characterized by dysregulated immune responses, with B and T cells playing critical roles in disease pathogenesis. While significant strides have been made in identifying specific autoantigens and leveraging monoclonal antibodies, the precise immunopathogenic mechanisms underlying immune cell involvement in PMN remain elusive. To comprehensively characterize the cellular, molecular, and immunological landscape, we employed single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cell samples (PBMC) obtained from 6 patients with PMN and 3 healthy controls (NC).We examined the heterogeneity and functional diversity of B cells in PMN.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_count: 9
  publication: PMID:40904455
  notes: Identified by GEO DataSets index search for Membranous nephropathy (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE171458
  title: Single-cell profiling reveals transcriptional signatures, novel epithelial cells and cell-cell crosstalk in idiopathic membranous nephropathy patients
  description: Our understanding of the pathogenesis of idiopathic membranous nephropathy is limited by an incomplete molecular characterization of the cell types in the kidney and interaction between the cells. Besides, the reason for the heterogeneity of these patients as well as the variety of clinical outcomes remains elusive. Therefore, we applied scRNA-seq to kidney biopsies of patients with IMN to identify gene expression at the single-cell level, elucidate cells involved in the progression of IMN, and uncover intercellular interactions.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_count: 8
  publication: PMID:34135910
  notes: Identified by GEO DataSets index search for Membranous nephropathy (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-07-31. Title, sample count, and organism are GEO's own values.
- accession: ega:EGAS00001005435
  title: Risk alleles of membranous nephropathy and recurrence of the disease on the grafted kidney
  description: The goal of the project was to identify risk alleles that are associated with recurrence of membranous nephropathy in the graft after kidney transplantation. First, we sequenced PLA2R1 and HLA-D loci in 248 patients with primary membranous nephropathy and identified two independent single nucleotide polymorphisms (SNPs) at risk for primary membranous nephropathy at each locus. Then we investigated whether primary membranous nephropathy at-risk variants were associated with recurrence in a retrospective cohort of 105 donor-recipient pairs and a replication cohort of 40 pairs.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Membranous nephropathy"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001007700
  title: GWAS membranous nephropathy Stanescu et al., 2011 UK cohort, chr2 region of interest, imputed
  description: '334 biopsy-confirmed membranous nephropathy (MN) cases and 349 ethnically matched healthy controls: the British cohort of the Stanescu et al., 2011 GWAS. Genotyped and imputed region of interest on chromosome 2 (hg19 chr2:160500000-161500000), as used to determine Neanderthal introgression near the PLA2R1 MN risk locus (lead SNP: rs4664308).'
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:21323541
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Membranous nephropathy"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: massive:MSV000092309
  title: 'Towards the definition of the molecular hallmarks of Idiopathic Membranous Nephropathy in serum proteome: a DIA-PASEF approach'
  description: Idiopathic Membranous Nephropathy (IMN) is a pathologically defined disorder of the glomerulus, primarily responsible for nephrotic syndromes (NS) in nondiabetic adults. The underlying molecular mechanisms are still not completely clarified. To explore possible molecular and functional signatures, an optimised MS-method based on next-generation data-independent-acquisition combined with ion-mobility was applied to serum of patients affected by IMN (n=15) or by other glomerulopathies (PN) (n=15).
  notes: Located via OmicsDI, which aggregates across omics repositories; this record comes from massive. Only repositories with no other discovery route in this project and with a working accession resolver are curated from OmicsDI -- GEO, ArrayExpress, PRIDE, MetaboLights and EGA hits are excluded as duplicates of dedicated passes. Matched because the disease is named in the dataset's own title ("Membranous nephropathy"). Retrieved 2026-08-02.
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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Membranous nephropathy. Core disease mechanisms, molecular and cellular pa...
Asta Scientific Corpus Retrieval 17 citations 2026-04-14T13:18:34.020048

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Membranous nephropathy. Core disease mechanisms, molecular and cellular pa...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 17
  • Snippets retrieved: 20

Relevant Papers

[1] Unraveling Primary Membranous Nephropathy Using Proteogenomic Studies

  • Authors: Omar Ragy, P. Hamilton, D. Kanigicherla
  • Year: 2021
  • Venue: Urinary Tract Infection and Nephropathy - Insights into Potential Relationship [Working Title]
  • URL: https://www.semanticscholar.org/paper/a3540dbb14ce21aa09f82627cc931ddfa6ffa444
  • DOI: 10.5772/intechopen.97622
  • Summary: This chapter focuses on the links identified between primary membranous nephropathy and underlying gene polymorphism, and pathways using both proteomics and transcriptomic analysis.
  • Evidence snippets:
  • Snippet 1 (score: 0.631) > Management of membranous nephropathy remains a continuing challenge in the field of nephrology. Over the last 50 years, we have been classifying and managing membranous nephropathy based on both histological and clinical phenotyping, which is the key feature guiding treatment decisions. However, in recent years other mechanisms have come to shed light on the heterogeneity of membranous nephropathy and clinical outcomes. With the emergence of proteogenomic analysis, the classification of other nephrotic syndromes has advanced immensely [1]. Therefore, the potential value for membranous nephropathy is to be considered. > Varied clinical manifestation may be due to the polymorphic gene expression in the immune system as well as at the glomerular filtration barrier site, which comprises podocytes, endothelial cells, and intervening glomerular basement membrane [2]. In addition to the multiple immune cascade pathways, underlying complex molecular and cellular processes are identified by proteomics and transcriptomics in glomerular disorders like Minimal Change Disease and focal segmental glomerulosclerosis (FSGS) [1]. Early data suggest that gene expression and molecular pathways are both potential emerging therapeutic targets in the era of precision medicine in these disorders. > Primary membranous nephropathy is considered an autoimmune disease, associated with autoantibodies recognizing a target antigen on the podocytes. The connection between the immune system and underlying cellular pathways in the pathophysiology of membranous nephropathy has been an area of extensive research. Even though membranous nephropathy does not follow the mendelian trait, the role of underlying genetic factors was examined in previous studies. > Although clinical and histological apparency of membranous nephropathy are seemingly similar, response to immunosuppressive therapy can be variable with poor response to treatment in some patients whilst about a third of the patients have minimal to no long-term consequence following spontaneous remission.

