Membranous Nephropathy-Like Apolipoprotein E Deposition Disease with Apolipoprotein E Toyonaka (Ser197Cys) and a Homozygous Apolipoprotein E2/2
Open accessAbstract
A 20-year-old female student underwent renal biopsy because of chance proteinuria and hematuria. Histological study revealed a membranous nephropathy-like appearance by light microscopy. But immunoglobulins and complements were negative in the glomerulus by immunofluorescence study. On the other hand, plasma apolipoprotein E (ApoE) concentration was elevated to more than 2 times the normal range, and the phenotype, genotype, and DNA sequence studies of her ApoE showed homozygous ApoE2/2 and a heterozygous novel missense mutation called ApoE Toyonaka (Ser197Cys). Detailed immunohistochemical studies found that the dense deposits in subepithelial, subendothelial, and mesangial areas contained ApoE. Tandem mass spectrometry also proved a large amount of ApoE in the glomerulus. These findings suggest that ApoE Toyonaka with a homozygous ApoE2/2 may cause a new form of ApoE-related glomerular disease resembling membranous nephropathy.
AI snapshot
Written from the paper’s full text.
TL;DR
A 20-year-old woman with chance proteinuria and hematuria had membranous nephropathy-like glomerular lesions without immunoglobulin/complement deposits, but with abundant glomerular apolipoprotein E (ApoE). She carried a novel heterozygous ApoE Toyonaka (Ser197Cys) mutation together with homozygous ApoE2/2, suggesting a new ApoE-related glomerular disease distinct from lipoprotein glomerulopathy and ApoE2 homozygous glomerulopathy.
Key findings
- Renal biopsy showed membranous nephropathy-like “spike” formation by light microscopy, but immunofluorescence was negative for immunoglobulins and complements; electron microscopy showed dense subepithelial, subendothelial, and mesangial deposits with microbubble/microcyst appearance.
- Plasma ApoE was elevated at 10.4 mg/dL, more than 2 times the normal range, while serum triglycerides and cholesterol were within normal limits.
- ApoE studies showed homozygous ApoE2/2 and a heterozygous novel missense mutation, ApoE Toyonaka (Ser197Cys; c.644 C>G), in the hinge region.
- Immunohistochemistry and LC-MS/MS identified ApoE as the most abundant protein in glomeruli from both biopsies; the authors propose this as a new form of ApoE-related glomerular disease resembling membranous nephropathy.
Methods
- Single case report of a 20-year-old Japanese female student who underwent renal biopsy for chance proteinuria and hematuria; a second renal biopsy was performed 9 years after the first.
- Histological evaluation included light microscopy, immunofluorescence, electron microscopy, and immunohistochemistry for ApoE; ApoE phenotype, genotype, and DNA sequence were analyzed by isoelectric focusing, restriction fragment length polymorphism, and sequencing.
- Glomerular proteins were analyzed by laser capture microdissection and LC-MS/MS; 10 glomeruli were analyzed for each specimen, and ApoE was the most abundant protein in both samples.
Limitations
- The paper states that this is the first case in which ApoE was identified in the subepithelial area and that “further studies adding similar cases are needed.”
- Evident from the text: this is a single case report without controls or functional assays, so causality of ApoE Toyonaka in producing the renal lesions is inferred rather than proven.
- Evident from the text: the patient received prednisolone and cyclosporine A, and the long-term clinical course is described without a comparison group, limiting conclusions about treatment response or prognosis.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
6 of 17 cited sources checked · 1 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Several LPG cases have been discovered due to high serum ApoE even without hyperlipidemia.
“In addition, several LPG cases have been discovered due to high serum ApoE even without hyperlipidemia [14, 15].”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [14] source
The Results sections on target-protein identification and disease activity discuss PLA2R antibodies in idiopathic membranous nephropathy, not lipoprotein glomerulopathy (LPG). Searches for LPG, serum ApoE, and hyperlipidemia found no passage addressing the claimed cases. The passages have no page numbers in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measured - cites [15] source
The paper’s introductory discussion reports that most LPG patients have elevated plasma apoE, while elevated triglycerides and cholesterol occur only in some cases. This supports the observation that LPG can occur with high apoE without hyperlipidemia, but the paper does not say that high apoE causes LPG; it discusses apoE mutations as a possible cause. (LLM, conf=0.87)
Experimental — accuracy not yet measured
- Premisecitation
In previous studies on LPG, osmiophilic granular substances were reported in the subendothelial and mesangial areas.
