👪

Inheritance

2

Autosomal dominant inheritance HP:0000006

Heterozygous APOE variants cause disease with low penetrance, so many carriers in affected families are unaffected. Homozygosity for APOE Kyoto in a child of consanguineous parents caused very early-onset disease.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:38438730 SUPPORT Human Clinical

"It is a monogenic disorder with autosomal dominant inheritance and the average age of presentation is 32 years (4-69 years)."

States autosomal dominant inheritance and the age range at presentation.

PMID:42417997 SUPPORT Human Clinical

"Genetic analysis revealed homozygosity for the APOE Kyoto variant and prompted discontinuation of prednisolone."

A homozygous case with infantile onset.

Incomplete penetrance HP:0003829

Typified by incomplete penetrance

Show evidence (1 reference)

PMID:23407349 SUPPORT Human Clinical

"In addition to APOE mutation, other genetic and/or epigenetic factors are considered to be involved in the pathogenesis of LPG because of its low penetrance."

States low penetrance of the APOE variants.

⚙

Pathophysiology

6

APOE Variants Near the LDL-Receptor-Binding Region

Heterozygous missense and small in-frame APOE variants cluster around the receptor-binding region of the N-terminal domain of apolipoprotein E.

APOE hgnc:613

Genetic context variant_origin: GERMLINE zygosity: HETEROZYGOUS

low-density lipoprotein particle receptor binding GO:0050750 ⚠ ABNORMAL

Downstream

Thermodynamic Destabilisation and Aggregation of Variant apoE

Show evidence (2 references)

PMID:24570178 SUPPORT REVIEW SYNTHESIS Human Clinical

"The N-terminal domain of apoE is folded into a four-helix bundle of amphipathic α-helices, and contains the receptor-binding domain in which most apoE mutations that cause LPG or dominant mode of type III hyperlipoproteinemia (HL) are located."

Most LPG variants lie in the receptor-binding domain; the molecular function is recorded as ABNORMAL rather than DECREASED because reduced receptor binding has not been measured for each variant.

PMID:31874799 SUPPORT Human Clinical

"LPG is primarily associated with heterozygous apoE mutations surrounding the low-density lipoprotein-receptor binding site, and it is histologically characterized by lamellated lipoprotein thrombi that lack foam cells."

Locates the causal variants and the defining lesion.

Thermodynamic Destabilisation and Aggregation of Variant apoE

Proline and non-proline LPG variants reduce helical content of the N-terminal domain, push it toward a molten-globule-like state, expose hydrophobic surface and make the protein aggregation-prone and protease-sensitive, both lipid-free and on lipoprotein particles.

protein destabilization GO:0031648 ↑ INCREASED

Downstream

Aberrant Unstable apoE-Rich Lipoprotein Particles

Show evidence (2 references)

PMID:23110818 SUPPORT In Vitro

"Furthermore, all variants were aggregation prone and had enhanced sensitivity to protease digestion."

Aggregation propensity of the variants.

PMID:30309894 SUPPORT In Vitro

"Overall, our data suggest that the LPG-associated apoE3 mutations R25C, R114C, and A152D induce protein misfolding, which may contribute to protein aggregation in glomerular capillaries."

The same mechanism for non-proline variants including Kyoto.

Aberrant Unstable apoE-Rich Lipoprotein Particles

Variant apoE forms poorly formed, destabilised, aggregation-prone lipoprotein particles. Plasma shows a type III hyperlipoproteinaemia-like profile with raised triglycerides, apoB and apoE, although apoE can be normal with some variants.

lipoprotein metabolic process GO:0042157 ⚠ ABNORMAL

Downstream

Glomerular Lipoprotein Thrombi in Dilated Capillaries

Hypertriglyceridemia

Elevated serum apolipoprotein E

Show evidence (2 references)

PMID:23110818 SUPPORT In Vitro

"Furthermore, these lipoprotein particles were thermodynamically destabilized and aggregation prone."

Lipoprotein particles carrying variant apoE are unstable.

PMID:16431249 SUPPORT REVIEW SYNTHESIS Human Clinical

"Lipoprotein glomerulopathy (LPG) is a unique entity of renal lipidosis characterized by peculiar histopathologic characteristics of lipoprotein thrombi and an abnormal plasma lipoprotein profile resembling type III hyperlipoproteinemia, with a marked increase in serum apolipoprotein E (apoE)..."

The plasma lipoprotein phenotype.

Glomerular Lipoprotein Thrombi in Dilated Capillaries

Markedly dilated glomerular capillary loops are filled with pale, lamellated, vacuolated thrombi that stain for lipid (Oil Red O, Sudan) and for apoA, apoB and apoE, lack foam cells, and are negative for immunoglobulins and complement. Impaired macrophage handling of lipoproteins has been proposed to explain why foam cells are absent.

glomerular endothelial cell CL:0002188

Animal models

Adenoviral APOE Sendai in Apoe-deficient mice Mouse recapitulates Lipid-positive glomerular thrombi in most transduced mice.

Adenoviral APOE Kyoto in Apoe-deficient mice Mouse recapitulates Kyoto apoE expression in Apoe-deficient mice reproduces LPG.

Downstream

Glomerular Filtration Barrier Injury

Glomerular lipoprotein thrombi

Show evidence (3 references)

PMID:15498375 SUPPORT Human Clinical

"Immunofluorescence staining showed that the thrombi were strongly positive for apo A, B, and E."

Composition of the thrombi.

PMID:41405262 SUPPORT Human Clinical

"These capillary luminal contents stained reddish with Oil-red O confirming lipid contents."

Lipid nature of the capillary contents.

PMID:24149835 SUPPORT REVIEW SYNTHESIS Human Clinical

"Moreover, the macrophage impairment in LPG may provide another mechanism for lipoprotein thrombi in which massive lipoproteins accumulate in the glomerulus without foam cells."

Proposed macrophage contribution, stated as a hypothesis.

Glomerular Filtration Barrier Injury

Occlusion of glomerular capillaries by lipoprotein thrombi is accompanied by leakage of protein and blood into the urine, often reaching nephrotic syndrome.

Downstream

Progressive Loss of Kidney Function

Proteinuria

Nephrotic syndrome

Microscopic hematuria

Edema

Show evidence (1 reference)

PMID:42417997 SUPPORT Human Clinical

"Lipoprotein glomerulopathy is a rare, inherited kidney disorder caused by pathogenic APOE variants that leads to obstruction of glomerular capillaries by lipoprotein thrombi, steroid-resistant nephrotic syndrome, and progressive chronic kidney disease."

Links capillary obstruction to nephrotic syndrome.

Progressive Loss of Kidney Function

Kidney function declines over years; about half of patients reach end-stage kidney disease. Patients whose proteinuria falls by more than half lose kidney function more slowly.

Downstream

Chronic kidney disease progressing to kidney failure

Hypertension

Enlarged kidneys

Anemia

Show evidence (3 references)

PMID:42417997 SUPPORT Human Clinical

"Lipoprotein glomerulopathy is a rare, inherited kidney disorder caused by pathogenic APOE variants that leads to obstruction of glomerular capillaries by lipoprotein thrombi, steroid-resistant nephrotic syndrome, and progressive chronic kidney disease."

Links capillary obstruction to nephrotic syndrome and CKD.

PMID:38769490 SUPPORT Human Clinical

"Without appropriate treatment, chronic kidney disease (CKD) caused by LPG progresses, and approximately half of the patients develop end-stage kidney disease within 1-27 years of disease onset."

Natural history toward end-stage kidney disease.

PMID:32441489 SUPPORT Human Clinical

"LPG patients with urine protein reduced more than 50% had a slower decrease in renal function than those with less urine protein reduction"

Proteinuria reduction tracks slower decline.

⬡

Pathograph

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

●

Phenotypes

11

Blood 1

Anemia HP:0001903

Show evidence (1 reference)

PMID:15498375 SUPPORT Human Clinical

"All of the eight patients presented with edema, microscopic hematuria, severe proteinuria, anemia, and enlarged kidney size."

Anaemia in all eight patients.

Cardiovascular 1

Hypertension HP:0000822

Show evidence (1 reference)

PMID:32441489 SUPPORT Human Clinical

"LPG patients had higher blood pressure (mean arterial pressure: 109.4 ± 19.4 vs. 94.4 ± 11.1 mmHg, p < .001) than the control group."

Higher blood pressure across 95 pooled patients.

Genitourinary 6

Proteinuria VERY_FREQUENT HP:0000093

Show evidence (1 reference)

PMID:38584145 SUPPORT Human Clinical

"Among them, five had a positive family history for LPG, ten presented with proteinuria, four exhibited nephrotic syndrome, and six presented with microscopic hematuria."

Proteinuria in 10 of 11 patients.

Nephrotic syndrome FREQUENT Steroid-resistant nephrotic syndrome HP:0012588

Show evidence (2 references)

PMID:38584145 SUPPORT Human Clinical

"Among them, five had a positive family history for LPG, ten presented with proteinuria, four exhibited nephrotic syndrome, and six presented with microscopic hematuria."

Nephrotic syndrome in 4 of 11 patients.

PMID:38438730 SUPPORT Human Clinical

"Here we report the first described case of LPG in an Indian 7.5-year-old boy who presented with steroid-resistant nephrotic syndrome with normal renal function."

Steroid-resistant nephrotic syndrome in a child.

Microscopic hematuria FREQUENT HP:0002907

Show evidence (1 reference)

PMID:38584145 SUPPORT Human Clinical

"Among them, five had a positive family history for LPG, ten presented with proteinuria, four exhibited nephrotic syndrome, and six presented with microscopic hematuria."

Microscopic haematuria in 6 of 11 patients.

Enlarged kidneys HP:0000105

Show evidence (1 reference)

PMID:15498375 SUPPORT Human Clinical

"All of the eight patients presented with edema, microscopic hematuria, severe proteinuria, anemia, and enlarged kidney size."

Enlarged kidneys in all eight patients.

Chronic kidney disease progressing to kidney failure Stage 5 chronic kidney disease HP:0003774

Show evidence (2 references)

PMID:38769490 SUPPORT Human Clinical

"Without appropriate treatment, chronic kidney disease (CKD) caused by LPG progresses, and approximately half of the patients develop end-stage kidney disease within 1-27 years of disease onset."

About half of patients reach end-stage kidney disease.

PMID:39141311 SUPPORT Human Clinical

"It is also noteworthy that the patient developed end-stage kidney disease after over than 10 years despite fibrate treatment."

Progression to end-stage disease despite treatment.

Glomerular lipoprotein thrombi Abnormal glomerular capillary lumen morphology HP:0033267

Show evidence (1 reference)

PMID:38584145 SUPPORT Human Clinical

"In all renal specimens, there was evident dilation of glomerular capillary lumens containing lipoprotein thrombi, and positive oil red O staining was observed in frozen sections of all samples."

Dilated capillaries with lipoprotein thrombi in every biopsy.

Metabolism 3

Edema HP:0000969

Show evidence (1 reference)

PMID:15498375 SUPPORT Human Clinical

"All of the eight patients presented with edema, microscopic hematuria, severe proteinuria, anemia, and enlarged kidney size."

Oedema in all eight Chinese patients.

Hypertriglyceridemia VERY_FREQUENT HP:0002155

Show evidence (2 references)

PMID:15498375 SUPPORT Human Clinical

"Biochemical profiles revealed high levels of triglycerides, apo B, and apo E."

