Apolipoprotein E–related glomerular disorders
Open accessAbstract
Of the glomerular disorders that occur due to apolipoprotein E (apoE) mutations, apoE2 homozygote glomerulopathy and lipoprotein glomerulopathy (LPG) have been characterized. 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, and occasionally with non-lamellated lipoprotein thrombi. Recently, several cases of apoE Toyonaka (Ser197Cys) combined with homozygous apoE2/2 have been reported, in which non-immune membranous nephropathy-like features were observed in glomeruli. Interestingly, in these cases, apoE accumulation was identified by tandem mass spectrometry. Therefore, it is speculated that these findings may arise from apoE molecules without lipids, which result from hinge damage by apoE Toyonaka and may cross the glomerular basement membrane as small molecules. 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. Recent studies have suggested that 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. Additionally, apoE5 may play a supporting role in the development of LPG and in lipid-induced kidney diseases via hyperlipoproteinemia. Thus, it is interesting that many apoE mutations contribute to characteristic glomerular disorders through various mechanisms. In particular, macrophages may uptake lipoproteins into the cytoplasm and contribute to the development of apoE2 homozygote glomerulopathy as foam cells, and their dysfunction may contribute to the accumulation of lipoproteins in the glomerulus, causing lipoprotein thrombi in LPG.
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Lipoprotein glomerulopathy (LPG) is a rare autosomal dominant disease.
“Lipoprotein glomerulopathy (LPG) is a rare autosomal dominant disease caused by mutations in APOE, the gene which encodes apolipoprotein E.”
From Lipoprotein glomerulopathy associated with the Osaka/Kurashiki APOE variant: two cases identified in Latin America (2021) · cites this paper as [1]
LPG is caused by pathogenic variants in APOE.
“LPG is caused by pathogenic variants in APOE, the gene which encodes apolipoprotein E (ApoE).”
From Lipoprotein glomerulopathy associated with the Osaka/Kurashiki APOE variant: two cases identified in Latin America (2021) · cites this paper as [1]
Typical LPG histology comprises glomeruli with increased size due to ectasia of capillary loops, filled with light and lamellated eosinophilic thrombi; electron microscopy confirms small lipid vacuoles typical of lipoproteins.
“The typical LPG histology comprises glomeruli with increased size due to ectasia of capillary loops, filled with light and lamellated eosinophilic thrombi. Electron microscopy confirms small lipid vacuoles typical of lipoproteins.”
From Lipoprotein glomerulopathy associated with the Osaka/Kurashiki APOE variant: two cases identified in Latin America (2021) · cites this paper as [1]
Hyperlipoproteinemia type III, high plasma apolipoproteins, proteinuria and microhematuria are common findings in LPG, and nephrotic syndrome and progressive loss of renal function are often observed.
“Hyperlipoproteinemia type III (increased LDL and triglyceride levels), high levels of plasma apolipoproteins, proteinuria and microhematuria are common findings, and nephrotic syndrome and progressive loss of renal function are often observed.”
From Lipoprotein glomerulopathy associated with the Osaka/Kurashiki APOE variant: two cases identified in Latin America (2021) · cites this paper as [1]
APOE mutations can lead to specific glomerular diseases, including APOE homozygote glomerulopathy, membranous nephropathy-like apoE deposition disease and lipoprotein glomerulopathy.
“As a result, APOE mutations can lead to specific glomerular diseases, including APOE homozygote glomerulopathy, membranous nephropathy-like apoE deposition disease and lipoprotein glomerulopathy [1].”
From Lipoprotein glomerulopathy associated with the Osaka/Kurashiki APOE variant: two cases identified in Latin America (2021) · cites this paper as [1]
LPG usually manifests in adulthood and predominantly affects males.
“LPG usually manifests in adulthood and predominantly affects males.”
From Lipoprotein glomerulopathy associated with the Osaka/Kurashiki APOE variant: two cases identified in Latin America (2021) · cites this paper as [1]
Structural abnormalities in apoE reduce its capacity to bind LDL and IDLs, impairing catabolism and clearance, while increasing binding affinity to heparin.