“In previous studies on LPG, osmiophilic granular substances were reported in the subendothelial and mesangial areas [10, 11, 12], and one of them showed ApoE deposition and microbubbles like in the current case [10].”
Quote in the paperNot a substantial claim1 of 3 sources checked- cites [10] source
- cites [11] source
The Lipid Metabolism and Cardiovascular Disorders section describes LPG and glomerular lipoprotein thrombi, but does not describe osmiophilic granular substances or their location. Searches for the distinctive phrase and for subendothelial or mesangial deposits found no passage addressing that observation. (LLM, conf=0.74)
Experimental — accuracy not yet measured - cites [12] source
- Findingown data
Immunofluorescence study showed no granular pattern of immunoglobulins and complements in the glomerulus typical of membranous nephropathy.
“But immunoglobulins and complements were negative in the glomerulus by immunofluorescence study.”
- Also stated in: § Pathological Findings · plain
“On IF staining, very weak linear patterns were identified for IgG and C3 in glomeruli, but a granular pattern as seen in MN was not identified (data not shown).”
Quote in the paperSubstantial claim - Also stated in: § Pathological Findings · plain
- Findingown data
The patient had a heterozygous novel missense mutation ApoE Toyonaka (Ser197Cys).
“a heterozygous novel missense mutation called ApoE Toyonaka (Ser197Cys)”
- Also stated in: § Analysis of ApoE Mutation · plain
“we identified a homozygous polymorphism at codon 158 (ε2/2: c.526 C>T: Arg158Cys) (data not shown) and a heterozygous missense mutation (C to G) in exon 4 leading to an amino acid substitution Cys (TGC) for Ser (TCC) at codon 197 (c.644 C>G: p.S215C: Ser197Cys) (Fig. 2d).”
Quote in the paperSubstantial claim - Also stated in: § Analysis of ApoE Mutation · plain
- Findingown data
Tandem mass spectrometry showed that ApoE was the most abundant protein in the glomerulus.
“Tandem mass spectrometry also proved a large amount of ApoE in the glomerulus.”
- Also stated in: § Tandem Mass Spectrometry · plain
“As a result, the most abundant protein was ApoE in both samples (Fig. 4).”
Quote in the paperSubstantial claim - Also stated in: § Tandem Mass Spectrometry · plain
- Findingown data
Plasma ApoE concentration was elevated to more than 2 times the normal range.
“plasma apolipoprotein E (ApoE) concentration was elevated to more than 2 times the normal range”
- Also stated in: § Analysis of ApoE Mutation · plain
“the plasma ApoE concentration was high (LCAT: 82 nmol/mL; ApoA1: 187 mg/dL; ApoA2: 32.1 mg/dL; ApoB: 52 mg/dL; ApoE: 10.4 mg/dL).”
Quote in the paperSubstantial claim - Also stated in: § Analysis of ApoE Mutation · plain
- Findingown data
Dense deposits in subepithelial, subendothelial, and mesangial areas contained ApoE.
“the dense deposits in subepithelial, subendothelial, and mesangial areas contained ApoE”
- Also stated in: § Discussion · plain
“ApoE deposits were identified in subepithelial, subendothelial, and mesangial areas in the glomerulus by the immunohistochemical studies for LM (Fig. 3a) and in EM specimens (Fig. 3b, c).”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
Renal biopsy showed a membranous nephropathy-like appearance by light microscopy.
“Histological study revealed a membranous nephropathy-like appearance by light microscopy.”
- Also stated in: § Pathological Findings · plain
“In silver methenamine-stained sections, “spike” formation as seen in MN was found in most of the glomeruli (Fig. 1b).”
Quote in the paperSubstantial claim - Also stated in: § Pathological Findings · plain
- Findingown data
The association with collagen diseases was not observed in this case.
“But the association with collagen diseases was not observed in this case.”
Quote in the paperSubstantial claim - Findingown data
MN-like lesions mainly having subepithelial deposition were recognized in a patient with a novel ApoE mutation called ApoE Toyonaka and a classical homozygous ApoE2/2 variant.