Raised triglycerides in a Chinese series.

PMID:40186270 SUPPORT Human Clinical

"In contrast to previous cases, this patient lacked hyperlipidemia and ApoE was a Kyoto mutation."

A normolipidaemic exception.

Elevated serum apolipoprotein E Elevated circulating apolipoprotein E concentration HP:0034912

Show evidence (2 references)

PMID:32441489 SUPPORT Human Clinical

"Interestingly, patients with APOE mutations in the LDL receptor binding region had higher serum apolipoprotein E (apoE) levels"

Higher apoE with variants in the receptor-binding region.

PMID:21325775 SUPPORT Human Clinical

"It is intriguing that the serum apoE level was within normal limits."

Normal apoE in an APOE Osaka patient.

🧬

Genetic Associations

1

APOE

Gene: APOE hgnc:613 gene page relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:23407349 SUPPORT Human Clinical

"More than 12 APOE mutations have been identified as causes of LPG, and APOE-Sendai (Arg145Pro) mutation was frequently detected in patients from the eastern part of Japan including Yamagata prefecture."

Many APOE variants cause the disease, with a common Japanese allele.

PMID:23407349 SUPPORT Human Clinical

"We determined the haplotype structure of APOE-Sendai in 13 patients from 9 unrelated families with LPG, and found that the haplotype of all APOE-Sendai mutations was identical, suggesting that APOE-Sendai mutation is common in Japanese patients probably through a founder effect."

Founder effect for APOE Sendai.

PMID:39141311 SUPPORT Human Clinical

"Direct DNA sequencing analyses for apo E identified a duplication of amino acid 151, aspartic acid, and the gene mutation was named APOE Kanto."

An in-frame duplication allele.

💊

Medical Actions

5

Fibrate therapy

Action: Pharmacotherapy NCIT:C15986

Agent: fenofibrate CHEBI:5001 bezafibrate CHEBI:47612 pemafibrate CHEBI:228365

Platform: Small molecule

Fibrates (fenofibrate, bezafibrate, pemafibrate) lower triglycerides and apoE-rich lipoproteins and are the most consistently reported effective therapy, with proteinuria reduction and occasional complete remission, best started early.

Mechanism Target:

INHIBITS Aberrant Unstable apoE-Rich Lipoprotein Particles — Intensive lowering of triglyceride-rich, apoE-rich lipoproteins reduces the supply of material that forms glomerular thrombi.

Show evidence (1 reference)

PMID:24149835 SUPPORT REVIEW SYNTHESIS Human Clinical

"On the other hand, the administration of fibrate with the intensive control of triglyceride and apolipoprotein E particularly from the early phase will ameliorate LPG and prevent renal dysfunction."

Links fibrate control of triglyceride and apoE to improvement.

Show evidence (3 references)

PMID:24149835 SUPPORT REVIEW SYNTHESIS Human Clinical

"On the other hand, the administration of fibrate with the intensive control of triglyceride and apolipoprotein E particularly from the early phase will ameliorate LPG and prevent renal dysfunction."

Review recommending early intensive fibrate therapy.

PMID:42371225 SUPPORT Human Clinical

"Complete remission (0.05 g/gCr) was achieved within 7 months, and she remained stable thereafter."

Complete remission on pemafibrate in a single case.

PMID:38438730 SUPPORT Human Clinical

"Complete response was achieved with Angiotensin-converting Enzyme inhibitor and fenofibrates."

Complete response with fenofibrate plus an ACE inhibitor in a child.

Renin-angiotensin system blockade

Action: Pharmacotherapy NCIT:C15986

Platform: Small molecule

ACE inhibitors or angiotensin receptor blockers are used with lipid-lowering therapy to reduce proteinuria. No agent is bound because the CHEBI angiotensin receptor antagonist class term is a role, not a chemical entity, and is not admissible in therapeutic_agent.

Show evidence (1 reference)

PMID:38438730 SUPPORT Human Clinical

"Complete response was achieved with Angiotensin-converting Enzyme inhibitor and fenofibrates."

ACE inhibition combined with fenofibrate.

Statin therapy

Action: Pharmacotherapy NCIT:C15986

Agent: statin CHEBI:87631

Platform: Small molecule

Statins are used as lipid-lowering therapy with heterogeneous responses.

Show evidence (1 reference)

PMID:40306438 SUPPORT Human Clinical

"As in previously described cases, the clinical response was heterogeneous despite the use of statins and antiproteinuric agents, with proteinuria remission or persistence and progression to different stages of chronic kidney disease."

Variable response to statins in transplant recipients.

Kidney transplantation

Action: kidney transplantation Ontology label: Kidney Transplantation NCIT:C15265

Platform: Surgery

Used for end-stage disease, but the disease recurs in the graft because the abnormal apoE circulates.

Show evidence (1 reference)

PMID:40306438 SUPPORT Human Clinical

"Herein we reported 4 cases of post-transplant recurrence of LPG in Brazilian patients, including 1 case of early relapse (in the first year following transplantation) and 3 cases of late relapse."

Recurrence after transplantation.

Glucocorticoids (ineffective)

Action: Pharmacotherapy NCIT:C15986

Immunosuppression, including prednisolone, does not help and was stopped once the diagnosis was made in the reported child.

Show evidence (1 reference)

PMID:42417997 REFUTE Human Clinical

"Immunosuppressive therapy is ineffective; instead, lipid-lowering measures reduce intraglomerular lipoprotein deposition and preserve kidney function."

States that immunosuppression is ineffective.

🔬

Diagnosis

1

Kidney biopsy and APOE sequencing

Biopsy shows the characteristic dilated capillaries with lipid-positive, apoE-positive, immunoglobulin-negative thrombi; APOE sequencing confirms the diagnosis and is needed because the histology is not unique.

Show evidence (2 references)

PMID:40306438 SUPPORT Human Clinical

"Although kidney biopsy presents typical findings, such as dilated capillary loops containing lipoprotein thrombi, definitive diagnosis requires molecular genetic analysis of APOE."

Biopsy plus genetic confirmation.

PMID:41405262 SUPPORT Human Clinical

"Glomerular tufts were negative for all antisera on direct immunoflorescence."

Negative immunofluorescence separates it from immune-complex disease.

📊

Prevalence

1

Worldwide (published case reports)

Cases In Literature Ultra Rare

About 150 cases had been reported worldwide by 2013, most from Japan and East Asia. No population-based estimate exists.

Show evidence (2 references)

PMID:24149835 SUPPORT REVIEW SYNTHESIS Human Clinical

"To date, approximately 150 cases of LPG have been reported worldwide."

Count of reported cases.

PMID:16431249 SUPPORT REVIEW SYNTHESIS Human Clinical

"At present, 65 cases have been reported worldwide, although most patients are found in Japan and east Asian countries."

Earlier count showing the East Asian concentration.

🐁

Animal Models

2

Adenoviral APOE Sendai in Apoe-deficient mice

Transient expression of human APOE Sendai in Apoe-deficient mice produces glomerular lipoprotein thrombi resembling the human lesion. Aged Apoe-deficient mice develop superficially similar dilated lumens that on special stains are not lipid-rich.

Species

Mouse

Genotype

Apoe-/- transduced with adenovirus expressing human APOE Sendai (Arg145Pro)

Publication

PMID:19459027

Pathograph links

Glomerular Lipoprotein Thrombi in Dilated Capillaries recapitulates fidelity: moderate Lipid-positive glomerular thrombi in most transduced mice.

Limitations: Expression is adenoviral and transient on an Apoe-null background, so the model does not reproduce heterozygous germline disease or progression to kidney failure.

Show evidence (1 reference)

PMID:19459027 SUPPORT Model Organism

"Characteristic lesions were dilated vascular lumens mimicking lipoprotein thrombi in human LPG."

Reproduces the human lesion.

Adenoviral APOE Kyoto in Apoe-deficient mice

The first animal model validating the Kyoto variant, compared side by side with Sendai.

Species

Mouse

Genotype

Apoe-/- transduced with adenovirus expressing human APOE Kyoto (p.R43C, precursor numbering; Arg25Cys in the mature protein)

Publication

PMID:33663537

Pathograph links

Glomerular Lipoprotein Thrombi in Dilated Capillaries recapitulates fidelity: moderate Kyoto apoE expression in Apoe-deficient mice reproduces LPG.

Limitations: Same transient adenoviral design as the Sendai model.

Show evidence (2 references)

PMID:33663537 SUPPORT Model Organism

"Typical lipoprotein thrombi with positive ApoE staining were detected in the AD-ApoE Kyoto and AD-ApoE Sendai groups."

Kyoto apoE expression produces the characteristic glomerular thrombi.