“Structural abnormalities in apoE reduce its capacity to bind LDL and IDLs, impairing catabolism and their clearance, while increase its binding affinity to other molecules such as heparin.”
From Lipoprotein glomerulopathy associated with the Osaka/Kurashiki APOE variant: two cases identified in Latin America (2021) · cites this paper as [1]
Current treatment of LPG includes hypolipemiants, in particular fibrates.
“Current treatment of LPG includes hypolipemiants, in particular fibrates.”
From Lipoprotein glomerulopathy associated with the Osaka/Kurashiki APOE variant: two cases identified in Latin America (2021) · cites this paper as [1]
Immunoadsorption with staphylococcal protein A and LDL apheresis using a heparin-induced extracorporeal lipoprotein precipitation system has yielded positive results in LPG.
“Immunoadsorption with staphylococcal protein A and LDL apheresis using a heparin-induced extracorporeal lipoprotein precipitation system has also yielded positive results [1, 5].”
From Lipoprotein glomerulopathy associated with the Osaka/Kurashiki APOE variant: two cases identified in Latin America (2021) · cites this paper as [1]
This disconnection of CT and lipid may negate the type III hyperlipidemia due to apoE2 homozygote.
“This disconnection of CT and lipid may negate the type III hyperlipidemia due to apoE2 homozygote [7].”
The deformed hinge region may markedly affect the three-dimensional structure of apoE and cause dysfunction of both NT and CT.
“The deformed hinge region may markedly affect the three-dimensional structure of apoE and cause dysfunction of both NT and CT [7].”
Due to the structural change in apoE caused by apoE Toyonaka, this disease may not be accompanied by dyslipidemia.
“Due to the structural change in apoE caused by apoE Toyonaka, this disease may not be accompanied by dyslipidemia.”
ApoE2 (Arg158Cys) and major LPG mutants (apoE Kyoto [Arg25Cys] and Sendai [Arg145Pro]), which are located in the NT, induce dyslipidemia.
“ApoE2 (Arg158Cys) and major LPG mutants (apoE Kyoto [Arg25Cys] and Sendai [Arg145Pro]), which are located in the NT, induce dyslipidemia [7, 11].”
Most homozygous APOE2 carriers are normolipidemic and less than 10% show type III hyperlipoproteinemia.
“most of homozygous APOE2 carrier are normolipidemic and less than 10% of them show type III hyperlipoproteinemia [14, 15].”
From A case report of youth-onset lipoprotein glomerulopathy with APOE Chicago mutation (2024) · cites this paper as [15]
ApoE2 (Arg158Cys) homozygote glomerulopathy has been reported in 10 cases worldwide.
“ApoE2 (Arg158Cys) homozygote glomerulopathy has been reported in 10 cases worldwide97, 98).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [97]
Since the discovery of lipoprotein glomerulopathy, 16 different apolipoprotein E mutations have been reported worldwide.
“So far, 16 different types of gene mutations have been reported worldwide (Fig. 5B).”
From A novel apolipoprotein E mutation, ApoE Ganzhou (Arg43Cys), in a Chinese son and his father with lipoprotein glomerulopathy: two case reports (2022) · cites this paper as [3]
Apolipoprotein E gene mutation is the initiator or a cause of lipoprotein glomerulopathy.
“It is believed that apolipoprotein E gene mutation is the initiator of the disease.”
From A novel apolipoprotein E mutation, ApoE Ganzhou (Arg43Cys), in a Chinese son and his father with lipoprotein glomerulopathy: two case reports (2022) · cites this paper as [3]
ApoE contains an LDL-receptor binding site (amino acids 136-150), a hinge site (amino acids 192-215), and a lipid binding region (amino acids 244-272).
