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Cited by 9Renal Diseases and GlomerulopathiesChronic Kidney Disease and DiabetesSystemic Lupus Erythematosus Research

Focal segmental glomerulosclerosis with heterozygous apolipoprotein E5 (Glu3Lys)

Open access
Sasaki, Masaru, Yasuno, Tetsuhiko, Ito, Kenji, Matsunaga, Akira, Hisano, Satoshi, Abe, Yasuhiro, Miyake, Katsuhisa, Masutani, Kosuke +2 more·2018·CEN Case Reports
DOI 10.1007/s13730-018-0331-4PMC PMC6181881
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Abstract

Apolipoprotein (apo) E5 is a rare apoE isoform. The apoE5 (Glu3Lys) variant, which is caused by the substitution of lysine with glutamic acid at codon 3, has a relative frequency of 0.1% in Japan. Previous studies have reported that apoE5 (Glu3Lys) is associated with hyperlipidemia and cardiovascular diseases, but this isoform has higher LDL receptor-binding activity than that of normal apoE3. Nephropathy associated with apoE5 (Glu3Lys) alone has not yet been reported. We present a case of a 51-year-old man with nephrotic syndrome. On renal biopsy, three glomeruli showed segmental sclerosis with hypertrophy of podocytes and intracapillary marked infiltration of intraglomerular foam cells. These findings were compatible with focal segmental glomerulosclerosis (FSGS). The patient had mild diabetes mellitus and monoclonal gammopathy of undetermined significance, but there were no specific findings of nephrolopathy related to these diseases. Various factors are involved in the pathogenesis of FSGS, including dyslipidemia and apoE activity. Our findings suggest that abnormal lipid metabolism by ApoE5 (Glu3Lys) is involved in the onset of FSGS.

AI snapshot

Written from the paper’s full text.

TL;DR

A 51-year-old Japanese man with nephrotic syndrome was found to have focal segmental glomerulosclerosis (FSGS), cellular variant, together with heterozygous apolipoprotein E5 (Glu3Lys)/apoE3. The authors suggest that abnormal lipid metabolism from apoE5 (Glu3Lys) may be involved in the onset of FSGS, but causality remains unproven.

Key findings

  • The patient had nephrotic syndrome with protein excretion of 12.4 g/gCr, albumin 2.5 g/dL, LDL cholesterol 208 mg/dL, and serum apoE 5.7 mg/dL (normal range 2.7–4.3 mg/dL).
  • Renal biopsy contained 31 glomeruli, 10 with global sclerosis; 3 showed segmental sclerosis with podocyte hyperplasia and marked intracapillary infiltration of intraglomerular foam cells, compatible with FSGS, cellular variant. No lipoprotein thrombi specific to lipoprotein glomerulopathy were detected.
  • ApoE phenotype was apoE3/5; RFLP showed genotype ε3/3, and APOE sequencing identified heterozygous apoE5 (Glu3Lys). The authors state this is the first case report of nephropathy in a patient with apoE5 (Glu3Lys) but no other apoE mutations.
  • The patient continued an angiotensin receptor blocker and an HMG-CoA reductase inhibitor; renal function was stable with nephrotic syndrome for 1 year.

Methods

  • Single case report of a 51-year-old Japanese man admitted to Fukuoka University Hospital for kidney disease; he had treated hypertension, diabetes mellitus, dyslipidemia, and hypothyroidism, and was diagnosed with monoclonal gammopathy of undetermined significance (MGUS).
  • Renal biopsy was examined by light microscopy, electron microscopy, and immunofluorescence. ApoE phenotype was analyzed by isoelectric focusing polyacrylamide gel electrophoresis; apoE genotype by restriction fragment length polymorphism; and APOE coding sequence by PCR and direct sequencing.
  • No formal comparative or statistical analysis was performed; findings are descriptive.