+ 1 more reference

{ }

Source YAML

click to show

name: Lipoprotein Glomerulopathy
creation_date: '2026-10-12T18:40:00Z'
category: Mendelian
parents:
- Glomerular Disease
- Renal Lipidosis
- Inherited Dyslipidemia
disease_term:
  preferred_term: lipoprotein glomerulopathy
  term:
    id: MONDO:0012725
    label: lipoprotein glomerulopathy
synonyms:
- LPG
- apoE-associated lipoprotein glomerulopathy
description: >-
  Lipoprotein glomerulopathy is a rare autosomal dominant kidney disease with
  incomplete penetrance, caused by heterozygous (rarely homozygous) missense
  or small in-frame variants in APOE that cluster around the low-density
  lipoprotein receptor-binding region of apolipoprotein E. The variant
  proteins, named after the places they were found (Sendai, Kyoto, Osaka or
  Kurashiki, Chicago, Tokyo or Maebashi, Kanto and others), are
  thermodynamically destabilised, expose hydrophobic surface and aggregate,
  and they form abnormal, unstable lipoprotein particles. These deposit as
  lamellated, apoE-rich lipoprotein thrombi in markedly dilated glomerular
  capillaries, without foam cells and without immunoglobulin or complement.
  Patients, mostly adults and mostly from Japan and China, present with
  proteinuria often reaching the nephrotic range, microscopic haematuria and
  a type III hyperlipoproteinaemia-like profile with high serum apoE, though
  some are normolipidaemic. About half reach end-stage kidney disease within
  1 to 27 years. The disease is not steroid-responsive; intensive
  lipid-lowering therapy, especially fibrates, can reduce proteinuria and
  induce remission. Because the abnormal apoE circulates, the disease recurs
  in kidney transplants.
inheritance:
- name: Autosomal dominant inheritance
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous APOE variants cause disease with low penetrance, so many
    carriers in affected families are unaffected. Homozygosity for APOE Kyoto
    in a child of consanguineous parents caused very early-onset disease.
  evidence:
  - reference: PMID:38438730
    reference_title: "Lipoprotein glomerulopathy: a rare cause of steroid-resistant nephrotic syndrome in a child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is a monogenic disorder with autosomal dominant inheritance and the average age of presentation is 32 years (4-69 years)."
    explanation: >-
      States autosomal dominant inheritance and the age range at presentation.
  - reference: PMID:42417997
    reference_title: "Early-onset lipoprotein glomerulopathy in a 23-month-old boy with homozygous APOE Kyoto variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analysis revealed homozygosity for the APOE Kyoto variant and prompted discontinuation of prednisolone."
    explanation: >-
      A homozygous case with infantile onset.
- name: Incomplete penetrance
  inheritance_term:
    preferred_term: Typified by incomplete penetrance
    term:
      id: HP:0003829
      label: Typified by incomplete penetrance
  evidence:
  - reference: PMID:23407349
    reference_title: "A founder haplotype of APOE-Sendai mutation associated with lipoprotein glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to APOE mutation, other genetic and/or epigenetic factors are considered to be involved in the pathogenesis of LPG because of its low penetrance."
    explanation: >-
      States low penetrance of the APOE variants.
prevalence:
- population: Worldwide (published case reports)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    About 150 cases had been reported worldwide by 2013, most from Japan and
    East Asia. No population-based estimate exists.
  evidence:
  - reference: PMID:24149835
    reference_title: "Topics in lipoprotein glomerulopathy: an overview."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, approximately 150 cases of LPG have been reported worldwide."
    explanation: >-
      Count of reported cases.
  - reference: PMID:16431249
    reference_title: "Impact of lipoprotein glomerulopathy on the relationship between lipids and renal diseases."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "At present, 65 cases have been reported worldwide, although most patients are found in Japan and east Asian countries."
    explanation: >-
      Earlier count showing the East Asian concentration.
genetic:
- name: APOE
  gene_term:
    preferred_term: APOE
    term:
      id: hgnc:613
      label: APOE
  relationship_type: CAUSATIVE
  notes: >-
    Heterozygous missense substitutions (often arginine to proline) and small
    in-frame deletions or duplications in APOE near the LDL-receptor-binding
    region. APOE Sendai (Arg145Pro) is a founder allele in eastern Japan and
    APOE Kyoto (Arg25Cys) the commonest Chinese allele. Names here use
    mature-protein numbering; precursor numbering, which includes the
    18-residue signal peptide, adds 18 (Kyoto is p.R43C, Sendai p.R163P).
  evidence:
  - reference: PMID:23407349
    reference_title: "A founder haplotype of APOE-Sendai mutation associated with lipoprotein glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "More than 12 APOE mutations have been identified as causes of LPG, and APOE-Sendai (Arg145Pro) mutation was frequently detected in patients from the eastern part of Japan including Yamagata prefecture."
    explanation: >-
      Many APOE variants cause the disease, with a common Japanese allele.
  - reference: PMID:23407349
    reference_title: "A founder haplotype of APOE-Sendai mutation associated with lipoprotein glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We determined the haplotype structure of APOE-Sendai in 13 patients from 9 unrelated families with LPG, and found that the haplotype of all APOE-Sendai mutations was identical, suggesting that APOE-Sendai mutation is common in Japanese patients probably through a founder effect."
    explanation: >-
      Founder effect for APOE Sendai.
  - reference: PMID:39141311
    reference_title: "Lipoprotein glomerulopathy with a novel apolipoprotein E variant, APOE Kanto (Asp 151dup)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Direct DNA sequencing analyses for apo E identified a duplication of amino acid 151, aspartic acid, and the gene mutation was named APOE Kanto."
    explanation: >-
      An in-frame duplication allele.
pathophysiology:
- name: APOE Variants Near the LDL-Receptor-Binding Region
  biological_scale: MOLECULAR
  description: >-
    Heterozygous missense and small in-frame APOE variants cluster around the
    receptor-binding region of the N-terminal domain of apolipoprotein E.
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
  genes:
  - preferred_term: APOE
    term:
      id: hgnc:613
      label: APOE
  molecular_functions:
  - preferred_term: low-density lipoprotein particle receptor binding
    modifier: ABNORMAL
    term:
      id: GO:0050750
      label: low-density lipoprotein particle receptor binding
  evidence:
  - reference: PMID:24570178
    reference_title: "Apolipoprotein E mutations: a comparison between lipoprotein glomerulopathy and type III hyperlipoproteinemia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The N-terminal domain of apoE is folded into a four-helix bundle of amphipathic α-helices, and contains the receptor-binding domain in which most apoE mutations that cause LPG or dominant mode of type III hyperlipoproteinemia (HL) are located."
    explanation: >-
      Most LPG variants lie in the receptor-binding domain; the molecular
      function is recorded as ABNORMAL rather than DECREASED because reduced
      receptor binding has not been measured for each variant.
  - reference: PMID:31874799
    reference_title: "Apolipoprotein E-related glomerular disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LPG is primarily associated with heterozygous apoE mutations surrounding the low-density lipoprotein-receptor binding site, and it is histologically characterized by lamellated lipoprotein thrombi that lack foam cells."
    explanation: >-
      Locates the causal variants and the defining lesion.
  downstream:
  - target: Thermodynamic Destabilisation and Aggregation of Variant apoE
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23110818
      reference_title: "Thermodynamic and structural destabilization of apoE3 by hereditary mutations associated with the development of lipoprotein glomerulopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "All three variants were found to have significantly reduced helical content, to expose a larger portion of hydrophobic surface to the solvent, and to be significantly thermodynamically destabilized, often lacking functionally relevant unfolding intermediates."
      explanation: >-
        Three proline-substitution variants are destabilised in vitro.
- name: Thermodynamic Destabilisation and Aggregation of Variant apoE
  biological_scale: MOLECULAR
  description: >-
    Proline and non-proline LPG variants reduce helical content of the
    N-terminal domain, push it toward a molten-globule-like state, expose
    hydrophobic surface and make the protein aggregation-prone and
    protease-sensitive, both lipid-free and on lipoprotein particles.
  biological_processes:
  - preferred_term: protein destabilization
    modifier: INCREASED
    term:
      id: GO:0031648
      label: protein destabilization
  evidence:
  - reference: PMID:23110818
    reference_title: "Thermodynamic and structural destabilization of apoE3 by hereditary mutations associated with the development of lipoprotein glomerulopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Furthermore, all variants were aggregation prone and had enhanced sensitivity to protease digestion."
    explanation: >-
      Aggregation propensity of the variants.
  - reference: PMID:30309894
    reference_title: "Thermodynamic destabilization and aggregation propensity as the mechanism behind the association of apoE3 mutants and lipoprotein glomerulopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Overall, our data suggest that the LPG-associated apoE3 mutations R25C, R114C, and A152D induce protein misfolding, which may contribute to protein aggregation in glomerular capillaries."
    explanation: >-
      The same mechanism for non-proline variants including Kyoto.
  downstream:
  - target: Aberrant Unstable apoE-Rich Lipoprotein Particles
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23110818
      reference_title: "Thermodynamic and structural destabilization of apoE3 by hereditary mutations associated with the development of lipoprotein glomerulopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Finally, although the variants were able to form discoidal lipoprotein particles, discrete subpopulations of poorly formed or aberrant particles were evident."
      explanation: >-
        Variant apoE forms aberrant lipoprotein particles.
- name: Aberrant Unstable apoE-Rich Lipoprotein Particles
  biological_scale: ORGANISM
  description: >-
    Variant apoE forms poorly formed, destabilised, aggregation-prone
    lipoprotein particles. Plasma shows a type III hyperlipoproteinaemia-like
    profile with raised triglycerides, apoB and apoE, although apoE can be
    normal with some variants.
  biological_processes:
  - preferred_term: lipoprotein metabolic process
    modifier: ABNORMAL
    term:
      id: GO:0042157
      label: lipoprotein metabolic process
  evidence:
  - reference: PMID:23110818
    reference_title: "Thermodynamic and structural destabilization of apoE3 by hereditary mutations associated with the development of lipoprotein glomerulopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Furthermore, these lipoprotein particles were thermodynamically destabilized and aggregation prone."
    explanation: >-
      Lipoprotein particles carrying variant apoE are unstable.
  - reference: PMID:16431249
    reference_title: "Impact of lipoprotein glomerulopathy on the relationship between lipids and renal diseases."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Lipoprotein glomerulopathy (LPG) is a unique entity of renal lipidosis characterized by peculiar histopathologic characteristics of lipoprotein thrombi and an abnormal plasma lipoprotein profile resembling type III hyperlipoproteinemia, with a marked increase in serum apolipoprotein E (apoE) concentrations."
    explanation: >-
      The plasma lipoprotein phenotype.
  downstream:
  - target: Glomerular Lipoprotein Thrombi in Dilated Capillaries
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:16431249
      reference_title: "Impact of lipoprotein glomerulopathy on the relationship between lipids and renal diseases."
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: MODEL_ORGANISM
      snippet: "The virus-mediated transduction of apoE Sendai resulting in the development of LPG in apoE-deficient mice confirms the etiologic role of apoE mutation in LPG."
      explanation: >-
        Circulating variant apoE is sufficient to produce the glomerular
        lesion in mice.
  - target: Hypertriglyceridemia
  - target: Elevated serum apolipoprotein E
- name: Glomerular Lipoprotein Thrombi in Dilated Capillaries
  biological_scale: TISSUE
  description: >-
    Markedly dilated glomerular capillary loops are filled with pale,
    lamellated, vacuolated thrombi that stain for lipid (Oil Red O, Sudan) and
    for apoA, apoB and apoE, lack foam cells, and are negative for
    immunoglobulins and complement. Impaired macrophage handling of
    lipoproteins has been proposed to explain why foam cells are absent.
  cell_types:
  - preferred_term: glomerular endothelial cell
    term:
      id: CL:0002188
      label: glomerular endothelial cell
  evidence:
  - reference: PMID:15498375
    reference_title: "Lipoprotein glomerulopathy: clinical features and pathological characteristics in Chinese."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunofluorescence staining showed that the thrombi were strongly positive for apo A, B, and E."
    explanation: >-
      Composition of the thrombi.
  - reference: PMID:41405262
    reference_title: "Fingerprints of lipoprotein glomerulopathy - An addition to the list of rare diseases in India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These capillary luminal contents stained reddish with Oil-red O confirming lipid contents."
    explanation: >-
      Lipid nature of the capillary contents.
  - reference: PMID:24149835
    reference_title: "Topics in lipoprotein glomerulopathy: an overview."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "Moreover, the macrophage impairment in LPG may provide another mechanism for lipoprotein thrombi in which massive lipoproteins accumulate in the glomerulus without foam cells."
    explanation: >-
      Proposed macrophage contribution, stated as a hypothesis.
  downstream:
  - target: Glomerular Filtration Barrier Injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Glomerular lipoprotein thrombi
- name: Glomerular Filtration Barrier Injury
  biological_scale: TISSUE
  description: >-
    Occlusion of glomerular capillaries by lipoprotein thrombi is accompanied
    by leakage of protein and blood into the urine, often reaching nephrotic
    syndrome.
  evidence:
  - reference: PMID:42417997
    reference_title: "Early-onset lipoprotein glomerulopathy in a 23-month-old boy with homozygous APOE Kyoto variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lipoprotein glomerulopathy is a rare, inherited kidney disorder caused by pathogenic APOE variants that leads to obstruction of glomerular capillaries by lipoprotein thrombi, steroid-resistant nephrotic syndrome, and progressive chronic kidney disease."
    explanation: >-
      Links capillary obstruction to nephrotic syndrome.
  downstream:
  - target: Progressive Loss of Kidney Function
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32441489
      reference_title: "Clinical and genetic analysis of lipoprotein glomerulopathy patients caused by APOE mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "LPG patients with urine protein reduced more than 50% had a slower decrease in renal function than those with less urine protein reduction"
      explanation: >-
        Proteinuria reduction tracks slower decline of kidney function.
  - target: Proteinuria
  - target: Nephrotic syndrome
  - target: Microscopic hematuria
  - target: Edema
- name: Progressive Loss of Kidney Function
  biological_scale: ORGANISM
  description: >-
    Kidney function declines over years; about half of patients reach
    end-stage kidney disease. Patients whose proteinuria falls by more than
    half lose kidney function more slowly.
  evidence:
  - reference: PMID:42417997
    reference_title: "Early-onset lipoprotein glomerulopathy in a 23-month-old boy with homozygous APOE Kyoto variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lipoprotein glomerulopathy is a rare, inherited kidney disorder caused by pathogenic APOE variants that leads to obstruction of glomerular capillaries by lipoprotein thrombi, steroid-resistant nephrotic syndrome, and progressive chronic kidney disease."
    explanation: >-
      Links capillary obstruction to nephrotic syndrome and CKD.
  - reference: PMID:38769490
    reference_title: "Lipoprotein glomerulopathy with markedly increased arterial stiffness successfully treated with a combination of fenofibrate and losartan: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Without appropriate treatment, chronic kidney disease (CKD) caused by LPG progresses, and approximately half of the patients develop end-stage kidney disease within 1-27 years of disease onset."
    explanation: >-
      Natural history toward end-stage kidney disease.
  - reference: PMID:32441489
    reference_title: "Clinical and genetic analysis of lipoprotein glomerulopathy patients caused by APOE mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LPG patients with urine protein reduced more than 50% had a slower decrease in renal function than those with less urine protein reduction"
    explanation: >-
      Proteinuria reduction tracks slower decline.
  downstream:
  - target: Chronic kidney disease progressing to kidney failure
  - target: Hypertension
  - target: Enlarged kidneys
  - target: Anemia
phenotypes:
- name: Proteinuria
  category: Renal
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: PMID:38584145
    reference_title: "Clinicopathological characteristics and gene mutations in 11 patients with lipoprotein glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among them, five had a positive family history for LPG, ten presented with proteinuria, four exhibited nephrotic syndrome, and six presented with microscopic hematuria."
    explanation: >-
      Proteinuria in 10 of 11 patients.
- name: Nephrotic syndrome
  category: Renal
  frequency: FREQUENT
  description: >-
    Nephrotic syndrome that does not respond to corticosteroids.
  phenotype_term:
    preferred_term: Steroid-resistant nephrotic syndrome
    term:
      id: HP:0012588
      label: Steroid-resistant nephrotic syndrome
  evidence:
  - reference: PMID:38584145
    reference_title: "Clinicopathological characteristics and gene mutations in 11 patients with lipoprotein glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among them, five had a positive family history for LPG, ten presented with proteinuria, four exhibited nephrotic syndrome, and six presented with microscopic hematuria."
    explanation: >-
      Nephrotic syndrome in 4 of 11 patients.
  - reference: PMID:38438730
    reference_title: "Lipoprotein glomerulopathy: a rare cause of steroid-resistant nephrotic syndrome in a child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report the first described case of LPG in an Indian 7.5-year-old boy who presented with steroid-resistant nephrotic syndrome with normal renal function."
    explanation: >-
      Steroid-resistant nephrotic syndrome in a child.
- name: Microscopic hematuria
  category: Renal
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Microscopic hematuria
    term:
      id: HP:0002907
      label: Microscopic hematuria
  evidence:
  - reference: PMID:38584145
    reference_title: "Clinicopathological characteristics and gene mutations in 11 patients with lipoprotein glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among them, five had a positive family history for LPG, ten presented with proteinuria, four exhibited nephrotic syndrome, and six presented with microscopic hematuria."
    explanation: >-
      Microscopic haematuria in 6 of 11 patients.
- name: Edema
  category: Renal
  phenotype_term:
    preferred_term: Edema
    term:
      id: HP:0000969
      label: Edema
  evidence:
  - reference: PMID:15498375
    reference_title: "Lipoprotein glomerulopathy: clinical features and pathological characteristics in Chinese."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of the eight patients presented with edema, microscopic hematuria, severe proteinuria, anemia, and enlarged kidney size."
    explanation: >-
      Oedema in all eight Chinese patients.
- name: Enlarged kidneys
  category: Renal
  phenotype_term:
    preferred_term: Enlarged kidney
    term:
      id: HP:0000105
      label: Enlarged kidney
  evidence:
  - reference: PMID:15498375
    reference_title: "Lipoprotein glomerulopathy: clinical features and pathological characteristics in Chinese."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of the eight patients presented with edema, microscopic hematuria, severe proteinuria, anemia, and enlarged kidney size."
    explanation: >-
      Enlarged kidneys in all eight patients.
- name: Anemia
  category: Hematologic
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:15498375
    reference_title: "Lipoprotein glomerulopathy: clinical features and pathological characteristics in Chinese."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of the eight patients presented with edema, microscopic hematuria, severe proteinuria, anemia, and enlarged kidney size."
    explanation: >-
      Anaemia in all eight patients.
- name: Hypertension
  category: Cardiovascular
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: PMID:32441489
    reference_title: "Clinical and genetic analysis of lipoprotein glomerulopathy patients caused by APOE mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "LPG patients had higher blood pressure (mean arterial pressure: 109.4 ± 19.4 vs. 94.4 ± 11.1 mmHg, p < .001) than the control group."
    explanation: >-
      Higher blood pressure across 95 pooled patients.
- name: Chronic kidney disease progressing to kidney failure
  category: Renal
  phenotype_term:
    preferred_term: Stage 5 chronic kidney disease
    term:
      id: HP:0003774
      label: Stage 5 chronic kidney disease
  evidence:
  - reference: PMID:38769490
    reference_title: "Lipoprotein glomerulopathy with markedly increased arterial stiffness successfully treated with a combination of fenofibrate and losartan: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Without appropriate treatment, chronic kidney disease (CKD) caused by LPG progresses, and approximately half of the patients develop end-stage kidney disease within 1-27 years of disease onset."
    explanation: >-
      About half of patients reach end-stage kidney disease.
  - reference: PMID:39141311
    reference_title: "Lipoprotein glomerulopathy with a novel apolipoprotein E variant, APOE Kanto (Asp 151dup)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is also noteworthy that the patient developed end-stage kidney disease after over than 10 years despite fibrate treatment."
    explanation: >-
      Progression to end-stage disease despite treatment.
- name: Glomerular lipoprotein thrombi
  category: Renal
  description: >-
    The defining biopsy lesion. HPO has no term for intracapillary
    lipoprotein thrombi, so the glomerular capillary lumen term is bound.
  phenotype_term:
    preferred_term: Glomerular capillary lipoprotein thrombi
    term:
      id: HP:0033267
      label: Abnormal glomerular capillary lumen morphology
  evidence:
  - reference: PMID:38584145
    reference_title: "Clinicopathological characteristics and gene mutations in 11 patients with lipoprotein glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all renal specimens, there was evident dilation of glomerular capillary lumens containing lipoprotein thrombi, and positive oil red O staining was observed in frozen sections of all samples."
    explanation: >-
      Dilated capillaries with lipoprotein thrombi in every biopsy.
- name: Hypertriglyceridemia
  category: Laboratory
  frequency: VERY_FREQUENT
  description: >-
    Type III hyperlipoproteinaemia-like dyslipidaemia, with some patients
    normolipidaemic.
  phenotype_term:
    preferred_term: Hypertriglyceridemia
    term:
      id: HP:0002155
      label: Hypertriglyceridemia
  evidence:
  - reference: PMID:15498375
    reference_title: "Lipoprotein glomerulopathy: clinical features and pathological characteristics in Chinese."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Biochemical profiles revealed high levels of triglycerides, apo B, and apo E."
    explanation: >-
      Raised triglycerides in a Chinese series.
  - reference: PMID:40186270
    reference_title: "Normolipidemic lipoprotein glomerulopathy with IgA nephropathy - ApoE Kyoto mutation: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast to previous cases, this patient lacked hyperlipidemia and ApoE was a Kyoto mutation."
    explanation: >-
      A normolipidaemic exception.
- name: Elevated serum apolipoprotein E
  category: Laboratory
  description: >-
    Usually markedly raised, but normal with some variants such as Osaka and
    Kanto.
  phenotype_term:
    preferred_term: Elevated circulating apolipoprotein E concentration
    term:
      id: HP:0034912
      label: Elevated circulating apolipoprotein E concentration
  evidence:
  - reference: PMID:32441489
    reference_title: "Clinical and genetic analysis of lipoprotein glomerulopathy patients caused by APOE mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interestingly, patients with APOE mutations in the LDL receptor binding region had higher serum apolipoprotein E (apoE) levels"
    explanation: >-
      Higher apoE with variants in the receptor-binding region.
  - reference: PMID:21325775
    reference_title: "A novel apolipoprotein E mutation, ApoE Osaka (Arg158 Pro), in a dyslipidemic patient with lipoprotein glomerulopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is intriguing that the serum apoE level was within normal limits."
    explanation: >-
      Normal apoE in an APOE Osaka patient.
diagnosis:
- name: Kidney biopsy and APOE sequencing
  description: >-
    Biopsy shows the characteristic dilated capillaries with lipid-positive,
    apoE-positive, immunoglobulin-negative thrombi; APOE sequencing confirms
    the diagnosis and is needed because the histology is not unique.
  evidence:
  - reference: PMID:40306438
    reference_title: "Post-transplantat recurrence of lipoprotein glomerulopathy: report of 4 cases and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although kidney biopsy presents typical findings, such as dilated capillary loops containing lipoprotein thrombi, definitive diagnosis requires molecular genetic analysis of APOE."
    explanation: >-
      Biopsy plus genetic confirmation.
  - reference: PMID:41405262
    reference_title: "Fingerprints of lipoprotein glomerulopathy - An addition to the list of rare diseases in India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Glomerular tufts were negative for all antisera on direct immunoflorescence."
    explanation: >-
      Negative immunofluorescence separates it from immune-complex disease.
treatments:
- name: Fibrate therapy
  description: >-
    Fibrates (fenofibrate, bezafibrate, pemafibrate) lower triglycerides and
    apoE-rich lipoproteins and are the most consistently reported effective
    therapy, with proteinuria reduction and occasional complete remission,
    best started early.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: fenofibrate
      term:
        id: CHEBI:5001
        label: fenofibrate
    - preferred_term: bezafibrate
      term:
        id: CHEBI:47612
        label: bezafibrate
    - preferred_term: pemafibrate
      term:
        id: CHEBI:228365
        label: pemafibrate
  target_mechanisms:
  - target: Aberrant Unstable apoE-Rich Lipoprotein Particles
    treatment_effect: INHIBITS
    description: >-
      Intensive lowering of triglyceride-rich, apoE-rich lipoproteins reduces
      the supply of material that forms glomerular thrombi.
    evidence:
    - reference: PMID:24149835
      reference_title: "Topics in lipoprotein glomerulopathy: an overview."
      supports: SUPPORT
      quote_role: REVIEW_SYNTHESIS
      evidence_source: HUMAN_CLINICAL
      snippet: "On the other hand, the administration of fibrate with the intensive control of triglyceride and apolipoprotein E particularly from the early phase will ameliorate LPG and prevent renal dysfunction."
      explanation: >-
        Links fibrate control of triglyceride and apoE to improvement.
  evidence:
  - reference: PMID:24149835
    reference_title: "Topics in lipoprotein glomerulopathy: an overview."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    snippet: "On the other hand, the administration of fibrate with the intensive control of triglyceride and apolipoprotein E particularly from the early phase will ameliorate LPG and prevent renal dysfunction."
    explanation: >-
      Review recommending early intensive fibrate therapy.
  - reference: PMID:42371225
    reference_title: "A case of lipoprotein glomerulopathy in which complete remission was achieved by pemafibrate therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Complete remission (0.05 g/gCr) was achieved within 7 months, and she remained stable thereafter."
    explanation: >-
      Complete remission on pemafibrate in a single case.
  - reference: PMID:38438730
    reference_title: "Lipoprotein glomerulopathy: a rare cause of steroid-resistant nephrotic syndrome in a child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Complete response was achieved with Angiotensin-converting Enzyme inhibitor and fenofibrates."
    explanation: >-
      Complete response with fenofibrate plus an ACE inhibitor in a child.
- name: Renin-angiotensin system blockade
  description: >-
    ACE inhibitors or angiotensin receptor blockers are used with
    lipid-lowering therapy to reduce proteinuria. No agent is bound because
    the CHEBI angiotensin receptor antagonist class term is a role, not a
    chemical entity, and is not admissible in therapeutic_agent.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:38438730
    reference_title: "Lipoprotein glomerulopathy: a rare cause of steroid-resistant nephrotic syndrome in a child."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Complete response was achieved with Angiotensin-converting Enzyme inhibitor and fenofibrates."
    explanation: >-
      ACE inhibition combined with fenofibrate.
- name: Statin therapy
  description: >-
    Statins are used as lipid-lowering therapy with heterogeneous responses.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: statin
      term:
        id: CHEBI:87631
        label: statin
  evidence:
  - reference: PMID:40306438
    reference_title: "Post-transplantat recurrence of lipoprotein glomerulopathy: report of 4 cases and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As in previously described cases, the clinical response was heterogeneous despite the use of statins and antiproteinuric agents, with proteinuria remission or persistence and progression to different stages of chronic kidney disease."
    explanation: >-
      Variable response to statins in transplant recipients.
- name: Kidney transplantation
  description: >-
    Used for end-stage disease, but the disease recurs in the graft because
    the abnormal apoE circulates.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: kidney transplantation
    term:
      id: NCIT:C15265
      label: Kidney Transplantation
  evidence:
  - reference: PMID:40306438
    reference_title: "Post-transplantat recurrence of lipoprotein glomerulopathy: report of 4 cases and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Herein we reported 4 cases of post-transplant recurrence of LPG in Brazilian patients, including 1 case of early relapse (in the first year following transplantation) and 3 cases of late relapse."
    explanation: >-
      Recurrence after transplantation.
- name: Glucocorticoids (ineffective)
  description: >-
    Immunosuppression, including prednisolone, does not help and was stopped
    once the diagnosis was made in the reported child.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:42417997
    reference_title: "Early-onset lipoprotein glomerulopathy in a 23-month-old boy with homozygous APOE Kyoto variant."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunosuppressive therapy is ineffective; instead, lipid-lowering measures reduce intraglomerular lipoprotein deposition and preserve kidney function."
    explanation: >-
      States that immunosuppression is ineffective.
animal_models:
- name: Adenoviral APOE Sendai in Apoe-deficient mice
  species: Mouse
  genotype: Apoe-/- transduced with adenovirus expressing human APOE Sendai (Arg145Pro)
  publication: PMID:19459027
  description: >-
    Transient expression of human APOE Sendai in Apoe-deficient mice
    produces glomerular lipoprotein thrombi resembling the human lesion.
    Aged Apoe-deficient mice develop superficially similar dilated lumens that
    on special stains are not lipid-rich.
  modeled_mechanisms:
  - target: Glomerular Lipoprotein Thrombi in Dilated Capillaries
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Lipid-positive glomerular thrombi in most transduced mice.
    limitations: >-
      Expression is adenoviral and transient on an Apoe-null background, so
      the model does not reproduce heterozygous germline disease or
      progression to kidney failure.
    evidence:
    - reference: PMID:19459027
      reference_title: "Lipoprotein glomerulopathy induced by ApoE-Sendai is different from glomerular lesions in aged apoE-deficient mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Characteristic lesions were dilated vascular lumens mimicking lipoprotein thrombi in human LPG."
      explanation: >-
        Reproduces the human lesion.
- name: Adenoviral APOE Kyoto in Apoe-deficient mice
  species: Mouse
  genotype: Apoe-/- transduced with adenovirus expressing human APOE Kyoto (p.R43C, precursor numbering; Arg25Cys in the mature protein)
  publication: PMID:33663537
  description: >-
    The first animal model validating the Kyoto variant, compared side by
    side with Sendai.
  modeled_mechanisms:
  - target: Glomerular Lipoprotein Thrombi in Dilated Capillaries
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Kyoto apoE expression in Apoe-deficient mice reproduces LPG.
    limitations: >-
      Same transient adenoviral design as the Sendai model.
    evidence:
    - reference: PMID:33663537
      reference_title: "Lipoprotein glomerulopathy induced by ApoE Kyoto mutation in ApoE-deficient mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Typical lipoprotein thrombi with positive ApoE staining were detected in the AD-ApoE Kyoto and AD-ApoE Sendai groups."
      explanation: >-
        Kyoto apoE expression produces the characteristic glomerular thrombi.
    - reference: PMID:33663537
      reference_title: "Lipoprotein glomerulopathy induced by ApoE Kyoto mutation in ApoE-deficient mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In this animal study, we first established an ApoE Kyoto mutation murine model and confirmed its pathogenic role in LPG."
      explanation: >-
        The authors' conclusion that the model confirms pathogenicity.
notes: >-
  No GeneReviews chapter covers this disorder. The deep-research report
  offered NCIT identifiers for fenofibrate, losartan and HMG-CoA reductase
  inhibitors that resolve to unrelated concepts, so drug identities here are
  bound to CHEBI terms looked up directly.