[2] Network analysis of membranous glomerulonephritis based on metabolomics data

  • Authors: Amir Taherkhani, S. Kalantari, Afsaneh Arefi Oskouie, M. Nafar, M. Taghizadeh et al.
  • Year: 2018
  • Venue: Molecular Medicine Reports
  • URL: https://www.semanticscholar.org/paper/7722ec312f589729d9818ddc9adf2c42a39b383b
  • DOI: 10.3892/mmr.2018.9477
  • PMID: 30221719
  • PMCID: 6172390
  • Citations: 21
  • Summary: The present study aimed to identify diagnostic metabolites that are involved in the development of the disease using topological features in the component-reaction-enzyme-gene (CREG) network for MGN using molecular complex detection and ClueGene Ontology.
  • Evidence snippets:
  • Snippet 1 (score: 0.544) > Membranous glomerulonephritis (MGN) is the most common cause of nephrotic syndrome in adults >60 years old (1,2). Rivera et al (3) suggested that MGN was the pathology in 15.9-32.9% of all nephrotic syndrome cases. Of all cases, 75% are classified as primary or idiopathic MGN; secondary MGN is associated with various conditions, including hepatitis infection, malignancy, systematic lupus erythematosus and drug intoxication (4,5). MGN is histopathologically characterized by the thickening of the glomerular basement membrane (GBM) and the subepithelial deposition of immune complexes (5). Electron microscopy has demonstrated that subepithelial/intramembranous immune deposits (immunoglobulin G and complement) cause podocyte damage, which is usually associated with nephrotic syndrome (4). A deterioration in renal function and the development of end-stage renal disease occur in ~40% of patients with primary MGN (5). Proteinuria (6,7), edema (8,9), hyperlipidemia (10,11) and hypoalbuminemia (12,13) are non-specific clinical symptoms of MGN. However, renal biopsy is the only definitive diagnostic approach, although it is an invasive procedure. Despite research in this field, the exact mechanisms of the development and progression of the disease have not been fully elucidated (14). > Systems biology gives meaning to large amounts of data derived from '-omics-' technologies (15). The '-omics-' technologies refer to high-throughput techniques, which may simultaneously detect a large number of molecules (including genes, transcriptomes, proteins and metabolites) in complex bio-samples (16). This approach may reduce the restrictions in the field of diagnosis and contribute to the understanding of the mechanisms involved in the pathogenesis of disease. > Metabolites are downstream products of gene expression and protein activity; therefore, they may provide an immediate indication of the biological phenotype (17).

[3] Membranous nephropathy as a rare renal manifestation of IgG4-related disease

  • Authors: AA Kurien, A. Raychaudhury, P. Walker
  • Year: 2015
  • Venue: Indian Journal of Nephrology
  • URL: https://www.semanticscholar.org/paper/f5bbbb54f2c78e995da4cf15a275ff623ff2a763
  • DOI: 10.4103/0971-4065.143300
  • PMID: 26060366
  • PMCID: 4446921
  • Citations: 6
  • Summary: A patient with IgG4 renal disease who had membranous nephropathy as well as TIN is reported, indicating a newly described immune-mediated disorder with tissue infiltration of IgG 4-positive plasma cells.
  • Evidence snippets:
  • Snippet 1 (score: 0.537) > Membranous nephropathy may be primary or secondary to a variety of causes. One of the major causes of primary membranous nephropathy is the development of antibodies against a podocyte antigen, M-type PLA2R. [5] utoimmune disease, infections, neoplasms and drugs are the main etiologic factors of secondary membranous nephropathy. Recently, a series of published literature suggested that IgG4-RD is another systemic disease, which is an etiological factor for secondary membranous nephropathy. [6] In 2011, the international symposium on IgG4-RD in the nomenclature consensus statement termed membranous nephropathy secondary to IgG4-RD as "IgG4-related membranous nephropathy". [7] Anti-PLA2R antibody staining is a useful marker for differentiating primary from secondary membranous nephropathy in adults. [8] Anti-PLA2R antibody staining was negative in this patient, as is expected in a case of secondary membranous nephropathy. Work up on our patient did not reveal any evidence of underlying autoimmune disease, infection or malignancy. No drug history was elicited. Considering a background of secondary membranous nephropathy, we attribute it to IgG4-RD because the following diagnostic criteria were fulfilled. [9] Clinical criteria of nephrotic syndrome with renal dysfunction • High serum IgG4 level and high IgG4/IgG ratio • Histological picture of membranous nephropathy confirmed by electron microscopy study along with interstitial fibrosis and dense infiltration of IgG4 positive plasma cells. > The etiopathogenesis of membranous nephropathy developing in the setting of IgG4-RD is unclear. > A hypothesis put forward by Fervenza et al. is that the proliferating plasma cells produce IgG4 that is autoreactive against podocyte antigens. [10]

[4] Membranous Nephropathy: Current Understanding in The Light of New Advances

  • Authors: H. Ozer, I. Baloglu, F. Fervenza, K. Turkmen
  • Year: 2023
  • Venue: Turkish Journal of Nephrology
  • URL: https://www.semanticscholar.org/paper/0ce05309e95ca7a35558cb30763ea134592caee3
  • DOI: 10.5152/turkjnephrol.2023.22123421
  • Citations: 1
  • Summary: Treatment in membranous nephropathy has turned to more specific therapies that are more selective in targeting antibody-producing cells, such as rituximab.
  • Evidence snippets:
  • Snippet 1 (score: 0.536) > Membranous nephropathy (MN) is a non-inflammatory autoimmune disease defined by the presence of subepithelial immune deposits localized between the podocyte and the glomerular basement membrane (GBM) on electron microscopy examination. Although terms such as membranous glomerulonephritis or epimembranous glomerulonephritis were used to name the disease in the past, the term membranous nephropathy is often preferred today, especially because of its noninflammatory character. It is the most common cause of primary nephrotic syndrome (NS) in adults, with an annual incidence of 1/100 000 cases. It is most often detected in the 40s and is more common in men than in women. 1,2 About 70%-80% of MN patients are classified as primary MN, while 20%-30% are classified as secondary MN. 3 The most common underlying causes of secondary MN are infections, drugs, malignancies, and autoimmune diseases. The frequency of secondary MN is higher in patients diagnosed with MN in childhood or advanced ages, and detailed research should be done on the underlying causes. factors trigger a loss of tolerance for an autoantigen, resulting in B cell activation and autoantibody production. These autoantibodies damage the podocytes through complement-related and complement-independent mechanisms, resulting in the development of proteinuria. 4,5 rly processes in elucidating the pathogenesis were presented with the Heymann nephritis model in the mouse. It has been shown that immune deposits accumulate in the subepithelial part of the GBM as a result of the binding of circulating immunocomplexes to antigens on the glomerular capillary membrane. Immune complex formations cause local activation of the complement system and result in complement-related cellular damage, GBM, and podocyte damage. 6 The injury process is chronic and ultimately results in severe proteinuria, which is the typical clinical manifestation of MN patients. > However, the podocyte protein targeted in the Heymann nephritis model is megalin, which has been identified in mice but is not expressed in humans.