Limitations

  • Stated in the paper: the patient’s parents had died, so it was unclear whether the apoE5 mutation was de novo or hereditary; the precise mechanisms linking apoE5 (Glu3Lys) to FSGS have not been elucidated, and accumulation of more cases is required.
  • Evident from the design: this is a single case report without controls, so it cannot establish that apoE5 (Glu3Lys) caused FSGS.
  • Evident from the text: the patient also had mild diabetes mellitus, MGUS, hypertension, and dyslipidemia, although the authors report no specific biopsy findings of diabetic or MGUS-related nephropathy.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1007/s13730-018-0331-4

Cites

14 of 14 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

10 of 20 cited sources checked · 8 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    In reported LPG cases with apoE5, other LPG-specific apoE variants (apoE-Chicago, apoE-Sendai) were also detected.

    “but apoE variants specific to LPG, e.g., apoE-Chicago [4] and apoE-Sendai [5], were also detected in these cases”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [4] Kodera H, Mizutani Y, Sugiyama S, et al. A case of lipoprotein glomerulopathy with ApoE Chicago and ApoE (Glu3Lys) treated with fenofibrate. Case Rep Nephrol Dial. 2017;7(2):112–20. source
    • cites [5] Takasaki S, Matsunaga A, Joh K, Saito T. A case of lipoprotein glomerulopathy with a rare apolipoprotein E isoform combined with neurofibromatosis type I. CEN Case Rep. 2018;7(1):127–31. source
  • Premisecitation

    Nephropathy associated with apoE5 (Glu3Lys) alone has not yet been reported.

    “Nephropathy associated with apoE5 (Glu3Lys) alone has not yet been reported.”
    • Also stated in: § Discussion · plain
      “there are no reports of kidney disorders related to apoE5, except a few cases of LPG caused by a combination of mutations specific to LPG [4,5].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [4] Kodera H, Mizutani Y, Sugiyama S, et al. A case of lipoprotein glomerulopathy with ApoE Chicago and ApoE (Glu3Lys) treated with fenofibrate. Case Rep Nephrol Dial. 2017;7(2):112–20. source
    • cites [5] Takasaki S, Matsunaga A, Joh K, Saito T. A case of lipoprotein glomerulopathy with a rare apolipoprotein E isoform combined with neurofibromatosis type I. CEN Case Rep. 2018;7(1):127–31. source

      The Discussion (page unavailable) says that the previously reported cases of lipoprotein glomerulopathy with apoE5 (Glu3Lys) also had apoE-Chicago, while the present case also had apoE-Sendai. This supports the claim for lipoprotein glomerulopathy, but the paper does not establish the broader assertion that no nephropathy associated with apoE5 alone has been reported. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
  • Premisecitation

    The specific role of apoE5 (Glu3Lys) in LPG is unknown.

    “the specific role of apoE (Glu3Lys) is unknown.”
    • Also stated in: § Introduction · hedged
      “the causative role of apoE5 is not clear.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [4] Kodera H, Mizutani Y, Sugiyama S, et al. A case of lipoprotein glomerulopathy with ApoE Chicago and ApoE (Glu3Lys) treated with fenofibrate. Case Rep Nephrol Dial. 2017;7(2):112–20. source
    • cites [5] Takasaki S, Matsunaga A, Joh K, Saito T. A case of lipoprotein glomerulopathy with a rare apolipoprotein E isoform combined with neurofibromatosis type I. CEN Case Rep. 2018;7(1):127–31. source
  • Findingown data

    The patient had mild diabetes mellitus.

    “The patient had mild diabetes mellitus and monoclonal gammopathy of undetermined significance”
    • Also stated in: § Discussion · plain
      “The patient was previously treated for diabetes mellitus by a local practitioner, but the diabetic condition was mild, as evidenced by the relatively low blood sugar and HbA1c levels and lack of retinopathy and neuropathy.”
    Quote in the paperNot a substantial claim
  • Findingown data

    The renal biopsy specimen contained 31 glomeruli, 10 of which showed global sclerosis.

    “Light microscopic observation revealed that the specimen contained 31 glomeruli, 10 of which showed global sclerosis.”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 11
  • May combine two claims. 20

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A few cases of LPG associated with apoE5 (Glu3Lys) have been reported.