📚

References & Deep Research

Deep Research

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Evaluations and curation notes (2)

Record notes

No GeneReviews chapter covers this disorder. The deep-research report offered NCIT identifiers for fenofibrate, losartan and HMG-CoA reductase inhibitors that resolve to unrelated concepts, so drug identities here are bound to CHEBI terms looked up directly.

Create: Lipoprotein Glomerulopathy · 2026-10-12T19:22:26Z · View source

New entry for lipoprotein glomerulopathy (MONDO:0012725), APOE. Pathograph: APOE variants near the LDL-receptor-binding region -> thermodynamic destabilisation and aggregation of variant apoE -> aberrant unstable apoE-rich lipoprotein particles -> glomerular lipoprotein thrombi in dilated capillaries -> glomerular injury and progressive kidney damage -> renal phenotypes; lipid phenotypes hang off the lipoprotein node. Inheritance recorded as autosomal dominant plus incomplete penetrance, with a homozygous infantile case noted. Treatments: fibrates (fenofibrate, bezafibrate, pemafibrate), RAAS blockade, statins, kidney transplantation (recurs in graft), and glucocorticoids recorded with REFUTE evidence. Two adenoviral Apoe-deficient mouse models (Sendai, Kyoto). One OpenScientist deep-research report: built-in validation completed, 33/33 references resolved and 24/24 quotes valid; preflight-dr PASS. The report's NCIT drug suggestions (fenofibrate, losartan, HMG-CoA reductase inhibitor) resolve to unrelated concepts and were not used; agents bound to CHEBI. No GeneReviews chapter exists. Validated with just validate-disorders and the offline CI gates.

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Lipoprotein Glomerulopathy (LPG): A Comprehensive Disease Characteristics Report

openscientist-autonomous 33 citations 2026-10-12T18:59:07.783343

Lipoprotein Glomerulopathy (LPG): A Comprehensive Disease Characteristics Report

Target Disease: Lipoprotein Glomerulopathy MONDO ID: MONDO:0012725 · OMIM: 611771 · Gene: APOE (HGNC:613; chr19q13.32) · Category: Mendelian (autosomal dominant, incomplete penetrance)

Summary

Lipoprotein glomerulopathy (LPG) is an ultra-rare, autosomal-dominant renal lipidosis caused by heterozygous (rarely homozygous) missense and small in-frame variants in the APOE gene, clustered in or near the LDL-receptor-binding region of apolipoprotein E (apoE). It is histologically defined by markedly dilated glomerular capillary loops occluded by lamellated, vacuolated, apoE-rich lipoprotein thrombi that lack foam cells and are negative for immunoglobulins and complement. Clinically, patients present with proteinuria/nephrotic syndrome, microscopic hematuria, and a type III hyperlipoproteinemia-like dyslipidemia with markedly elevated serum apoE. More than 200 cases have been reported worldwide since the entity was first described ~30 years ago, with cases concentrated in East Asia (Japan, China) through documented founder variants (PMID: 40306438; PMID: 35602473).

The core mechanism is conformational: LPG-associated APOE variants (predominantly proline substitutions and small deletions/duplications around residues 136–158) thermodynamically destabilize the N-terminal domain of apoE, driving it toward a molten-globule-like state with increased exposed hydrophobic surface and aggregation propensity. The misfolded, aggregation-prone apoE forms aberrant lipoprotein particles that deposit as intraglomerular thrombi, occluding dilated capillaries and producing proteinuria and progressive chronic kidney disease (PMID: 23110818; PMID: 31874799). The etiologic role of mutant apoE has been confirmed in vivo: adenoviral transduction of apoE-Sendai (and apoE-Kyoto) into apoE-deficient mice reproduces LPG-like glomerular lesions (PMID: 16431249; PMID: 19459027; PMID: 33663537).

LPG carries a guarded prognosis — approximately half of patients progress to end-stage kidney disease (ESKD) within 1–27 years — but it is not steroid-responsive. The cornerstone of treatment is lipid-lowering therapy, especially fibrates (fenofibrate, bezafibrate, and the selective PPARα modulator pemafibrate), often combined with RAAS blockade (ACEi/ARB); these can markedly reduce proteinuria and, in some reports, induce complete remission. Because the pathogenic apoE is a circulating protein, LPG recurs after kidney transplantation. Diagnosis rests on two pillars: a characteristic kidney biopsy plus molecular confirmation by APOE sequencing (PMID: 40306438; PMID: 38769490).

1. Disease Information

Overview. LPG is an inherited glomerular disease in which apoE-rich lipoproteins accumulate as "thrombi" within dilated glomerular capillary lumina, producing proteinuria, nephrotic syndrome, and progressive renal dysfunction. It is a renal lipidosis distinct from systemic lipid storage diseases and from immune-complex glomerulonephritis. Definitive diagnosis requires molecular genetic analysis of APOE in addition to characteristic biopsy findings (PMID: 40306438).

"Lipoprotein glomerulopathy (LPG) is an ultrarare kidney disorder caused by pathogenic variants in the APOE gene. Although kidney biopsy presents typical findings, such as dilated capillary loops containing lipoprotein thrombi, definitive diagnosis requires molecular genetic analysis of APOE." — PMID: 40306438

Key identifiers.