[5] Identification Exploring the Mechanism and Clinical Validation of Mitochondrial Dynamics-Related Genes in Membranous Nephropathy Based on Mendelian Randomization Study and Bioinformatics Analysis

  • Authors: Qiuyuan Shao, Nan Li, Huimin Qiu, Min Zhao, Chunming Jiang et al.
  • Year: 2025
  • Venue: Biomedicines
  • URL: https://www.semanticscholar.org/paper/dae27fc292080b60dbd3afb20a41bc95678b8048
  • DOI: 10.3390/biomedicines13061489
  • PMID: 40564208
  • PMCID: 12191289
  • Summary: These findings elucidate the molecular underpinnings of MDG-mediated mechanisms in MN, revealing novel diagnostic biomarkers and therapeutic targets and underscore the interplay between mitochondrial dynamics and immune dysregulation in MN progression, providing a foundation for precision medicine strategies.
  • Evidence snippets:
  • Snippet 1 (score: 0.514) > Membranous nephropathy (MN) is a prominent glomerular pathology characterized by the deposition of subepithelial immune complexes along the glomerular basement membrane, leading to the clinical manifestation of nephrotic syndrome [1]. Epidemiological studies indicate that the global incidence of membranous nephropathy (MN) is approximately 8-10 cases per million population. The incidence is marginally higher in the United States, reaching 12 cases per million population [2]. In China, MN accounts for over 20% of primary glomerular diseases, with primary MN constituting approximately 80% of all MN cases [2,3]. Among White adults, MN represents the most common etiology of primary nephrotic syndrome [3]. The clinical trajectory of MN exhibits considerable heterogeneity: while spontaneous remission occurs in roughly one-third of cases, another third maintain stable renal function despite persistent proteinuria. The remaining third face a substantial risk of progression to end-stage renal disease in the absence of timely diagnosis and intervention. Existing therapeutic regimens-centered on immunosuppressive therapy and supportive management-often fail to prevent relapse, highlighting a critical need for novel and more effective treatment strategies [4,5]. Elucidating the molecular mechanisms underlying MN is therefore imperative for the discovery of reliable diagnostic biomarkers and the development of targeted therapeutic interventions to improve clinical outcomes. > Mitochondrial dynamics (MD), encompassing mitochondrial fusion, fission, and turnover processes, are essential for maintaining organellar integrity and bioenergetic function. These dynamic processes are integral to ATP generation and exert regulatory influence over key cellular activities, including apoptosis and intracellular signaling pathways [6,7]. Disruptions in MD have been implicated in the pathophysiology of MN, where impaired mitochondrial function may amplify oxidative stress and inflammatory responses, thereby exacerbating renal injury [8,9].
  • Snippet 2 (score: 0.474) > Membranous nephropathy (MN) constitutes a leading etiology of adult-onset nephrotic syndrome, where current therapeutic approaches, including immunosuppressive regimens, frequently fail to address either the underlying molecular pathogenesis or the persistent risk of disease recurrence [45]. Notably, dysregulation of mitochondrial dynamics (MD) disrupts cellular bioenergetic homeostasis, driving aberrant cellular fate determination through compromised mitochondrial quality control. In the renal tubular compartment, MD abnormalities may induce tubular epithelial atrophy, inflammatory cascades, and programmed cell death-pathobiological processes that collectively propagate renal disease progression [46]. Nevertheless, the precise mechanistic involvement of MD in MN pathogenesis remains incompletely characterized. To elucidate the molecular mechanisms underpinning MN, this study investigated the involvement of MD in disease pathogenesis. Transcriptomic datasets from public repositories were integrated with MR and machine-learning methodologies to identify MD-associated genes implicated in MN. Four candidate genes-MYO9A, NFKBIZ, RTTN, and USP40-were suggested to be involved in the pathological process of MN. Additionally, scRNA-seq analysis identified mesenchymal-epithelial transitioning cells as pivotal in the disease microenvironment. This comprehensive molecular characterization advances our current understanding of MN pathophysiology and lays a foundation for the development of targeted therapeutic interventions aimed at improving clinical outcomes. > Myosin IXA (MYO9A), a member of the myosin superfamily ubiquitously expressed in eukaryotic cells, exhibits low-level constitutive expression in renal tubular epithelial cells (particularly within proximal tubules and collecting ducts), while demonstrating significantly higher expression in renal interstitial fibroblasts [46]. This motor protein primarily modulates intracellular cytoskeletal architecture and dynamic remodeling, facilitating cellular migration and proliferative responses that contribute to progressive renal fibrogenesis [47].