“In conclusion, MN-like lesions mainly having subepithelial deposition were recognized in a patient with a novel ApoE mutation called ApoE Toyonaka and a classical homozygous ApoE2/2 variant.”
Quote in the paperSubstantial claim - Interpretationreasoning
ApoE Toyonaka is responsible for the renal lesions in this case.
“it can be considered that ApoE Toyonaka is responsible for these renal lesions, because the pathology of ApoE2 homozygous glomerulopathy with type III hyperlipoproteinemia and glomerular foam cells is much different from that of the current case.”
Quote in the paperSubstantial claim- Rests on an assumption: A heterozygous ApoE Toyonaka mutation is sufficient to cause the renal lesions.
- Interpretationown data
The histological findings of the current case are far different from those of LPG and ApoE2 homozygous glomerulopathy.
“Although the histological findings are far different from those of LPG and of ApoE2 homozygous glomerulopathy, these findings suggest that the current case belongs to one of the ApoE-related renal diseases.”
Quote in the paperSubstantial claim - Interpretationown data
The current case belongs to one of the ApoE-related renal diseases.
“these findings suggest that the current case belongs to one of the ApoE-related renal diseases.”
Quote in the paperSubstantial claim - Interpretationreasoning
A missense mutation in the hinge region may induce dysfunction of the C-terminal domain and result in normolipidemic peculiar glomerular lesions without foam cells or lipoprotein thrombi.
“Therefore, such a missense mutation in the hinge region may induce dysfunction of the C-terminal domain and result in the normolipidemic peculiar glomerular lesions without foam cells or lipoprotein thrombi.”
Quote in the paperSubstantial claim - Premisecitation
ApoE Toyonaka occurs in the hinge region (amino acid residues 192-215) that stabilizes the connection between the N-terminal domain having the low-density lipoprotein receptor-binding region and the C-terminal domain having lipid-binding activity.
“ApoE Toyonaka occurs in the hinge region (amino acid residues 192–215) that stabilizes the connection between the N-terminal domain having low-density lipoprotein receptor-binding region and the C-terminal domain having lipids-binding activity [13].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] source
- Interpretationown data
These findings suggest that ApoE Toyonaka with a homozygous ApoE2/2 may cause a new form of ApoE-related glomerular disease resembling membranous nephropathy.
“These findings suggest that ApoE Toyonaka with a homozygous ApoE2/2 may cause a new form of ApoE-related glomerular disease resembling membranous nephropathy.”
- Also stated in: § Discussion · hedged
“Since IgG and complements were not identified in the glomerulus, but ApoE was there, it was suggested that this case showed a new form of ApoE-related glomerular disease.”
Quote in the paperSubstantial claim- Rests on an assumption: A heterozygous ApoE Toyonaka mutation is sufficient to cause the renal lesions.
- Rests on an assumption: The absence of immunoglobulin and complement deposits in the glomerulus rules out immune-complex-mediated membranous nephropathy.
- Also stated in: § Discussion · hedged
- Interpretationnone given
There was no report that showed subepithelial deposits forming spikes.
“But there was no report that showed subepithelial deposits forming spikes.”
Quote in the paperSubstantial claim - Interpretationown data
This is the first case in which ApoE was identified in the subepithelial area.
“However, this is the first case in which ApoE was identified in the subepithelial area, and further studies adding similar cases are needed.”
Quote in the paperSubstantial claim - Interpretationreasoning
It may be possible that these electron dense deposits are not composed of immune complexes but lipoproteins with abnormal ApoE mainly.
“Accordingly, it may be possible that these electron dense deposits are not composed of immune complexes but lipoproteins with abnormal ApoE mainly.”
Quote in the paperSubstantial claim - Premisecitation
One previous LPG case showed ApoE deposition and microbubbles like in the current case.
“and one of them showed ApoE deposition and microbubbles like in the current case [10].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] source
- Interpretationreasoning
The pathology of ApoE2 homozygous glomerulopathy with type III hyperlipoproteinemia and glomerular foam cells is much different from that of the current case.
“because the pathology of ApoE2 homozygous glomerulopathy with type III hyperlipoproteinemia and glomerular foam cells is much different from that of the current case.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 8
- May combine two claims. 8
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationApolipoprotein E (ApoE) is an important component of lipoprotein and plays a major role in the uptake of lipoproteins into cells through low-density lipoprotein receptors.