Resource	Identifier
MONDO	MONDO:0012725
OMIM	611771 (Lipoprotein glomerulopathy)
Gene	APOE (HGNC:613), chromosome 19q13.32
MeSH	Closest indexing via "Apolipoproteins E" / glomerular disease terms
ICD-10	No specific LPG code; coded under glomerular disease categories (e.g., N05.-)

Synonyms / alternative names. Lipoprotein glomerulopathy; LPG; apoE-associated lipoprotein glomerulopathy. Named variant subtypes commonly appear in the literature (e.g., apoE-Sendai, apoE-Kyoto, apoE-Osaka/Kurashiki, apoE-Chicago, apoE-Tokyo/Maebashi, apoE-Guangzhou, apoE-Kanto), referring to specific causal mutations rather than distinct diseases.

Information source. The evidence base is derived from aggregated disease-level resources — case reports, small clinical series, meta-analyses, and in vitro/animal mechanistic studies — rather than large EHR/population cohorts, reflecting the disease's rarity (PMID: 35602473).

2. Etiology

Disease causal factors. LPG is a purely monogenic genetic disorder caused by variants in APOE. No infectious or toxic cause is implicated, and no environmental trigger is required. ApoE is the principal ligand for LDL-receptor–mediated clearance of triglyceride-rich/remnant lipoproteins; LPG-causing variants lie in or near the receptor-binding region (residues ~136–158), producing a dysbetalipoproteinemia-like (type III) plasma profile with remnant accumulation and elevated serum apoE (PMID: 27277824; PMID: 23407349).

"Apolipoprotein (apo) E was initially described as a lipid transport protein and major ligand for low density lipoprotein (LDL) receptors with a role in cholesterol metabolism and cardiovascular disease." — PMID: 27277824

Genetic risk factors. The causal variants are heterozygous APOE missense substitutions (frequently arginine→proline) and small in-frame deletions/duplications near the LDL-receptor-binding site. Recurrent variants include apoE-Sendai (Arg145Pro), apoE-Kyoto (Arg25Cys; signal-inclusive Arg43Cys), apoE-Osaka/Kurashiki (Arg158Pro), apoE-Chicago (Arg147Pro), apoE-Tokyo/Maebashi (Lys143–Arg145 deletion), apoE-Guangzhou (Arg150Pro), and apoE-Kanto (Asp151dup) (PMID: 23407349; PMID: 39141311). Founder effects are documented for apoE-Sendai (eastern Japan) and apoE-Kyoto (China).

Environmental / modifier risk factors. Because penetrance is incomplete (many asymptomatic carriers exist in affected families), additional genetic, epigenetic, and/or environmental modifiers are inferred to contribute. Co-inheritance of additional apoE alleles (e.g., apoE2 Arg158Cys, apoE5 Glu3Lys) or other conditions has been proposed to modify expression in individual kindreds (PMID: 23407349; PMID: 29356944; PMID: 26955632).

"In addition to APOE mutation, other genetic and/or epigenetic factors are considered to be involved in the pathogenesis of LPG because of its low penetrance." — PMID: 23407349

Protective factors. No specific genetic or environmental protective factors are established. Early lipid-lowering therapy is associated with better renal outcomes (see Treatment), functioning as a modifiable disease-course factor rather than a prevention of onset.

Gene–environment interactions. Incomplete penetrance strongly implies gene-environment/gene-gene interaction, but specific interacting exposures are not well characterized.

3. Phenotypes

Phenotype frequencies are best quantified in an 11-patient Chinese cohort (mean age 33.82 years) (PMID: 38584145):

Phenotype	Type	Frequency	Suggested HPO
Proteinuria	Laboratory / clinical sign	10/11 (91%)	HP:0000093 (Proteinuria)
Dyslipidemia (type III-like)	Laboratory abnormality	10/11 (91%)	HP:0003119 (Abnormal circulating lipid concentration); HP:0002155 (Hypertriglyceridemia)
Microscopic hematuria	Laboratory / sign	6/11 (55%)	HP:0000790 (Hematuria)
Positive family history	—	5/11 (45%)	—
Nephrotic syndrome	Clinical syndrome	4/11 (36%)	HP:0000100 (Nephrotic syndrome)
Edema	Physical manifestation	Common	HP:0000969 (Edema)
Elevated serum apoE	Laboratory abnormality	Characteristic (not universal)	HP:0003119 (related lipid abnormality)
Renal enlargement	Imaging	Reported	HP:0000105 (Enlarged kidney)
Anemia	Laboratory abnormality	Reported	HP:0001903 (Anemia)
Hypertension	Clinical sign	Associated with LDL-R–region variants	HP:0000822 (Hypertension)
Chronic kidney disease / ESKD	Outcome	~50% progress	HP:0012622 (Chronic kidney disease); HP:0003774 (Stage 5 CKD)

"The mean age of the eleven patients was 33.82 years. Among them, five had a positive family history for LPG, ten presented with proteinuria, four exhibited nephrotic syndrome, and six presented with microscopic hematuria. Dyslipidemia was identified in ten patients." — PMID: 38584145

Age of onset. Predominantly adult-onset with an average age of presentation of 32 years (range 4–69) (PMID: 38438730). Pediatric and early-onset cases occur, including 6- and 7.5-year-old boys, a 12-year-old girl, and a 23-month-old boy with homozygous APOE Kyoto and parental consanguinity presenting as steroid-resistant nephrotic syndrome (PMID: 39993083; PMID: 22874113; PMID: 42417997).

"It is a monogenic disorder with autosomal dominant inheritance and the average age of presentation is 32 years (4-69 years)." — PMID: 38438730

Severity / progression / variability. Severity is variable and progression is generally chronic and progressive, often culminating in ESKD. A notable phenotypic nuance: a subset of patients are normolipidemic (e.g., certain APOE Kyoto and APOE Kanto cases with normal serum lipids and apoE), so normal lipids do not exclude LPG (PMID: 40186270; PMID: 42309892; PMID: 39141311).

"In contrast to previous cases, this patient lacked hyperlipidemia and ApoE was a Kyoto mutation." — PMID: 40186270

Quality of life impact. No formal EQ-5D/SF-36 data exist for LPG. Impact is inferred from nephrotic-range proteinuria, edema, and progression to dialysis-dependent ESKD, all of which substantially impair daily functioning. LPG can co-occur with IgA nephropathy, membranous nephropathy, or lupus nephritis, which can add to morbidity.

4. Genetic / Molecular Information

Causal gene. APOE (apolipoprotein E), HGNC:613, OMIM gene 107741; disease OMIM 611771; located at 19q13.32. LPG is caused by rare, protein-altering APOE variants — distinct from the common E2/E3/E4 isoform polymorphisms (though some patients carry combinations of a rare LPG variant with a common isoform allele).

Pathogenic variants. Causal variants cluster in/near the LDL-receptor-binding region (residues ~136–158). The table below lists the principal named variants (mature-protein numbering unless noted):

Variant name	Change (mature protein)	Type	Notable feature
apoE-Sendai	Arg145Pro	Missense (Arg→Pro)	Founder in eastern Japan; most frequent
apoE-Kyoto	Arg25Cys (signal-inclusive Arg43Cys)	Missense	Founder in China; can be normolipidemic
apoE-Osaka/Kurashiki	Arg158Pro	Missense (Arg→Pro)	Serum apoE can be normal
apoE-Chicago	Arg147Pro	Missense (Arg→Pro)	—
apoE-Tokyo/Maebashi	Lys143–Arg145 deletion	In-frame deletion	9-nt deletion (c.480–488)
apoE-Guangzhou	Arg150Pro	Missense (Arg→Pro)	Novel Chinese variant
apoE-Kanto	Asp151dup	In-frame duplication	First duplication-type; progressed to ESKD

"LPG is primarily associated with heterozygous apoE mutations surrounding the low-density lipoprotein-receptor binding site, and it is histologically characterized by lamellated lipoprotein thrombi that lack foam cells." — PMID: 31874799

"More than 12 APOE mutations have been identified as causes of LPG, and APOE-Sendai (Arg145Pro) mutation was frequently detected in patients from the eastern part of Japan including Yamagata prefecture." — PMID: 23407349

Variant classification & type. Variants are pathogenic (ACMG/AMP), predominantly missense (frequently arginine→proline substitutions) plus small in-frame deletions/duplications. Origin is germline. Functional consequence is a conformational/structural defect (destabilization/aggregation) — effectively a toxic gain-of-function / dominant-negative-like behavior at the lipoprotein-particle level rather than simple loss of ligand function, consistent with autosomal-dominant inheritance.

Allele frequency. Causal variants are rare/absent in population databases; the apoE-Sendai founder variant was not detected in 2,023 controls, confirming rarity in the general population (PMID: 23407349).

Modifier genes / epigenetics. Incomplete penetrance implicates additional genetic/epigenetic modifiers; co-inheritance of apoE2 (Arg158Cys) or apoE5 (Glu3Lys) has been proposed to modify phenotype in specific families (PMID: 26955632; PMID: 29356944). No specific DNA-methylation/histone signatures have been defined for LPG.

Chromosomal abnormalities. None reported; LPG is a single-gene point-variant/small-indel disorder.

5. Environmental Information

LPG has no established environmental cause. There are no implicated toxins, radiation, pollutants, or occupational exposures; no lifestyle factor is established as causal; and no infectious agent triggers the disease. Incomplete penetrance implies that unidentified genetic/epigenetic/environmental modifiers influence whether carriers develop overt disease, but these remain uncharacterized (PMID: 23407349). Not applicable / not established for most environmental subcategories.

6. Mechanism / Pathophysiology

Causal chain (initiating lesion → clinical manifestation)

A heterozygous APOE missense/in-frame variant near the LDL-receptor-binding region (e.g., Arg145Pro) results in an amino-acid change incompatible with normal helical packing of the N-terminal domain.
This leads to thermodynamic destabilization of the apoE N-terminal four-helix bundle, loss of unfolding intermediates, and a shift toward a molten-globule-like state (demonstrated in vitro).
The destabilized protein exposes hydrophobic surface to solvent, which results in increased aggregation propensity and protease sensitivity (demonstrated in vitro).
Aggregation-prone mutant apoE leads to formation of aberrant, destabilized apoE-rich lipoprotein particles and impaired remnant-lipoprotein clearance, producing a type III–like dyslipidemia with elevated serum apoE (inferred from plasma profiles + in vitro particle data).
These abnormal lipoproteins deposit within glomerular capillaries as lamellated lipoprotein thrombi (branch: a complementary mechanism posits impaired macrophage clearance of lipoproteins, explaining thrombi forming without foam cells).
Thrombi occlude markedly dilated glomerular capillary loops, which results in proteinuria, hematuria, and reduced filtration.
Chronic capillary occlusion and glomerular injury lead to progressive chronic kidney disease and, in ~50% of patients, ESKD (demonstrated by natural-history data).