[6] Membranous nephropathy: Systems biology-based novel mechanism and traditional Chinese medicine therapy

  • Authors: Hua Miao, Ya-mei Zhang, Xiaoyong Yu, Liang Zou, Ying-yong Zhao
  • Year: 2022
  • Venue: Frontiers in Pharmacology
  • URL: https://www.semanticscholar.org/paper/3fa43ea5478f6dc7da789c08449dd33e7900f1c6
  • DOI: 10.3389/fphar.2022.969930
  • PMID: 36176440
  • PMCID: 9513429
  • Citations: 43
  • Influential citations: 2
  • Summary: The identification of nephritogenic autoantibodies against neutral endopeptidase, phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A) antigens provide more specific concept-driven intervention strategies for treatments by specific B cell-targeting monoclonal antibodies to inhibit antibody production and antibody-antigen immune complex deposition.
  • Evidence snippets:
  • Snippet 1 (score: 0.498) > Membranous nephropathy (MN) is a major cause of antibody-associated nephrotic syndrome among adults (Gianassi et al., 2019;Ronco et al., 2021). The development of disease is triggered by accumulation of immune complex deposition in the subepithelial region with local complement activation and injury to podocytes and glomerular basement membrane (GBM) thickening (Feng et al., 2020). While 70%-80% of MN is classified as idiopathic or primary MN, the rest of MN is triggered by secondary causes, such as infections, malignancies or autoimmune diseases (Ronco et al., 2021). The two distinct types require different management approaches. In primary MN, approximately 30% of patients can improve by spontaneous remission, while the remainder show persistent proteinuria or progression to end-stage renal disease (Ronco et al., 2021). In the most severe cases, immunosuppressant treatment is required. Secondary MN requires treatment of the underlying diseases. In most patients, MN is an autoimmune disease mediated by autoantibodies directed against phospholipase A 2 receptor (PLA 2 R) or, more unusually, thrombospondin type-1 domaincontaining 7A (THSD7A) (Deng et al., 2021). However, THSD7A is not specific for primary MN. When secondary causes are excluded, the disease is called primary MN. To date, the diagnosis of MN can only be determined by renal biopsy. In recent years, MN pathogenesis was investigated by using both patients and animal models to help understand the underlying molecular mechanisms for development of immune complex deposition in GBM (Sinico et al., 2016). > This review considers the underlying molecular pathomechanisms of MN, with a particularly focus on novel pathomechanisms such as dysbiosis of gut microbiota, dysregulation of Non-coding RNAs (long non-coding RNAs, microRNAs), aberrant expression of identified proteins by using proteomics and the disorder of endogenous metabolites by metabolomics, as well as altered DNA methylation.

[7] Analysis of gene expression and use of connectivity mapping to identify drugs for treatment of human glomerulopathies

  • Authors: Chen-Fang Chung, J. Papillon, José R. Navarro-Betancourt, Julie Guillemette, Ameya Bhope et al.
  • Year: 2023
  • Venue: Frontiers in Medicine
  • URL: https://www.semanticscholar.org/paper/7b53c0748f67b7956b93e7db636b343c4d2c520d
  • DOI: 10.3389/fmed.2023.1122328
  • PMID: 36993805
  • PMCID: 10042326
  • Citations: 8
  • Summary: The possibility for modulating the UPR or autophagy pharmacologically as therapy for GN is opened, and one of these drugs attenuated injury of glomerular cells is shown to be cytoprotective.
  • Evidence snippets:
  • Snippet 1 (score: 0.480) > Human glomerular diseases, including primary glomerulonephritis (GN)-membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS) and IgA nephropathy (IgAN), as well as diabetic nephropathy (DN) are leading causes of chronic kidney disease, and have a major impact on health (1). Current therapies of GN and DN are only partially effective, significantly toxic and lack specificity. Thus, mechanism-based therapies are desirable. > Glomerular visceral epithelial cells (GECs, podocytes), mesangial and endothelial cells may all be involved in the pathogenesis of GN and DN. Among these cells, podocytes are vital in maintaining glomerular capillary wall permselectivity (2,3) and podocyte injury is believed to be key to the pathogenesis of GN and DN. Injury may be initiated by autoantibodies to glomerular components or circulating immune complexes that deposit in glomeruli and lead to the activation of complement (MN and IgAN) (4). Alternatively, a circulating factor toxic to podocytes induces injury (FSGS) (5). In DN, hyperglycemia and oxidative stress lead to podocyte and mesangial injury (6). These distinct stimuli may activate or disturb various metabolic pathways in glomerular cells; e.g. in podocytes this results in disruption of the cytoskeleton, membrane composition and structure, adhesion to the glomerular basement membrane, or the function of organelles (due to ATP depletion). Conversely, other pathways may be activated in parallel in the glomerulus to attenuate cell injury or promote repair. These pathways may include protein kinases, cytokines, endoplasmic reticulum (ER) stress/unfolded protein response (UPR), ubiquitinproteasome system and autophagy (7).

[8] Targeting necroptosis in fibrosis

  • Authors: Emad H. M. Hassanein, Islam M. Ibrahim, Mostafa S Abd El-Maksoud, Mostafa K Abd El-Aziz, Esraa K. Abd-alhameed et al.
  • Year: 2023
  • Venue: Molecular Biology Reports
  • URL: https://www.semanticscholar.org/paper/d1916874c90b07113252310014a74ec21f0f6020
  • DOI: 10.1007/s11033-023-08857-9
  • PMID: 37910384
  • PMCID: 10676318
  • Citations: 7
  • Summary: This review helps to clarify the role of necroptosis in fibrosis and will encourage clinical efforts to target this pathway of programmed cell death.
  • Evidence snippets:
  • Snippet 1 (score: 0.478) > Chronic kidney disease (CKD) is a significant epidemiological clinical problem with a high prevalence Fig. 1 The main mechanism of fibrosis and mortality rate. End-stage renal disease can be developed from CKD and result in serious complications [27]. Diabetic nephropathy, hypertension, and chronic interstitial glomerulonephritis are the most common causes of CKD. These diseases can cause structural and functional changes in the kidney. Chronic inflammation can cause renal fibrosis and is a major predisposing factor in CKD [28]. In addition, various cells, like macrophages, participate in renal fibrosis [29][30][31]. Renal fibrosis frequently leads to renal interstitial fibrosis with tubular atrophy and abnormal ECM deposition as the main pathological causes [32]. Renal fibrosis characterized by inflammatory cell infiltration, fibroblast activation, ECM component deposition, and microvascular thinning [33]. Many molecules and cells, such as angiotensin II (Ang II), are linked to the progression of renal fibrosis [34]. Animal models such as surgical, chemical, physical, genetic, and in vitro models are essential for understanding renal fibrosis biopathology and evaluating new therapies [35]. However, there are no available drugs for renal fibrosis. As a result, improving our understanding of renal fibrosis's cellular and molecular mechanisms is critical to eliminating renal fibrosis [36]. Alleviation of fibrosis alone is not sufficient to repair kidney function without restoring lost nephron tissue after damage. It is worth noting that encouraging endogenous tissue regeneration could be a promising treatment option for kidney disease [37].