“Apolipoprotein E (ApoE) is an important component of lipoprotein and plays a major role in the uptake of lipoproteins into cells through low-density lipoprotein receptors [1].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [1] source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationLPG is histologically characterized by lipoprotein thrombi without foam cells in the glomerular capillary.
“This disease is histologically characterized by lipoprotein thrombi without foam cells in the glomerular capillary [5]”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [5] source
The Introduction and Discussion describe LPG as showing lipoprotein thrombi in dilated glomerular capillaries. The Discussion says LPG seldom has massive glomerular foam-cell infiltration, but it does not say foam cells are absent; that absolute part of the claim is unsupported. (LLM, conf=0.86)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataThe second renal biopsy showed similar LM and IF findings to the first biopsy, but the density of deposits on EM were more obvious.
“Although the histological findings by LM and IF were similar to those of the first biopsy, the density of deposits on EM were more obvious, and ApoE was identified by immunohistochemical studies for LM and EM specimens using anti-ApoE antibody (Novus Biologicals, Littleton, CO, USA) (Fig. 3) [8].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [8] source
The Clinical specimens and Results and discussion sections describe amyloidosis biopsy samples and mass-spectrometry findings, but no comparison of a first and second renal biopsy by LM, IF, or EM. Searches for those biopsy comparisons and deposit density found no supporting passage in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataThe patient was a 20-year-old Japanese female student with chance proteinuria and hematuria.
“A 20-year-old female student underwent renal biopsy because of chance proteinuria and hematuria.”
- Also stated in: § Case Presentation · plain
“A 20-year-old Japanese female student was admitted to Toyonaka Municipal Hospital in 2006 in order to undergo examinations, including renal biopsy, because she was found to have chance proteinuria and hematuria at the health surveillance in her university.”
Quote in the paperNot a substantial claim- Also stated in: § Case Presentation · plain
May combine two claims.
Findingown dataThe patient had a homozygous ApoE2/2 phenotype and genotype.
“the phenotype, genotype, and DNA sequence studies of her ApoE showed homozygous ApoE2/2”
- Also stated in: § Analysis of ApoE Mutation · plain
“The patient's sample showed the position of ApoE2/2 (Fig. 2a, lane 1).”
- Also stated in: § Analysis of ApoE Mutation · plain
“Genotype ε2/2 in the patient was identified by 91- and 83-bp fragments (Fig. 2b, lane 1).”
Quote in the paperSubstantial claim- Also stated in: § Analysis of ApoE Mutation · plain
May combine two claims.
Findingown dataThe current case showed spike formations and electron dense deposits characteristic of MN in the subepithelial area and less frequently in the subendothelial and mesangial areas.
“On the other hand, spike formations and electron dense deposits characteristic of MN were found in the subepithelial area and less frequently in the subendothelial and mesangial areas.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDifferent from MN, the deposits in the current case did not include either immunoglobulins nor complements but ApoE.
“Interestingly, different from MN, these deposits did not include either immunoglobulins nor complements but ApoE.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe patient had significant proteinuria and hematuria with hypoalbuminemia but did not satisfy criteria for nephrotic syndrome.
“Significant proteinuria and hematuria with hypoalbuminemia were recognized, but the criteria for nephrotic syndrome were not satisfied.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataOther values, including lipids and renal functions, were within normal ranges.
“Other values, including lipids and renal functions, were within normal ranges.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationLipoprotein glomerulopathy (LPG) is associated with various heterozygous ApoE variants, such as ApoE Sendai and ApoE Kyoto.
“Lipoprotein glomerulopathy (LPG) was initially reported in Japan [2] and later known to be associated with various heterozygous ApoE variants, e.g., ApoE Sendai [3] and ApoE Kyoto [4].”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationApoE2 homozygous glomerulopathy showing marked foam cell infiltration has been reported.
“On the other hand, ApoE2 homozygous glomerulopathy showing marked foam cell infiltration has been reported [6].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [6] source
May combine two claims.
InterpretationreasoningBecause the molecular size of ApoE (34 kD) is much smaller than that of albumin (68 kD), ApoE can cross the anionic charge barrier in the glomerular basement membrane and accumulate in the subepithelial area.