    “A few cases of LPG associated with apoE5 (Glu3Lys) have been reported”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [4] Kodera H, Mizutani Y, Sugiyama S, et al. A case of lipoprotein glomerulopathy with ApoE Chicago and ApoE (Glu3Lys) treated with fenofibrate. Case Rep Nephrol Dial. 2017;7(2):112–20. source
    • cites [5] Takasaki S, Matsunaga A, Joh K, Saito T. A case of lipoprotein glomerulopathy with a rare apolipoprotein E isoform combined with neurofibromatosis type I. CEN Case Rep. 2018;7(1):127–31. source

  • May combine two claims.

    Premisecitation

    Homozygotic E2 glomerulopathy and LPG are representative renal diseases induced by apoE mutations.

    “Homozygotic E2 glomerulopathy and LPG are representative renal diseases induced by apoE mutations, e.g., homozygous E2 (Arg158Cys) [12] and various novel heterozygous apoE variants [13], respectively.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [12] Kawanishi K, Sawada A, Ochi A, et al. Glomerulopathy with homozygous apolipoprotein E2: A report of tree cases and review of the literature. Case Rep Nephrol Urol. 2013;3:128–35. source
    • cites [13] Saito T, Matsunaga A, Oikawa S. Impact of lipoprotein glomerulopathy on the relationship between lipids and renal diseases. Am J Kidney Dis. 2006;47:199–211. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    ApoE combined with triglycerides and cholesterol forms lipoproteins and plays a central role in lipoprotein metabolism.

    “ApoE combined with triglycerides and cholesterol forms lipoproteins and plays a central role in lipoprotein metabolism [11].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [11] Tudorache IF, Trusca VG, Gafencu AV. Apolipoprotein E—a multifunctional protein with implications in various pathologies as a result of its structural features. Comput Struct Biotechnol J. 2017;15:359–65. source

      The Introduction says apoE is associated with nearly all plasma lipoprotein particles and is mainly involved in lipid metabolism. The Lipid Metabolism and Cardiovascular Disorders section says lipidation of apoE can generate HDL and describes its binding to triglyceride-rich VLDL. It does not specifically say that apoE combines with both triglycerides and cholesterol to form lipoproteins. (LLM, conf=0.80)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    The skeletal survey was negative for lytic lesions or pathological fractures.

    “The skeletal survey was negative for lytic lesions or pathological fractures.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The patient had focal segmental glomerulosclerosis (FSGS), cellular variant.

    “These findings were compatible with focal segmental glomerulosclerosis (FSGS).”
    • Also stated in: § Pathological findings · plain
      “These findings were compatible with FSGS, cellular variant (Fig. 1a-c).”
    • Also stated in: § Clinical course · plain
      “we diagnosed the patient to have FSGS with heterozygous apoE5/3.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    The patient's fasting blood glucose was 102 mg/dL and hemoglobin A1c was 6.0%.

    “fasting blood glucose 102 mg/dL; hemoglobin A1c, 6.0%”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The patient had heterozygous apoE5 (Glu3Lys) with wild-type apoE3 (apoE5/3).

    “We report a case of hyperlipidemic focal segmental glomerulosclerosis (FSGS) associated with heterozygous apoE5 (Glu3Lys) and wild-type apoE3.”
    • Also stated in: § Phenotypic, genotypic and DNA sequencing analyses of apoE · plain
      “the apoE3/5 phenotype was detected in the patient (Fig. 2a).”
    • Also stated in: § Clinical course · plain
      “we diagnosed the patient to have FSGS with heterozygous apoE5/3.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The patient had no diabetic retinopathy or neuropathy.

    “findings of diabetic retinopathy and neuropathy were lacking.”
    • Also stated in: § Discussion · plain
      “lack of retinopathy and neuropathy.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    The patient's lipid profile showed low-density lipoprotein cholesterol 208 mg/dL, triglycerides 141 mg/dL, and high-density lipoprotein cholesterol 81 mg/dL.

    “triglycerides, 141 mg/dL; low-density lipoprotein cholesterol, 208 mg/ dL; high-density lipoprotein cholesterol, 81 mg/dL.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Mild-to-moderate interstitial fibrosis with tubular atrophy and arteriosclerosis were observed.

    “mildto-moderate interstitial fibrosis with tubular atrophy, and arteriosclerosis were observed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The patient did not have type III hyperlipoproteinemia or intraglomerular lipoprotein thrombi characteristic of LPG.