“ApoE contains several primary domains, including LDL-receptor binding site (LRBS, amino acids 136–150), hinge site (HR, amino acids 192–215), and lipid binding region (LBR, amino acids 244 to 272) [3].”
From A novel apolipoprotein E mutation, ApoE Ganzhou (Arg43Cys), in a Chinese son and his father with lipoprotein glomerulopathy: two case reports (2022) · cites this paper as [3]
APOE gene mutation leads to elevated serum apolipoprotein E (ApoE) levels and glomerular capillary occlusion by massive lipoprotein thrombi composed of ApoB and ApoE, causing glomerular damage and renal impairment.
“APOE gene mutation leads to elevated serum apolipoprotein E (ApoE) levels, and glomerular capillary lumens become occluded by massive lipoprotein thrombi composed of ApoB and ApoE, thereby resulting in glomerular damage and renal impairment.1, 2, 3”
From The First Case of Lipoprotein Glomerulopathy in a Patient With Male Infertility (2026) · cites this paper as [1]
Lipoprotein glomerulopathy (LPG) is a rare hereditary glomerular disease characterized by lipoprotein thrombi deposition in glomerular capillaries and caused by pathogenic variants in the APOE gene.
“Lipoprotein glomerulopathy (LPG) is a rare hereditary glomerular disease with lipoprotein thrombi deposition in glomerular capillaries, which is caused by pathogenic variants in APOE gene.”
From The First Case of Lipoprotein Glomerulopathy in a Patient With Male Infertility (2026) · cites this paper as [1]
Without early intervention, renal failure can be progressive in LPG.
“Without early intervention, renal failure can be progressive.[8]”
From A boy and his mother with lipoprotein glomerulopathy: Two case reports and literature review (2025) · cites this paper as [8]
Literature reports that there have been a total of 6 cases of LPG patients undergoing kidney transplantation worldwide, with 5 cases experiencing LPG recurrence in the transplanted kidney, and ApoE abnormalities in the recipients may induce lipoprotein thrombosis in the transplanted kidney.
“Literature reports that there have been a total of 6 cases of LPG patients undergoing kidney transplantation worldwide, with 5 cases experiencing LPG recurrence in the transplanted kidney, and ApoE abnormalities in the recipients may induce lipoprotein thrombosis in the transplanted kidney.[8]”
From A boy and his mother with lipoprotein glomerulopathy: Two case reports and literature review (2025) · cites this paper as [8]
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The First Case of Lipoprotein Glomerulopathy in a Patient With Male Infertility
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- Authors
- Saito, T., Matsunaga, A., Fukunaga, M., Nagahama, K., Hara, S., & Muso, E.
- Affiliations
- Fukuoka University (JP)
- Okinawa Miyako Hospital (JP)
- Kyorin University (JP)
- Kobe City Medical Center General Hospital (JP)
- Kyoto Kacho University (JP)
- Corresponding author
- Saito, Takao
- Venue
- Kidney International
- Publisher
- Elsevier BV
- Published
- 2020-02
- Volume
- 97
- Issue
- 2
- Pages
- 279-288
- ISSN
- 0085-2538 (ISSN-L)
- OpenAlex
- W2990680675
- Semantic Scholar
- 0efc9787f9efa47aa2f6ad028a2f72bc5f841589
- Cited by
- 77
- References
- 109
- Citations by year
- 2026: 10 · 2025: 14 · 2024: 13 · 2023: 13 · 2022: 13 · 2021: 11 · 2020: 3
- FWCI
- 1.06
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Kidney International (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Science, Technology, Sport and Culture (10670982, 14571043, 16590806, 18590917, 21591049)
- Ministry of Health, Labour and Welfare
- Topics
- Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- apolipoprotein E, lipoprotein glomerulopathy, glomerulosclerosis, foam cells, macrophages, membranous nephropathy, hyperlipoproteinemia, glomerular basement membrane
- MeSH terms
- Apolipoproteins E, Homozygote, Humans, Kidney Diseases, Kidney Glomerulus, Apolipoprotein E2
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