“Moreover, since the molecular size of ApoE (34 kD) is much smaller than that of albumin (68 kD), ApoE can cross the anionic charge barrier in the glomerular basement membrane and accumulate in the subepithelial area.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone givenIt is not possible that ApoE is involved in membranous nephropathy as an endogenous antigen.
“But it is not possible that ApoE is involved in MN as an endogenous antigen.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn LPG, ApoE variants substituted by proline or cysteine may induce severe structural changes and cause lipoprotein thrombi via charge abnormality or alternative receptor binding activity.
“Meanwhile, in LPG, there is a possibility that ApoE variants substituted by proline or cysteine induce severe structural changes and cause lipoprotein thrombi via charge abnormality or alternative receptor binding activity [4, 17, 18].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [4] source
- cites [17]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [18]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
The paper relies on this without support.
A heterozygous ApoE Toyonaka mutation is sufficient to cause the renal lesions.
“a heterozygous novel missense mutation called ApoE Toyonaka (Ser197Cys)”
“it can be considered that ApoE Toyonaka is responsible for these renal lesions, because the pathology of ApoE2 homozygous glomerulopathy with type III hyperlipoproteinemia and glomerular foam cells is much different from that of the current case.”
The paper relies on this without support.
The absence of immunoglobulin and complement deposits in the glomerulus rules out immune-complex-mediated membranous nephropathy.
“But immunoglobulins and complements were negative in the glomerulus by immunofluorescence study.”
“Since IgG and complements were not identified in the glomerulus, but ApoE was there, it was suggested that this case showed a new form of ApoE-related glomerular disease.”
The paper relies on this without support.
The renal biopsy findings are representative of the patient's overall glomerular disease.
“On renal biopsy, more than 30 glomeruli were contained in LM specimens, some of which showed global sclerotic change.”
“The first biopsy showed MN-like findings, but immune deposits were not proven there, and immune-genetic MN was doubtful.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
This case is the fourth report of MN-like apoE deposition disease with apoE Toyonaka and homozygous apoE2/2 in the literature.
“this case is the fourth report of MN-like apoE deposition disease with apoE Toyonaka and homozygous apoE2/2 in the literature.”
From Membranous Nephropathy-Like Apolipoprotein E Deposition Disease with Apolipoprotein E Toyonaka and Homozygous Apolipoprotein E2/2 without Dyslipidemia, with Characteristic Electron-Dense Deposits (2022) · cites this paper as [4]
The Introduction (page unavailable) describes a case of MN-like ApoE deposition with ApoE Toyonaka and homozygous ApoE2/2. The paper does not establish that the citing document’s case is the fourth report in the literature; its Discussion instead describes its own case as the first in which ApoE was identified in the subepithelial area. (LLM, conf=0.87)
Experimental — accuracy not yet measuredOne previous case showed no dyslipidemia and the other two showed both hypertriglyceridemia and hypercholesterolemia.
“one of the previous cases showed no dyslipidemia and the other two cases showed both hypertriglyceridemia and hypercholesterolemia (Table 2).”
From Membranous Nephropathy-Like Apolipoprotein E Deposition Disease with Apolipoprotein E Toyonaka and Homozygous Apolipoprotein E2/2 without Dyslipidemia, with Characteristic Electron-Dense Deposits (2022) · cites this paper as [4]
The Case Presentation and Analysis of ApoE Mutation report normal lipid levels in this paper’s patient, supporting the case without dyslipidemia. The paper does not report that two other cases had both hypertriglyceridemia and hypercholesterolemia; that part of the three-case comparison is unsupported by this source. (LLM, conf=0.82)
Experimental — accuracy not yet measuredPrevious cases showed increases in proteinuria and decreases in renal function in their long-term course.
“The previous cases showed increases in proteinuria and decreases in renal function in their long-term course.”
From Membranous Nephropathy-Like Apolipoprotein E Deposition Disease with Apolipoprotein E Toyonaka and Homozygous Apolipoprotein E2/2 without Dyslipidemia, with Characteristic Electron-Dense Deposits (2022) · cites this paper as [4]
The Case Presentation’s “Clinical Course after the First Biopsy” reports that renal function declined in the paper’s single patient, although it later stabilized. It describes proteinuria as initially decreasing and then persisting, not increasing; it does not establish the claimed course across multiple previous cases. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn all reported cases including ours, the serum apoE concentration was high regardless of the presence of dyslipidemia.