[9] Chronic kidney disease enhances alternative pathway activity: a new paradigm

  • Authors: Diana I. Jalal, Joshua M. Thurman, Richard J. H. Smith
  • Year: 2025
  • Venue: The Journal of Clinical Investigation
  • URL: https://www.semanticscholar.org/paper/edd1c33a4f3bdefe1d963d95d22ca44188abaa1c
  • DOI: 10.1172/JCI188353
  • PMID: 40309771
  • PMCID: 12043098
  • Citations: 3
  • Summary: The need for ongoing research efforts that may lead to opportunities to target the alternative pathway of complement with the goal of improving kidney and cardiovascular outcomes in persons with reduced kidney function is highlighted.
  • Evidence snippets:
  • Snippet 1 (score: 0.478) > Alternative pathway activation contributes to several kidney diseases (51). In some diseases (e.g., C3 glomerulopathy [C3G] and complement-mediated thrombotic microangiopathy/atypical hemolytic uremic syndrome [aHUS]), uncontrolled complement activation is the primary driver of kidney injury (52). In other kidney diseases, secondary activation of the alternative pathway occurs and contributes to disease progression. For example, there is strong preclinical and clinical evidence for a role of the alternative pathway in immune-complex membranoproliferative glomerulonephritis (53), lupus nephritis (54,55), membranous nephropathy (56), IgA nephropathy (57), antineutrophil cytoplasmic antibody associated vasculitis (58), and acute tubular injury (59,60). Although the underlying mechanisms of complement activation vary across these conditions, shared involvement of the complement system suggests that there are anatomic or physiologic features of the kidney that render it particularly susceptible to alternative pathway-mediated injury. > Many of the mechanisms of complement dysregulation first identified in C3G and aHUS have subsequently been observed in the other, more prevalent, kidney diseases. A good example is autoantibodies against factor H (FHAA), which were first appreciated as a cause of aHUS but have recently been detected in patients with C3G, recurrent membranous nephropathy, and monoclonal gammopathy of renal significance (61,62). Similarly, the role of factor H-related proteins (FHRs) in complement control has been elucidated by studying C3G and then translated to other diseases. For example, elevated levels of FHR1 and FHR5 have been shown to promote alternative pathway activation and to correlate with faster disease progression in IgA nephropathy (63,64). In diabetic kidney disease, alternative pathway activation and reduced expression of factor H have been reported (65,66) and urinary levels of FHR2 have been shown to predict CKD progression (67).

[10] SPP1 as a biomarker for idiopathic membranous nephropathy progression and its regulatory role in inflammation and fibrosis

  • Authors: Shuting Pang, Rongbin Zhou, Zige Liu, Boji Xie, Fugang Liu et al.
  • Year: 2025
  • Venue: Frontiers in Immunology
  • URL: https://www.semanticscholar.org/paper/41b35d9a14d8bb8d16ff1f49a9c8462c12ba2dbf
  • DOI: 10.3389/fimmu.2025.1671891
  • PMID: 41080598
  • PMCID: 12510867
  • Citations: 2
  • Summary: SPP1 was identified as a promising biomarker for IMN, demonstrating a critical role in promoting fibrosis and inflammatory responses associated with the disease, and its potential as a novel therapeutic target for IMN intervention is suggested.
  • Evidence snippets:
  • Snippet 1 (score: 0.474) > Idiopathic Membranous Nephropathy (IMN) accounts for approximately 30% of adult nephrotic syndrome cases (1), with nearly 40% of patients progressing to end-stage renal disease (2,3). Early detection and timely intervention can significantly improve outcomes while reducing the socioeconomic burden. Pathologically, IMN is characterized by immune complex deposition, complementmediated proteinuria, and progressive renal impairment (4). Current clinical staging relies on histopathological features including the degree of glomerular basement membrane thickening, presence of spike formations, and immunoglobulin deposition patterns (5). These pathological classifications facilitate disease progression monitoring and prognosis prediction. The disease pathogenesis involves inflammatory cell infiltration and subsequent release of vasoactive mediators, leading to vascular hyperpermeability, leukocyte recruitment, and other inflammatory injuries (6). These processes represent critical pathological hallmarks that drive IMN progression to chronic kidney disease. Ultimately, renal fibrosis progression and sustained immune activation form the core pathological mechanisms in IMN development, suggesting that modulation of inflammatory responses may serve as a promising therapeutic strategy. > Genetic alterations are closely associated with disease pathogenesis. Accumulating evidence indicates that differentially expressed genes may serve as both reliable disease biomarkers and promising therapeutic targets (7). In recent years, RNA sequencing (RNA-seq), particularly single-cell RNA sequencing (scRNA-seq), has revolutionized our understanding of cellular heterogeneity and intercellular communication networks owing to its unparalleled capacity for comprehensive and precise gene expression profiling (8). This cutting-edge technology has substantially advanced research in renal pathophysiology, facilitating the identification of diagnostic biomarkers and discovery of novel therapeutic targets. > Urine contains various exfoliated renal cells with significant research value. Studies have demonstrated that urine from both healthy and diseased kidneys contains sufficient exfoliated proximal tubular cells (PTCs) that can reflect renal functional changes (9).

[11] CKD therapy to improve outcomes of immune-mediated glomerular diseases.