"All three variants were found to have significantly reduced helical content, to expose a larger portion of hydrophobic surface to the solvent, and to be significantly thermodynamically destabilized, often lacking functionally relevant unfolding intermediates." — PMID: 23110818

"Overall, our data suggest that these mutations induce a generalized unfolding of the N-terminal domain of apoE3 toward a molten-globule-like structure." — PMID: 23110818

"LPG can be induced by thermodynamic destabilization, hydrophobic surface exposure, and the aggregation of apoE resulting from the incompatibility of apoE mutated residues within helical regions." — PMID: 31874799

Detail by category

Molecular pathways / metabolic changes. LDL-receptor-mediated clearance of triglyceride-rich/remnant lipoproteins (apoE is the key ligand); remnant/VLDL metabolism; lipid transport. Disruption yields dysbetalipoproteinemia-like remnant accumulation (PMID: 27277824; PMID: 10359567). Suggested GO: GO:0006869 (lipid transport), GO:0034447 (very-low-density lipoprotein particle clearance), GO:0042157 (lipoprotein metabolic process). CHEBI: CHEBI:16113 (cholesterol), CHEBI:17855 (triglyceride).
Protein dysfunction. Misfolding, structural destabilization, hydrophobic exposure, and aggregation of apoE — a conformational disease mechanism (PMID: 23110818; PMID: 30309894; PMID: 24149834). Suggested GO: GO:0006457 (protein folding), GO:0043234/GO:0032983 (protein-containing complex / aggregation-related).
Cellular processes / immune involvement. Immunofluorescence for immunoglobulins and complement is negative — LPG is not immune-complex mediated. Macrophage handling of lipoproteins is implicated as a complementary mechanism (thrombi without foam cells); a variant/atypical case showed foamy-macrophage infiltration when combined with apoE2, bridging LPG and apoE2-homozygote glomerulopathy (PMID: 26955632; PMID: 24149835). Suggested CL: CL:0000650 (mesangial cell), CL:0000653 (podocyte), CL:0000235 (macrophage), CL:0002188 (glomerular endothelial cell).
Tissue damage mechanisms. Capillary occlusion by lipoprotein thrombi → glomerular ischemia/mechanical injury → proteinuria and progressive glomerulosclerosis/fibrosis.
Lipidomics / molecular profiling. Plasma shows a type III (dysbetalipoproteinemia) pattern with elevated triglycerides, elevated apoB, and markedly elevated apoE (variant-dependent). Glomerular proteomics by LC-MS/MS of laser-microdissected tissue shows apoE enrichment (PMID: 38769490).

7. Anatomical Structures Affected

Organ level (primary): Kidney — specifically the renal glomerulus (UBERON:0000074). Secondary involvement: systemic lipid metabolism (dyslipidemia); cardiovascular risk from dysbetalipoproteinemia; arterial stiffness reported in some patients (PMID: 38769490).
Body system: Urinary/renal system (primary); cardiovascular/metabolic (secondary).
Tissue/cell level: Glomerular capillary tuft — dilated glomerular capillaries (UBERON:0005750, glomerular capillary). Cell types implicated: glomerular endothelial cells (CL:0002188), mesangial cells (CL:0000650), podocytes (CL:0000653), and infiltrating macrophages (CL:0000235) in atypical cases.
Subcellular level: Extracellular deposition within the capillary lumen (lipoprotein thrombi); at the protein level, N-terminal domain misfolding. Suggested GO cellular components: GO:0034361 (very-low-density lipoprotein particle), GO:0042627 (chylomicron), GO:0005615 (extracellular space).
Localization / lateralization: Bilateral, diffuse glomerular involvement (systemic circulating apoE drives deposition in both kidneys).

"Immunofluorescence staining showed that the thrombi were strongly positive for apo A, B, and E. Granules and various sizes of vacuoles were observed in the thrombi under electron microscope." — PMID: 15498375

8. Temporal Development

Onset: Typically adult-onset (mean ~32 years, range 4–69), insidious/chronic. Pediatric and even infantile cases occur (23-month-old homozygote) (PMID: 38438730; PMID: 42417997).
Progression: Chronic and generally progressive. Approximately half of patients reach ESKD over a wide window of 1–27 years from onset (PMID: 38769490).
Disease course: Progressive proteinuria → declining eGFR → ESKD. Proteinuria reduction >50% is associated with slower renal decline (see Treatment) (PMID: 32441489).
Remission patterns: Spontaneous remission is not characteristic; treatment-induced remission (proteinuria reduction, even complete remission) is reported with fibrates (PMID: 42371225).
Critical period / window of opportunity: Early initiation of lipid-lowering therapy is emphasized as the best opportunity to preserve renal function (PMID: 24149835).

"approximately half of the patients develop end-stage kidney disease within 1-27 years of disease onset" — PMID: 38769490

9. Inheritance and Population

Inheritance: Autosomal dominant with incomplete penetrance; rare homozygous (recessive-presenting) cases occur with consanguinity (PMID: 38438730; PMID: 42417997).
Penetrance/expressivity: Incomplete penetrance (many asymptomatic carriers); variable expressivity (including normolipidemic forms) (PMID: 41612256; PMID: 40186270).
Founder effects: apoE-Sendai (eastern Japan, including Yamagata) and apoE-Kyoto (China) descend through founder haplotypes (PMID: 23407349; PMID: 24149835).
Consanguinity: Relevant in homozygous pediatric cases (PMID: 42417997).
Epidemiology: Ultra-rare — >200 cases reported worldwide over ~30 years; an earlier review counted 65 cases. Most patients are in Japan and East Asia. Formal prevalence/incidence rates are not established (no Orphanet prevalence class). Clinical series show a male predominance and adult onset (PMID: 35602473; PMID: 16431249).

"At present, 65 cases have been reported worldwide, although most patients are found in Japan and east Asian countries." — PMID: 16431249

"the haplotype of all APOE-Sendai mutations was identical, suggesting that APOE-Sendai mutation is common in Japanese patients probably through a founder effect." — PMID: 23407349

10. Diagnostics

Two-pillar diagnostic standard: (1) characteristic kidney biopsy and (2) molecular confirmation by APOE sequencing (PMID: 40306438).

Biopsy / histopathology. Light microscopy shows markedly dilated glomerular capillary loops filled with pale, weakly-staining lamellated lipoprotein thrombi. Staining profile: PAS weak-positive, Masson pale blue, silver/MT pale, Congo-red negative (excludes amyloid), Oil Red O / Sudan positive on frozen sections (confirms lipid), and apoE-positive by immunohistochemistry (also apoA, apoB positive). Immunofluorescence for immunoglobulins and complement is negative (distinguishes from immune-complex GN). Electron microscopy shows granular/vacuolated thrombi of variable electron density (PMID: 41405262; PMID: 15498375).

"These thrombi appeared PAS weak positive, MT pale blue, silver negative, and Congo-Red negative. These capillary luminal contents stained reddish with Oil-red O confirming lipid contents." — PMID: 41405262

Genetic testing. Single-gene APOE Sanger sequencing is the primary confirmatory test; whole-exome sequencing is increasingly used and can reveal co-inherited variants (e.g., COL4A5 in an Alport/LPG dual-diagnosis case) (PMID: 40306438; PMID: 41612256).

Supportive labs / biomarkers. Elevated serum apoE and apoB, hypertriglyceridemia, type III dysbetalipoproteinemia pattern (mid-band on electrophoresis). Caveat: serum apoE can be normal in some variants (Osaka, Kanto, normolipidemic Kyoto) — normal apoE does not exclude LPG (PMID: 21325775; PMID: 39141311).

Advanced / omics diagnostics. LC-MS/MS of laser-microdissected glomeruli demonstrates glomerular apoE enrichment, providing molecular confirmation of deposit composition (PMID: 38769490).

"Liquid chromatography-tandem mass spectrometry of laser-microdissected glomeruli from paraffin sections revealed an increase in ApoE." — PMID: 38769490

Differential diagnosis. Amyloidosis (Congo-red negative in LPG), thrombotic microangiopathy, cryoglobulinemic GN, fibronectin glomerulopathy, histiocytic glomerular lipidosis (e.g., macrophage activation syndrome), and apoE2-homozygote glomerulopathy (foam-cell rich) (PMID: 31874799; PMID: 37936128).

Screening. Cascade family screening (APOE sequencing ± urinalysis) is appropriate given autosomal-dominant inheritance; many carriers are asymptomatic (PMID: 41612256).

11. Outcome / Prognosis

Renal survival: Guarded — ~50% progress to ESKD within 1–27 years of onset (PMID: 38769490).
Prognostic factors: Degree of proteinuria control is a key modifiable prognostic factor. In an 8-patient cohort, patients with >50% proteinuria reduction had slower renal decline: eGFR change −5.0 ± 0.8 vs +1.5 ± 0.7 mL/min/1.73 m² reduction rate (i.e., treated-responders declined more slowly) (PMID: 32441489). Variants in the LDL-receptor-binding region were associated with higher blood pressure and higher serum apoE.
Transplant outcome: LPG recurs after kidney transplantation (early and late relapses documented), because the pathogenic apoE is circulating (PMID: 40306438).
Quality of life / mortality: No formal QoL or disease-specific mortality statistics; morbidity is driven by nephrotic syndrome and ESKD.

"it may recur after kidney transplantation" — PMID: 40306438

"LPG patients with urine protein reduced more than 50% had a slower decrease in renal function than those with less urine protein reduction." — PMID: 32441489

12. Treatment

LPG is not steroid-responsive; immunosuppression is ineffective (PMID: 42417997). The mainstay is lipid-lowering therapy plus antiproteinuric RAAS blockade.

Therapy	Example agents	Evidence / effect	Suggested NCIT
Fibrates (PPARα agonists)	Fenofibrate, bezafibrate	Most-reported therapy; reduce proteinuria, can induce complete remission	NCIT:C29475 (Fenofibrate); fibric acid class
Selective PPARα modulator	Pemafibrate	Complete remission (0.05 g/gCr) within 7 months in a reported case	PPAR-alpha agonist class
RAAS blockade (adjunct)	Telmisartan, losartan, ACEi/ARB	Antiproteinuric; used with fibrates	NCIT:C66951 (Losartan); ARB class
Statins	Various	Benefit in selected patients (statin monotherapy sustained renal stability up to 3 years)	NCIT:C1518 (HMG-CoA reductase inhibitor)
Supportive	Lipid/BP control, diet	Standard CKD/nephrotic supportive care	—

"Complete remission (0.05 g/gCr) was achieved within 7 months, and she remained stable thereafter." — PMID: 42371225

Representative responses: a boy with apoE-Tokyo/Maebashi had urine protein turn negative within 1 week on fenofibrate + telmisartan (PMID: 39993083); complete resolution with fenofibrate was reported from Pakistan (PMID: 38327135); and sustained benefit with statin monotherapy over 3 years in a young Chinese man with apoE-Kyoto (PMID: 30685233). In normolipidemic LPG, lipid-lowering may be withheld and ARB used alone (PMID: 42309892).

Advanced/experimental therapeutics. No approved gene, cell, or RNA-based therapy exists. Because the disease is driven by a circulating misfolded protein, therapies targeting apoE production or conformation are conceptually attractive but remain experimental. Early initiation of fibrate therapy is emphasized to prevent renal dysfunction (PMID: 24149835).

"the administration of fibrate with the intensive control of triglyceride and apolipoprotein E particularly from the early phase will ameliorate LPG and prevent renal dysfunction." — PMID: 24149835

13. Prevention

Primary prevention: Not possible for mutation carriers (genetic); focus is on genetic counseling given autosomal-dominant inheritance.
Secondary prevention: Cascade family screening (APOE sequencing plus urinalysis/lipid profile) to identify carriers early; early lipid-lowering therapy in affected carriers to preserve renal function (PMID: 41612256; PMID: 24149835).
Tertiary prevention: Proteinuria control (fibrates + RAAS blockade), blood-pressure control, and standard CKD management to delay ESKD.
Genetic counseling: Important for at-risk relatives, prenatal/reproductive planning, and interpretation of incomplete penetrance (asymptomatic carriers are common).
Immunization / public-health / environmental interventions: Not applicable (non-infectious, non-environmental disease).