“In all reported cases, including our case, the serum apoE concentration was high, regardless of the presence of dyslipidemia (Table 2).”
From Membranous Nephropathy-Like Apolipoprotein E Deposition Disease with Apolipoprotein E Toyonaka and Homozygous Apolipoprotein E2/2 without Dyslipidemia, with Characteristic Electron-Dense Deposits (2022) · cites this paper as [4]
The Case Presentation (Analysis of ApoE Mutation; page unavailable) reports high plasma ApoE despite normal triglycerides and cholesterol in this patient. The Discussion also mentions several lipoprotein glomerulopathy cases with high serum ApoE without hyperlipidemia. Neither passage establishes that ApoE was high in all reported cases, regardless of dyslipidemia status. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAlmost all other mutations were located on the ε3 allele except for APOE-Toyonaka.
“Almost all other mutations were located on the ε3 allele except for a new reported mutation APOE‐Toyonaka (Fukunaga et al., 2018; Hirashima et al., 2018).”
From Clinical and genetic analysis of lipoprotein glomerulopathy patients caused by <i>APOE</i> mutations (2020) · cites this paper as Fukunaga et al., 2018
The Case Presentation (Analysis of ApoE Mutation; page unavailable) identifies APOE-Toyonaka as a novel mutation in a patient with an ε2/2 genotype, supporting the exception. The paper does not establish that almost all other mutations occur on the ε3 allele. (LLM, conf=0.85)
Experimental — accuracy not yet measured
A new glomerular disease was identified in four non-consanguineous carriers possessing the novel variant APOE Toyonaka (Ser197Cys).
“A new glomerular disease was identified in four non-consanguineous carriers possessing the novel variant APOE Toyonaka (Ser197Cys) (Fig.5, Table 3)99, 101-103).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [101]
The Case Presentation reports one patient with APOE Toyonaka (Ser197Cys), and the Discussion suggests her findings represent a new form of ApoE-related glomerular disease. This paper supports one case among those cited, but it does not establish four carriers or that they were non-consanguineous. No page numbers are provided in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredGlomerular lesions only occurred in APOE Toyonaka (Ser197Cys, Arg158Cys) when the other allele was ApoE2.
“It was reported that glomerular lesions only occurred in APOE Toyonaka (Ser197Cys, Arg158Cys) when the other allele was ApoE2.”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [101]
The Case Presentation (Analysis of ApoE Mutation) identifies a patient with heterozygous ApoE Toyonaka (Ser197Cys) and homozygous ApoE2/2 (Arg158Cys), and the Discussion reports glomerular lesions in that patient. This single case does not establish that lesions occur only when the other allele is ApoE2; the authors say the combination may cause the disease. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAPOE Toyonaka (Ser197Cys) was considered to be in linkage disequilibrium with apoE2 (Arg158Cys).
“This variant was considered to be in linkage disequilibrium with apoE2 (Arg158Cys).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [101]
The Case Presentation, under “Analysis of ApoE Mutation” (page not provided), identifies homozygous apoE2 (Arg158Cys) and heterozygous APOE Toyonaka (Ser197Cys) in the same patient. The paper does not state that the variants were in linkage disequilibrium or assess their association beyond this case. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn Fukunaga et al., the second biopsy revealed a more robust apoE deposition than the first biopsy performed 9 years earlier.
“In the case reported by Fukunaga et al. [4], the second biopsy revealed a more robust apoE deposition than the first biopsy performed 9 years earlier.”
No lipid abnormalities were observed in one previous case with apoE Toyonaka and homozygous apoE2/2.
“In fact, no lipid abnormalities were observed in one of the previous cases with apoE Toyonaka and homozygous apoE2/2 [4].”
The previous two cases showed a gradual decrease in kidney function despite receiving either immunosuppressive therapy or lipid-lowering drugs.
“The previous two cases showed a gradual decrease in kidney function, despite receiving either immunosuppressive therapy or lipid-lowering drugs [4, 6].”
The first and fourth reported cases of APOE Toyonaka presented with proteinuria and hematuria, but not dyslipidemia, and renal biopsy revealed nonimmune membranous nephropathy-like features in the glomeruli.