  • Authors: Hans-Joachim Anders, G. Fernández-Juárez, A. Vaglio, P. Romagnani, J. Floege
  • Year: 2023
  • Venue: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
  • URL: https://www.semanticscholar.org/paper/47e9fb8b19765676d2dc40010ab473813eb996a1
  • DOI: 10.1093/ndt/gfad069
  • PMID: 37218706
  • Citations: 16
  • Summary: Non-pharmacological interventions include reducing salt intake, normalizing body weight, avoiding superimposed kidney injuries, smoking cessation, and regular physical activity, and drug interventions to attenuate CKD progression in immune-mediated kidney disorders are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.468) > The management of IgA nephropathy, membranous nephropathy, lupus nephritis, ANCA-associated vasculitis, C3 glomerulonephritis, autoimmune podocytopathies and other immune-mediated glomerular disorders is focused on two major treatment goals, namely preventing overall mortality and the loss of kidney function. As minimizing irreversible kidney damage best serves both goals, the management of immune-mediated kidney disorders must focus on the two central pathomechanisms of kidney function decline, i.e. controlling the underlying immune disease process, e.g. with immunotherapies, and controlling the non-immune mechanisms of chronic kidney disease (CKD) progression. Here we review the pathophysiology of these non-immune mechanisms of CKD progression and discuss non-drug and drug interventions to attenuate CKD progression in immune-mediated kidney disorders. Non-pharmacological interventions include reducing salt intake, normalizing body weight, avoiding superimposed kidney injuries, smoking cessation, and regular physical activity. Approved drug interventions include inhibitors of the renin-angiotensin-aldosterone system and of the sodium-glucose-transporter-2. Numerous additional drugs to improve CKD care are currently being tested in clinical trials. Here we discuss about how and when to use these drugs in the different clinical scenarios of immune-mediated kidney diseases.

[12] Bioinformatics Analysis Reveals a Shared Pathway for Common Forms of Adult Nephrotic Syndrome

  • Authors: Dengfeng Li, Liang Liu, M. Murea, B. Freedman, Lijun Ma
  • Year: 2023
  • Venue: Kidney360
  • URL: https://www.semanticscholar.org/paper/e63be82d34013bce442e57bb003357e86ed12bb6
  • DOI: 10.34067/KID.0000000000000074
  • PMID: 36763793
  • PMCID: 10278839
  • Citations: 3
  • Summary: Key Points Dysregulation of the focal adhesion pathway is present in the three most common forms of glomerular disease, that is, Focal segmental glomerulosclerosis, membranous nephropathy, and minimal change disease. Zyxin is seen to be upregulated in the glomerular compartment of patients with the three most common forms of glomerular disease. Background Focal segmental glomerulosclerosis, membranous nephropathy, and minimal change disease are common causes of nephrotic syndrome. Although tr...
  • Evidence snippets:
  • Snippet 1 (score: 0.461) > Key Points Dysregulation of the focal adhesion pathway is present in the three most common forms of glomerular disease, that is, Focal segmental glomerulosclerosis, membranous nephropathy, and minimal change disease. Zyxin is seen to be upregulated in the glomerular compartment of patients with the three most common forms of glomerular disease. Background Focal segmental glomerulosclerosis, membranous nephropathy, and minimal change disease are common causes of nephrotic syndrome. Although triggers for these diseases differ, disease progression may share common molecular mechanisms. The aim of this study was to investigate the presence of molecular pathways that are dysregulated across these glomerular diseases. Methods The gene expression dataset GSE200828 from the Nephrotic Syndrome Study Network study was obtained from the Gene Expression Omnibus database. R and Python packages, Cytoscape software, and online tools (DAVID and STRING) were used to identify core genes and topologically relevant nodes and molecular pathways. Single-cell RNA sequencing analysis was applied to identify the expression patterns of core genes across kidney cell types in glomerular compartments. Results A total of 1087 differentially expressed genes were identified, including 691 upregulated genes and 396 downregulated genes, which are common in all three forms of nephrotic syndrome compared with kidney donor controls (FDR P<0.01). A multiapproach bioinformatics analysis narrowed down to 28 similarly dysregulated genes across the three proteinuric glomerulopathies. The most topologically relevant nodes belonged to the adherens junction, focal adhesion, and cytoskeleton pathways, where zyxin covers all of those gene ontology terms. Conclusions We report that dysregulation of cell adhesion complexes was present in the three most common forms of glomerular disease. Zyxin could be a biomarker in all three common forms of nephrotic syndrome. If further functional studies confirm its role in their development, zyxin could be a potential therapeutic target.

[13] Membranous nephropathy: Clearer pathology and mechanisms identify potential strategies for treatment

  • Authors: E. Chung, Yuanmin Wang, Karen Keung, M. Hu, H. McCarthy et al.
  • Year: 2022
  • Venue: Frontiers in Immunology
  • URL: https://www.semanticscholar.org/paper/7b40cada96927dcd51cc90ac2b900cd8de74fa74
  • DOI: 10.3389/fimmu.2022.1036249
  • PMID: 36405681
  • PMCID: 9667740
  • Citations: 21
  • Summary: Current understanding of the immune mechanisms driving PMN from animal models and clinical studies are summarized, and the implications on the development of future targeted therapeutic strategies are summarized.
  • Evidence snippets:
  • Snippet 1 (score: 0.456) > Primary membranous nephropathy (PMN) is one of the common causes of adult-onset nephrotic syndrome and is characterized by autoantibodies against podocyte antigens causing in situ immune complex deposition. Much of our understanding of the disease mechanisms underpinning this kidneylimited autoimmune disease originally came from studies of Heymann nephritis, a rat model of PMN, where autoantibodies against megalin produced a similar disease phenotype though megalin is not implicated in human disease. In PMN, the major target antigen was identified to be M-type phospholipase A2 receptor 1 (PLA2R) in 2009. Further utilization of mass spectrometry on immunoprecipitated glomerular extracts and laser micro dissected glomeruli has allowed the rapid discovery of other antigens (thrombospondin type-1 domain-containing protein 7A, neural epidermal growth factor-like 1 protein, semaphorin 3B, protocadherin 7, high temperature requirement A serine peptidase 1, netrin G1) targeted by autoantibodies in PMN. Despite these major advances in our understanding of the pathophysiology of PMN, treatments remain non-specific, often ineffective, or toxic. In this review, we summarize our current understanding of the immune mechanisms driving PMN from animal models and clinical studies, and the implications on the development of future targeted therapeutic strategies.
  • Snippet 2 (score: 0.456) > Primary membranous nephropathy (PMN) is one of the common causes of adult-onset nephrotic syndrome and is characterized by autoantibodies against podocyte antigens causing in situ immune complex deposition. Much of our understanding of the disease mechanisms underpinning this kidney-limited autoimmune disease originally came from studies of Heymann nephritis, a rat model of PMN, where autoantibodies against megalin produced a similar disease phenotype though megalin is not implicated in human disease. In PMN, the major target antigen was identified to be M-type phospholipase A2 receptor 1 (PLA2R) in 2009. Further utilization of mass spectrometry on immunoprecipitated glomerular extracts and laser micro dissected glomeruli has allowed the rapid discovery of other antigens (thrombospondin type-1 domain-containing protein 7A, neural epidermal growth factor-like 1 protein, semaphorin 3B, protocadherin 7, high temperature requirement A serine peptidase 1, netrin G1) targeted by autoantibodies in PMN. Despite these major advances in our understanding of the pathophysiology of PMN, treatments remain non-specific, often ineffective, or toxic. In this review, we summarize our current understanding of the immune mechanisms driving PMN from animal models and clinical studies, and the implications on the development of future targeted therapeutic strategies.

