A case of nephrotic syndrome showing contemporary presence of apolipoprotein E2 homozygote glomerulopathy and membranous nephropathy-like findings modified by apolipoprotein E Toyonaka
Open accessAbstract
A 79-year-old man was admitted to our hospital for proteinuria due to nephrotic syndrome. Renal biopsy revealed focal sclerosis and foam cell infiltration in the glomerulus. In addition, electron microscopic findings (EM) revealed peculiar electron-dense deposits (EDDs) in both sides of the glomerular basement membrane. Although subepithelial deposits had spike formation highly resembling those seen in membranous nephropathy (MN), immunoglobulins and complements were not identified by immunofluorescence study, and microbubbles appeared in high magnification of EM different from the immune disease. The analysis of apolipoprotein (Apo) E showed an elevated concentration of plasma ApoE. The phenotype, genotype, and DNA sequence studies revealed homozygous ApoE2/2 and a novel missense mutation called ApoE Toyonaka (Ser197Cys). This case may confirm the independent responsibility of ApoE2/2 and ApoE Toyonaka for ApoE2 homozygote glomerulopathy and MN-like EDD findings, respectively.
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Previous 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 [5]
The Case presentation (Patient; page unavailable) records rising proteinuria in this paper’s patient, from 5.4 to 9.15 g/g Cr, and the Clinical course after biopsy reports a later relapse with increased proteinuria. These passages concern one patient, not previous cases, and do not report a long-term decline in renal function. (LLM, conf=0.78)
Experimental — accuracy not yet measuredThe 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 [5]
The Case presentation > Patient section reports substantial proteinuria in this paper’s patient: 5.4 g/g Cr at initial admission and 9.15 g/g Cr at the second hospitalization. It does not establish that all three previously reported cases had proteinuria ≥2.0 g/day at diagnosis; its measurements are also in g/g Cr, not g/day. The 0.8 g/day figure describes the citing authors’ present case, not this source’s patient. (LLM, conf=0.76)
Experimental — accuracy not yet measuredThis 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 [5]
The Introduction and case presentation describe this patient as having MN-like lesions, ApoE Toyonaka, and homozygous ApoE2/2. The Discussion identifies one earlier case with the same combination, but the paper does not say this case was the fourth report in the literature. (LLM, conf=0.86)
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 [5]
The Case presentation > Patient section reports elevated serum ApoE (13.6 mg/dL, versus a normal range of 2.8–4.6 mg/dL) in a patient who also had elevated cholesterol and triglycerides. Our copy does not establish that serum ApoE was high in all reported cases or in cases without dyslipidemia. (LLM, conf=0.86)
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 [5]
The Discussion (page not available) describes the authors’ MN-like ApoE case and a similar case reported by Fukunaga et al. The Case presentation places the authors’ patient at a hospital in Osaka. Our copy does not establish that there were four cases or that all four came from west-central mainland Japan. (LLM, conf=0.82)
Experimental — accuracy not yet measured
Almost 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 Hirashima et al., 2018
The Case presentation > Analysis of ApoE mutation (page unavailable) identifies APOE-Toyonaka in a patient with an ε2/2 genotype, supporting its distinction from mutations on an ε3 allele. The paper does not establish that almost all other mutations are located on ε3 alleles; its Discussion contrasts Toyonaka with other mutations by protein region, not allele. (LLM, conf=0.84)
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 [102]
The Case presentation, under “Analysis of ApoE mutation” (page unavailable), identifies both homozygous apoE2 (Arg158Cys) and heterozygous ApoE Toyonaka (Ser197Cys) in the patient. It does not state or establish that the variants are in linkage disequilibrium; their co-occurrence in this case does not establish that relationship. (LLM, conf=0.85)
Experimental — accuracy not yet measuredA 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 [102]
The Introduction describes a possible new form of APOE-related glomerular disease, and the Case presentation identifies APOE Toyonaka (Ser197Cys) in the patient. This paper reports one patient, not four non-consanguineous carriers, and does not establish that the proposed disease was identified in such a group. Page numbers are unavailable 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 [102]
The Case presentation (page unavailable) identifies both ApoE2/2 and heterozygous ApoE Toyonaka (Ser197Cys) in a patient with glomerular lesions, and notes a previous case with the same combination. The Discussion (page unavailable) says the combination may contribute to MN-like lesions and calls for further cases; it does not establish that lesions occur only when the other allele is ApoE2. (LLM, conf=0.87)
Experimental — accuracy not yet measuredOur case did not show foam cell or lipoprotein thrombi that were observed in the two previous cases.
“Our case did not show foam cell or lipoprotein thrombi that were observed in the two previous cases [5, 6].”
The other case was treated with prednisolone, cyclosporine, and fibrate, which led to a decrease in proteinuria.
“The other case was treated with prednisolone, cyclosporine, and fibrate, which led to a decrease in proteinuria [5].”
The other two cases of APOE Toyonaka were accompanied by marked hyperlipidemia and histologically showed foam cells and non-lamellar lipoprotein thrombi frequently observed in apoE2 homozygote glomerulopathy.
“The other two cases were accompanied by marked hyperlipidemia and histologically showed foam cells and non-lamellar lipoprotein thrombi frequently observed in apoE2 homozygote glomerulopathy99, 102).”
From Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features (2025) · cites this paper as [102]
One 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).”
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Sorted by citations
APOE gene variants in primary dyslipidemia
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Apolipoprotein E–related glomerular disorders
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Impact of Apolipoprotein E Variants: A Review of Naturally Occurring Variants and Clinical Features
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Self-citation
- Authors
- Hirashima, H., Komiya, T., Toriu, N., Hara, S., Matsunaga, A., Saito, T., & Muso, E.
- Affiliations
- Kansai Electric Power (Japan) (JP)
- Kobe University (JP)
- Fukuoka University (JP)
- Venue
- Clinical Nephrology – Case Studies
- Publisher
- Dustri-Verlgag Dr. Karl Feistle
- Published
- 2018-11-30
- Volume
- 6
- Issue
- 01
- Pages
- 45-51
- ISSN
- 2196-5293 (ISSN-L)
- PMC
- PMC6287602
- OpenAlex
- W2903137400
- Cited by
- 8
- References
- 3
- Citations by year
- 2025: 1 · 2022: 2 · 2021: 2 · 2020: 1 · 2019: 2
- FWCI
- 1.02
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- cc-by
- Locations
- Clinical Nephrology - Case Studies (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (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
- nephrotic syndrome, proteinuria, electron-dense deposits, glomerular basement membrane, focal glomerulosclerosis
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