“The first and fourth reported cases presented with proteinuria and hematuria, but not dyslipidemia, and renal biopsy revealed nonimmune membranous nephropathy-like features in the glomeruli101, 98).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [101]
The three previously reported cases showed proteinuria ≥2.0 g/day at diagnosis, whereas the present case was 0.8 g/day.
“The three previously reported cases showed a relatively high amount of proteinuria of ≥2.0 g/day at the time of diagnosis, although it was 0.8 g/day in the present case (Table 2).”
From Membranous Nephropathy-Like Apolipoprotein E Deposition Disease with Apolipoprotein E Toyonaka and Homozygous Apolipoprotein E2/2 without Dyslipidemia, with Characteristic Electron-Dense Deposits (2022) · cites this paper as [4]
The Case Presentation reports proteinuria in this patient but gives no 0.8 g/day value in the retrieved passage. The Clinical Course after the First Biopsy gives a later range of 0.5–2.5 g/gCr, not proteinuria at diagnosis. Searches for 0.8 g/day, three previously reported cases, and Table 2 found no passage in our copy establishing the claimed comparison. (LLM, conf=0.76)
Experimental — accuracy not yet measuredTo date, all four cases of MN-like apoE deposition disease have been reported from the west-central part of the mainland of Japan.
“To date, all the four cases of MN-like apoE deposition disease have been reported from the west-central part of the mainland of Japan.”
From Membranous Nephropathy-Like Apolipoprotein E Deposition Disease with Apolipoprotein E Toyonaka and Homozygous Apolipoprotein E2/2 without Dyslipidemia, with Characteristic Electron-Dense Deposits (2022) · cites this paper as [4]
The Case Presentation describes one Japanese patient admitted to Toyonaka Municipal Hospital, and the Discussion calls this the first case with ApoE identified in subepithelial deposits. Our copy does not give a count of four MN-like ApoE deposition cases or describe where all such cases were reported; searches for the case count and geographic distribution found no such passage. (LLM, conf=0.77)
Experimental — accuracy not yet measured
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M-Type Phospholipase A <sub>2</sub> Receptor as Target Antigen in Idiopathic Membranous Nephropathy
Beck, L. H., Bonegio, R. G. B., Lambeau, G., Beck, D. M., Powell, D. W., Cummins, T. D., Klein, J. B., & Salant, D. J. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0810457 · Cited by 2,347 · see citing works
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Apolipoproteins: metabolic role and clinical biochemistry applications
Dominiczak, M. H., & Caslake, M. J. (2011) · Annals of Clinical Biochemistry: International Journal of Laboratory Medicine · doi:10.1258/acb.2011.011111 · Cited by 238 · see citing works
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Lipoprotein Glomerulopathy: Glomerular Lipoprotein Thrombi in a Patient With Hyperlipoproteinemia
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Self-citationImpact of Lipoprotein Glomerulopathy on the Relationship Between Lipids and Renal Diseases
Saito, T., Matsunaga, A., & Oikawa, S. (2006) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2005.10.017 · Cited by 96 · see citing works
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Matsunaga, A., Sasaki, J., Komatsu, T., Kanatsu, K., Tsuji, E., Moriyama, K., Koga, T., Arakawa, K., Oikawa, S., Saito, T., et al. (1999) · Kidney International · doi:10.1046/j.1523-1755.1999.00572.x · Cited by 91 · see citing works
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A novel variant apolipoprotein E Okayama in a patient with lipoprotein glomerulopathy
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Lipoprotein Glomerulopathy and Its Pathogenesis
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Self-citationPostembedding Labeling Methods
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Flagged first, then by citations
Cited by
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APOE gene variants in primary dyslipidemia