[14] Targeting Hepatic Stellate Cells for the Prevention and Treatment of Liver Cirrhosis and Hepatocellular Carcinoma: Strategies and Clinical Translation

  • Authors: Hao Xiong, Jinsheng Guo
  • Year: 2025
  • Venue: Pharmaceuticals
  • URL: https://www.semanticscholar.org/paper/76e92127053136900f7e3f10e2c9278251ced5d2
  • DOI: 10.3390/ph18040507
  • PMID: 40283943
  • PMCID: 12030350
  • Citations: 8
  • Summary: HSC-targeted approaches using specific surface markers and receptors may enable the selective delivery of drugs, oligonucleotides, and therapeutic peptides that exert optimized anti-fibrotic and anti-HCC effects.
  • Evidence snippets:
  • Snippet 1 (score: 0.456) > Significant progress has been made in elucidating the cellular and molecular mechanisms of liver fibrosis; however, only a few findings have been successfully translated into clinical applications. Firstly, the high cost of drug development and target validation necessitates prolonged timelines and substantial financial investment. Secondly, as regulatory requirements become more stringent, there is an increasing demand for drugs with well-defined clinical efficacy and safety profiles. Moreover, the efficacy observed in animal models often fails to fully translate to clinical settings due to differences in pharmacokinetics, extracellular matrix (ECM) cross-linking, and disease pathophysiology. Despite advancements in anti-fibrotic drug development, accurately identifying ideal noninvasive biomarkers for fibrotic activity and establishing consensus on optimal clinical endpoints remain significant challenges [113,114]. > Currently, addressing the underlying cause remains the only proven strategy to halt or reverse liver fibrosis progression, while the development of effective anti-fibrotic therapies continues to pose a major challenge in liver disease management. Over the past few decades, substantial progress has been made in elucidating the cellular and molecular mechanisms underlying liver fibrosis. Liver fibrosis is a complex pathological change involving multiple cells, factors, and pathways, and the study of the cellular and molecular mechanisms of its occurrence and development provides an important theoretical basis and therapeutic target for clinical drug development. It is anticipated that improved animal models and well-designed clinical trials will facilitate the successful translation of anti-fibrotic research into effective clinical treatments in the near future.

[15] From molecular signatures to predictive biomarkers: modeling disease pathophysiology and drug mechanism of action

  • Authors: A. Heinzel, P. Perco, G. Mayer, R. Oberbauer, A. Lukas et al.
  • Year: 2014
  • Venue: Frontiers in Cell and Developmental Biology
  • URL: https://www.semanticscholar.org/paper/36d6c03a528c1358c0ae5b667cca5ce73b2fbee5
  • DOI: 10.3389/fcell.2014.00037
  • PMID: 25364744
  • PMCID: 4207010
  • Citations: 23
  • Summary: This work exemplifies a computational workflow for expanding from statistics-based association analysis toward deriving molecular pathway and process models for characterizing phenotypes and drug mechanism of action, in turn providing precision medicine hypotheses utilizing predictive biomarkers.
  • Evidence snippets:
  • Snippet 1 (score: 0.455) > In such scenario a biomarker needs to serve as proxy of key mechanistic factors characterizing and driving a disease on a patient-specific level, combined with educating on the specific interference of disease mechanism with drug mechanism of action. For capturing these constraints a detailed molecular map of a clinical phenotype and its interference with a drug mechanism of action is needed, and here integration of Omics profiling adds to identifying such mechanisms (Fechete et al., 2011;Mühlberger et al., 2012). > An a priori stratification of patients based on an appropriately chosen biomarker panel reflecting the pathophysiology of a given patient (group) allowing to determine a match with a specific drug's mechanism of action appears as promising approach. As recently discussed by Himmelfarb et al. fresh approaches are critical in finding therapies to kidney disease benefiting patients, outlining the importance of improving the translational aspect in clinical research (Himmelfarb and Tuttle, 2013). Here, omics technologies have added significantly to the data landscape characterizing chronic kidney disease, however, in a first instance mainly expanding the candidate set of apparently relevant processes and pathways, going in hand with a large number of biomarker candidates, which individually hamper clinically relevant assessment on disease progression (Fechete et al., 2011;Hellemons et al., 2012). > Integrative approaches in the realm of Systems Biology have been proposed for reaching a consensus description of chronic kidney disease pathophysiology, including molecular models of DN as well as of the reno-cardial axis (He et al., 2012;Komorowsky et al., 2012;Mayer et al., 2012;Heinzel et al., 2013). Still, a translation process needs to be followed, joining disease pathophysiology, stratification markers allowing enrichment strategies, combined with on a molecular mechanistic level matching drugs for allowing precision medicine (Mirnezami et al., 2012). In this work we exemplify such procedure on DN being the major clinical presentation leading to end stage renal disease.
  • Snippet 2 (score: 0.444) > Omics profiling significantly expanded the molecular landscape describing clinical phenotypes. Association analysis resulted in first diagnostic and prognostic biomarker signatures entering clinical utility. However, utilizing Omics for deepening our understanding of disease pathophysiology, and further including specific interference with drug mechanism of action on a molecular process level still sees limited added value in the clinical setting. We exemplify a computational workflow for expanding from statistics-based association analysis toward deriving molecular pathway and process models for characterizing phenotypes and drug mechanism of action. Interference analysis on the molecular model level allows identification of predictive biomarker candidates for testing drug response. We discuss this strategy on diabetic nephropathy (DN), a complex clinical phenotype triggered by diabetes and presenting with renal as well as cardiovascular endpoints. A molecular pathway map indicates involvement of multiple molecular mechanisms, and selected biomarker candidates reported as associated with disease progression are identified for specific molecular processes. Selective interference of drug mechanism of action and disease-associated processes is identified for drug classes in clinical use, in turn providing precision medicine hypotheses utilizing predictive biomarkers.