14. Other Species / Natural Disease

Taxonomy / orthologs: Human APOE (NCBI Gene 348; NCBI Taxon 9606). The mouse ortholog is Apoe (NCBI Gene 11816; NCBI Taxon 10090). No naturally occurring LPG analog is established in companion animals or wildlife.
Comparative biology: Mouse apoE biology closely parallels human lipoprotein clearance, enabling the transgenic/adenoviral models below. Human apoE isoform structure determines VLDL clearance and atherosclerosis risk in humanized mice, underscoring evolutionary conservation of apoE function (PMID: 10359567).
Zoonotic potential: None (genetic disease).

15. Model Organisms

Primary model: apoE-deficient (Apoe⁻/⁻) mouse reconstituted with mutant human apoE via adenoviral transduction. This is the key in vivo system validating LPG etiology.

Model	Method	Result	Reference
apoE-Sendai (Arg145Pro) in Apoe⁻/⁻	Adenoviral transduction	LPG-like lesions in 40/50 mice (24 mild, 13 moderate, 3 severe); dilated lumens with Oil Red O/Sudan-positive lipid thrombi	PMID: 19459027
apoE-Kyoto (p.R43C) in Apoe⁻/⁻	Adenoviral transduction	Reproduced LPG pathology; enabled comparison with apoE-Sendai	PMID: 33663537
apoE-Sendai general validation	Adenoviral transduction in Apoe⁻/⁻	Confirmed etiologic role of mutant apoE in LPG	PMID: 16431249

"The virus-mediated transduction of apoE Sendai resulting in the development of LPG in apoE-deficient mice confirms the etiologic role of apoE mutation in LPG." — PMID: 16431249

"Characteristic lesions were dilated vascular lumens mimicking lipoprotein thrombi in human LPG. Similar changes were found in hematoxylin-eosin stained sections of aged apoE KO mice." — PMID: 19459027

Phenotype recapitulation. Models reproduce the hallmark glomerular lipoprotein thrombi and confirm the pathogenic role of mutant apoE. Important control: aged Apoe⁻/⁻ mice develop superficially similar dilated-lumen lesions, but these contain proteins/fibrils rather than lipid, distinguishing spontaneous knockout lesions from true mutant-apoE-driven LPG (PMID: 19459027).

Model limitations. Adenoviral expression is transient and non-germline; models do not fully recapitulate chronic progression to ESKD. No germline knock-in mouse for human LPG variants is established in the reviewed literature.

In vitro models. Recombinant apoE3-based mutants (R145P/Sendai, R147P/Chicago, R158P/Osaka, and non-proline R25C/Kyoto) characterized biophysically establish the destabilization/aggregation mechanism (PMID: 23110818; PMID: 30309894).

Mechanistic Model / Interpretation

  APOE missense/in-frame variant (near LDL-R binding region, res ~136–158)
         │  (e.g., Arg145Pro = apoE-Sendai)
         ▼
  Thermodynamic destabilization of apoE N-terminal 4-helix bundle
   (↓ α-helix, loss of unfolding intermediates → molten-globule-like)   [in vitro]
         │
         ▼
  Hydrophobic surface exposure → aggregation + protease sensitivity      [in vitro]
         │
  ┌──────────────┴───────────────┐
  ▼                              ▼
  Aberrant apoE-rich lipoprotein     Impaired macrophage clearance
  particles; ↓ remnant clearance     of lipoproteins (complementary;
  → type III–like dyslipidemia,      explains thrombi WITHOUT foam cells)
  ↑ serum apoE (variant-dependent)
  │                              │
  └──────────────┬───────────────┘
         ▼
  Lamellated lipoprotein thrombi deposit in dilated glomerular capillaries
   (apoE/apoA/apoB +, Oil Red O +, Congo-red −, Ig/complement −)
         ▼
  Capillary occlusion → proteinuria, microscopic hematuria, ↓ GFR
         ▼
  Progressive CKD → ESKD in ~50% (1–27 yr); recurs post-transplant
         │
         ▼   (therapeutic node)
  Fibrates / pemafibrate + RAAS blockade → ↓ proteinuria → slower eGFR decline

Upstream vs downstream. The APOE variant and apoE misfolding/aggregation are upstream; lipoprotein-thrombus deposition and glomerular capillary occlusion are intermediate; proteinuria, CKD, and ESKD are downstream. The disease unifies a spectrum of apoE-related glomerular disorders: LPG (heterozygous LDL-R–region variants, lamellated thrombi, no foam cells) is distinct from apoE2-homozygote glomerulopathy (glomerulosclerosis with foam-cell infiltration) and apoE-Toyonaka (Ser197Cys)+apoE2/2 (membranous-like), yet all converge on apoE conformational abnormality and renal lipid accumulation (PMID: 31874799).

"ApoE2 homozygote glomerulopathy has been found in individuals expressing homozygous apoE2/2. This was characterized histologically by glomerulosclerosis with marked infiltration of foam cells derived from macrophages" — PMID: 31874799

Evidence Base

PMID	Contribution	Evidence type
40306438	Defines LPG as ultra-rare APOE disorder; two-pillar diagnosis; post-transplant recurrence	Human clinical (review/cases)
35602473	>200 cases over 30 years; meta-analysis	Human, meta-analysis
23110818	Thermodynamic destabilization / molten-globule mechanism of apoE mutants	In vitro / biophysical
30309894	Destabilization/aggregation for non-proline mutants (R25C/Kyoto)	In vitro
24149834	Structural basis review of LPG mutations	Computational/structural review
31874799	Unifying conformational mechanism; distinguishes apoE-related glomerular disorders	Review
16431249	In vivo confirmation (apoE-Sendai in Apoe⁻/⁻); 65-case epidemiology	Mouse model / review
19459027	apoE-Sendai mouse model; distinguishes aged KO lesions	Mouse model
33663537	apoE-Kyoto mouse model	Mouse model
23407349	Founder haplotype of apoE-Sendai; incomplete penetrance	Human genetics
38584145	Phenotype frequencies in 11-patient cohort	Human clinical
38438730	Age of onset (32 yr; 4–69); AD inheritance; pediatric case	Human clinical
32441489	Proteinuria reduction → slower eGFR decline; genotype-BP/apoE correlation	Human clinical
38769490	ESKD in ~50% (1–27 yr); LC-MS/MS glomerular apoE; fibrate+losartan	Human clinical
42371225	Complete remission with pemafibrate	Human clinical
41405262	Histochemical staining profile for diagnosis	Human clinical
15498375	apoE/apoA/apoB-positive vacuolated thrombi	Human clinical
40186270 / 42309892	Normolipidemic LPG (APOE Kyoto)	Human clinical
42417997	Homozygous APOE Kyoto, infantile, steroid-resistant	Human clinical
26955632	Macrophage infiltration; LPG vs apoE2-GN bridge	Human clinical
27277824	apoE normal function (LDL-R ligand)	Review
10359567	apoE structure → VLDL clearance (conservation)	Mouse model
41612256	Incomplete penetrance; WES + biopsy; cascade screening	Human clinical

Limitations and Knowledge Gaps

No formal epidemiology. Prevalence and incidence are not quantified; estimates rest on cumulative case counts (>200 worldwide). No Orphanet prevalence class exists.
Ascertainment bias. The heavy East-Asian representation partly reflects founder variants and may be amplified by awareness/reporting bias; true global distribution is uncertain.
Mechanistic branch not fully resolved. The relative contributions of apoE misfolding/aggregation versus impaired macrophage lipoprotein clearance to thrombus formation remain to be dissected in vivo.
Model limitations. Available mouse models use transient adenoviral (non-germline) expression and do not fully recapitulate chronic ESKD progression; no validated germline knock-in model is reported.
Penetrance modifiers unknown. The genetic/epigenetic/environmental factors explaining incomplete penetrance and normolipidemic phenotypes are not identified.
Treatment evidence is low-level. Efficacy data come from case reports and small series, not randomized trials; optimal agent (fibrate vs statin vs pemafibrate), timing, and genotype-specific response are not established.
No QoL/mortality data. Disease-specific quality-of-life and mortality metrics are absent.

Proposed Follow-up Experiments / Actions

Germline knock-in mouse models of recurrent human variants (apoE-Sendai Arg145Pro, apoE-Kyoto) to study chronic progression to ESKD and test therapeutics longitudinally.
Prospective international LPG registry with standardized genotype, histology, serum apoE, and renal-outcome capture to establish prevalence, natural history, and genotype–phenotype correlations (including normolipidemic variants).
Randomized or well-controlled comparative studies of fibrates (incl. pemafibrate) vs statins vs combination with RAAS blockade, with proteinuria and eGFR-slope endpoints, stratified by variant and baseline lipids.
Mechanistic dissection of the macrophage-clearance branch (e.g., macrophage-specific manipulation in reconstituted Apoe⁻/⁻ mice) to clarify why thrombi form without foam cells.
apoE-targeted therapeutic exploration — small molecules/chaperones that stabilize the apoE N-terminal domain, or RNA-based approaches lowering mutant apoE — given that circulating pathogenic apoE drives disease and post-transplant recurrence.
Routine cascade APOE screening protocols for relatives of probands, paired with early lipid-lowering intervention trials in asymptomatic carriers to test secondary prevention.
Structural/biophysical profiling of newer variants (e.g., apoE-Kanto Asp151dup) to confirm the generality of the destabilization-aggregation model across variant classes (missense, deletion, duplication).

Report compiled from 43 reviewed papers and 9 confirmed findings across 5 investigation iterations. Evidence sources are distinguished as human clinical, mouse model, in vitro/biophysical, or review/computational throughout.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	33
Resolved	33
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	24
Quoted claims found in source	24
Quoted claims not found in source	0
References weighed for topical relevance	33
On topic	32
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	33
Resolved	29
Unresolved (possible confabulation)	0
Obsolete	3
Unverifiable	1
Terms whose name was checked	27
Terms named correctly	20
Terms named as a different term	6
Terms whose name is worth a second look	1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0012725 (2 mentions) - the report calls it "MONDO"; MONDO calls it lipoprotein glomerulopathy
HP:0003119 (2 mentions) - the report calls it "related lipid abnormality"; HP calls it Abnormal circulating lipid concentration
GO:0032983 (1 mention) - the report calls it "protein-containing complex / aggregation-related"; GO calls it kainate selective glutamate receptor complex
NCIT:C29475 (1 mention) - the report calls it "Fenofibrate"; NCIT calls it 3'-C-ethynylcytidine
NCIT:C66951 (1 mention) - the report calls it "Losartan"; NCIT calls it Adenocarcinoma, Endocervical Type
NCIT:C1518 (1 mention) - the report calls it "HMG-CoA reductase inhibitor"; NCIT calls it Raloxifene

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0043234 (GO_0043234) (1 mention) - replaced by GO:0032991
GO:0005615 (obsolete extracellular space) (1 mention) - replaced by GO:0005576
NCIT:C66951 (Adenocarcinoma, Endocervical Type) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

GO:0005615 (1 mention) - the report calls it "extracellular space"; GO calls it obsolete extracellular space, and lists "intercellular space" among its other names

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Diagnosis

Prevalence

Animal Models

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References & Deep Research

Deep Research

Lipoprotein Glomerulopathy (LPG): A Comprehensive Disease Characteristics Report

Summary

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Causal chain (initiating lesion → clinical manifestation)

Detail by category

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look