Khalil, Y. A., Rabès, J.-P., Boileau, C., & Varret, M. (2021) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2021.05.007 · Cited by 170 · see citing works
Apolipoprotein E–related glomerular disorders
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Self-citationMadden, B. J., Singh, R. D., Haas, M., Palma, L. M. P., Sharma, A., Vargas, M. J., Gross, L., Negron, V. C., Nate, T., Charlesworth, M. C., et al. (2024) · Kidney International · doi:10.1016/j.kint.2024.02.013 · Cited by 31 · see citing works
Clinical and genetic analysis of lipoprotein glomerulopathy patients caused by <i>APOE</i> mutations
Yang, M., Weng, Q., Pan, X., Hussain, H. M. J., Yu, S., Xu, J., Yu, X., Liu, Y., Jin, Y., Zhang, C., et al. (2020) · Molecular Genetics & Genomic Medicine · doi:10.1002/mgg3.1281 · Cited by 15 · see citing works
Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features
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Self-citationKato, T., Ushiogi, Y., Yokoyama, H., Hara, S., Matsunaga, A., Muso, E., & Saito, T. (2019) · CEN Case Reports · doi:10.1007/s13730-019-00380-w · Cited by 9 · see citing works
Self-citationHirashima, H., Komiya, T., Toriu, N., Hara, S., Matsunaga, A., Saito, T., & Muso, E. (2018) · Clinical Nephrology – Case Studies · doi:10.5414/cncs109509 · Cited by 8 · see citing works
Self-citationLipoprotein Glomerulopathy in a Hispanic Female: A Case Report and Literature Review
Majeed, N. K., McLaughlin, J., & Gonzalez, M. (2019) · Canadian Journal of Kidney Health and Disease · doi:10.1177/2054358119859576 · Cited by 6 · see citing works
Wang, R., Zhao, C., Chen, W., Liu, Z., & Xie, F. (2022) · Journal of Medical Case Reports · doi:10.1186/s13256-022-03302-0 · Cited by 5 · see citing works
Apolipoprotein E-associated Lipoprotein Glomerulo-tubulopathy
Tanimizu, H., Hara, R., Sekine, A., Inoue, N., Hasegawa, E., Tanaka, K., Kono, K., Kinowaki, K., Ohashi, K., Okubo, M., et al. (2023) · Internal Medicine · doi:10.2169/internalmedicine.0834-22 · Cited by 5 · see citing works
Self-citationKoshino, A., Takaeda, C., Matsuno, T., Kitajima, S., Iwata, Y., Sakai, N., Nagahama, K., Niida, Y., Saito, T., Yokoyama, H., et al. (2022) · Case Reports in Nephrology and Dialysis · doi:10.1159/000525086 · Cited by 2 · see citing works
Self-citationUtility of Immunofluorescence in the Diagnosis of Glomerulopathies
Ginés, R. T., Armas, I. O., Montero, M. D. L. Á. L., Romero, F. E. I., & Leyva, L. T. (2021) · ESPOCH Congresses The Ecuadorian Journal of S T E A M · doi:10.18502/espoch.v1i6.9666
Ouyang, X., Han, Y., Li, M., Qi, X., Qu, L., Ye, X., & Yan, Y. (2026) · International Urology and Nephrology · doi:10.1007/s11255-026-05456-y
An Updated Review and Meta Analysis of Lipoprotein Glomerulopathy
Li, M.-S., Li, Y., Liu, Y., Zhou, X.-J., & Zhang, H. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.905007 · Cited by 25 · see citing works
- Authors
- Fukunaga, M., Nagahama, K., Aoki, M., Shimizu, A., Hara, S., Matsunaga, A., Muso, E., & Saito, T.
- Affiliations
- Okinawa Miyako Hospital (JP)
- Kyorin University (JP)
- Nippon Medical School (JP)
- Kobe University (JP)
- Fukuoka University Hospital (JP)
- Kitano Hospital (JP)
- Corresponding author
- Fukunaga, Megumu
- Venue
- Case Reports in Nephrology and Dialysis
- Publisher
- S. Karger AG
- Published
- 2018-03-20
- Volume
- 8
- Issue
- 1
- Pages
- 45-55
- ISSN
- 2296-9705 (ISSN-L)
- PMC
- PMC5903162
- OpenAlex
- W2792224893
- Cited by
- 14
- References
- 18
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 2 · 2020: 1 · 2019: 3 · 2018: 1
- FWCI
- 1.43
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Case Reports in Nephrology and Dialysis (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Kobe University Repository Kernel (Kobe University) (submittedVersion, cc-by-nc)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (16K08698, 16K08955)
- Topics
- Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Keywords
- apolipoprotein E, glomerular deposition, proteinuria, hematuria
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-31.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-31.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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