[16] Screening and Analysis of Key Genes in miRNA-mRNA Regulatory Network of Membranous Nephropathy

  • Authors: Yawei Hou, Yameng Li, Yichuan Wang, Wenpu Li, Zhenwei Xiao
  • Year: 2021
  • Venue: Journal of Healthcare Engineering
  • URL: https://www.semanticscholar.org/paper/5b503266a2d3bf122032014fb94e36f17b57080e
  • DOI: 10.1155/2021/5331948
  • PMID: 34824764
  • PMCID: 8610666
  • Citations: 5
  • Summary: The miRNA regulatory network genes may participate in the regulation of podocyte autophagy, lipid metabolism, and renal fibrosis through mTOR, PDGFR-β, LKB1, and VEGF/VEGFR signaling pathways, thereby affecting the occurrence and development of membranous nephropathy.
  • Evidence snippets:
  • Snippet 1 (score: 0.452) > biopsy cannot be performed in some patients due to various reasons, there are certain limitations in clinical applications. erefore, exploring the potential regulatory mechanism of MN and identifying new potential biomarkers and drug target genes have important guiding significance for subsequent clinical diagnosis and treatment. > MicroRNA is a type of endogenous noncoding smallmolecule single-stranded RNA widely found in eukaryotes. It usually consists of 21-25 nucleotides and is highly conserved. It does not have an open reading frame itself. It participates in post-transcriptional gene regulation, affects the pathophysiological process of the body, and is related to cell development, differentiation, proliferation, apoptosis, immune regulation, tumorigenesis, etc. [9]. e study [10] found that, compared with the healthy group, the expression of miRNA-186 in the kidney tissue of patients with membranous nephropathy was significantly downregulated, and in vitro experiments proved that miRNA-186 via Toll-like receptor 4 (TLR4), P2X7, and caspase-3 participates in podocyte apoptosis, leading to increased basement membrane permeability, which in turn leads to membranous nephropathy. e study [9] found that, compared with healthy persons, increased levels of miRNA-193a were found in the urine of membranous nephropathy patients and are associated with an increase in urinary protein levels, thus increasing the severity of the disease. In addition, overexpression of miRNA-193a often indicates poor prognosis. However, there are few reports about the miRNA-miRNA regulatory network and the deep molecular mechanism of MN, especially the miRNA-mediated regulatory mechanism and the molecular network involved in the prevention and treatment of MN are still unclear. Hence, the experiment intends to use the MN-related miRNA and mRNA expression data sets in the GEO database to construct a miRNA-mRNA regulatory network using bioinformatics methods, screen key miRNA-mRNA regulatory relationship pairs, and analyze target functions and related signal pathways to explore their mechanism of action and provide important theoretical references and scientific basis for early diagnosis and targeted therapy of MN.

[17] Gene Expression as a Guide to the Development of Novel Therapies in Primary Glomerular Diseases

  • Authors: P. Garantziotis, S. Doumas, Ioannis Boletis, E. Frangou
  • Year: 2021
  • Venue: Journal of Clinical Medicine
  • URL: https://www.semanticscholar.org/paper/773b7048c3ca5e4e2c851f6bfcc5c03c68946ec9
  • DOI: 10.3390/jcm10112262
  • PMID: 34073694
  • PMCID: 8197155
  • Citations: 1
  • Summary: Novel drugs and small-molecule compounds that may reverse each glomerulonephritis phenotype are identified, suggesting they should be further tested as precise therapy in primary glomerular diseases.
  • Evidence snippets:
  • Snippet 1 (score: 0.448) > Primary glomerulonephritides encompass a heterogeneous group of glomerular diseases characterized by abnormal activation of innate and/or adaptive immune responses due to kidney-intrinsic factors [1]. Although relatively rare, they represent the most common cause of end-stage renal disease in young adults and are associated with increased morbidity, mortality and healthcare costs [2]. Current clinicopathological classification includes minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), immunoglobulin and complement-mediated glomerular diseases with a membranoproliferative glomerular pattern (MPGN), immunoglobulin A nephropathy (IgAN) and thin basement membrane nephropathy (TBMN) [1]. Despite improvements in understanding the underlying pathogenic mechanism of each glomerular disease, therapy still remains nonspecific and includes general supportive measures coupled with immunosuppression [3,4]. Disease-specific therapy targeting kidney-intrinsic injury still remains a major challenge in nephrology. > Recent advances in omics technologies have provided insights into the molecular mechanisms underlying complex traits, such as glomerular diseases. Gene expression represents the intermediate phenotype between genetic variation and disease phenotypic variation and thus may inform about genetic and environmental effects on cells and tissues. Specifically, the comparison of gene expression variation between distinct conditions can delineate transcriptional differences and specific molecular pathways [5]. To this end, highthroughput genome-wide gene expression studies have described the transcriptome of the peripheral blood and kidneys of animal models and patients with glomerular diseases and uncovered molecular pathways implicated in their pathogenesis [6]. However, gene expression patterns unique to each primary glomerular disease remain to be defined. > Computational systems biology combines knowledge-driven experimental data with simulation-based analyses and tests hypotheses with in silico experiments. This provides a powerful tool to understand complex biological processes and identify novel drugs or drugs to be repurposed [7].

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