    “the lipoprotein thrombus specific to LPG was not detected in any glomeruli.”
    • Also stated in: § Discussion · plain
      “Although type III hyperlipoproteinemia or intraglomerular lipoprotein thrombi for the diagnosis of LPG was not observed in this case”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Lipoprotein analysis by agarose gel electrophoresis showed a pattern consistent with type IIa hyperlipoproteinemia, with a slight elevation of the preβ band.

    “A lipoprotein analysis by agarose gel electrophoresis showed a pattern consistent with type IIa hyperlipoproteinemia, with a slight elevation of the preβ band.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    Bone marrow aspiration and biopsy revealed 3% plasma cells with normal cytogenesis.

    “Bone marrow aspiration and biopsy revealed 3% plasma cells with normal cytogenesis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Renal biopsy showed three glomeruli with segmental sclerosis, hyperplasia/hypertrophy of podocytes, and intracapillary marked infiltration of intraglomerular foam cells.

    “On renal biopsy, three glomeruli showed segmental sclerosis with hypertrophy of podocytes and intracapillary marked infiltration of intraglomerular foam cells.”
    • Also stated in: § Pathological findings · plain
      “Three glomeruli showed segmental sclerosis with hyperplasia of podocytes and intracapillary marked infiltration of intraglomerular foam cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Electron microscopy showed foam cells containing bubbled lipid droplets in the glomeruli, but no electron-dense deposits.

    “Based on electron microscopy, foam cells containing bubbled lipid droplets were observed in the glomeruli, but there were no electron-dense deposits (Fig. 1c).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The patient's serum apoE level was 5.7 mg/dL, above the normal range of 2.7-4.3 mg/dL.

    “The serum apoE level was 5.7 mg/dL (normal range 2.7-4.3 mg/dL).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    The patient had no family history of diabetes, dyslipidemia, or kidney diseases.

    “In addition, there was no family history of diabetes, dyslipidemia, or kidney diseases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Urinalysis showed protein excretion of 12.4 g/gCr and mild hematuria.

    “Urinalysis showed substantial protein excretion (12.4 g/gCr) and mild hematuria in sediments (red blood cells 5-9/hpf).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The patient had been treated for hypertension, diabetes, dyslipidemia, and hypothyroidism for 15 years.

    “He had been treated for hypertension, diabetes, dyslipidemia, and hypothyroidism for 15 years by a local practitioner”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Immunofluorescence did not identify immunoglobulins, light chains, or complements.

    “Neither immunoglobulins and light chains nor complements were identified by immunofluorescence.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Genotype ε3/3 in the patient was identified by 91- and 48-bp fragments, and other major isoforms apoE2 (Arg158Cys) and apoE4 (Cys112Arg) were excluded.

    “Genotype ε3/3 in the patient was identified by 91-and 48-bp fragments (Fig. 2b), and other major isoforms, apoE2 (Arg158Cys) and apoE4 (Cys112Arg), were excluded.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The patient had monoclonal gammopathy of undetermined significance (MGUS).

    “The patient had mild diabetes mellitus and monoclonal gammopathy of undetermined significance”
    • Also stated in: § Case report · plain
      “Based on these findings, the patient was diagnosed with monoclonal gammopathy of undetermined significance (MGUS).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Physical examination revealed pitting edema of the lower extremities.

    “Physical examination revealed no particular abnormalities, other than pitting edema of the lower extremities.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The patient's blood pressure was 184/105 mmHg.

    “blood pressure of 184/105 mmHg.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The patient had no corneal arcus or xanthoma.

    “Systemic manifestations characteristic of lipidosis, such as corneal arcus and xanthoma, were not recognized.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Previous studies have reported that apoE5 (Glu3Lys) is associated with hyperlipidemia and cardiovascular diseases.

    “Previous studies have reported that apoE5 (Glu3Lys) is associated with hyperlipidemia and cardiovascular diseases”
    • Also stated in: § Introduction · plain
      “Previous studies have shown that apoE5 (Glu3Lys) is involved in hyperlipoproteinemia and cardiovascular diseases”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Dong LM, Yamamura T, Yamamoto A. Enhanced binding activity of an apolipoprotein E mutant, APO E5, to LDL receptors on human fibroblasts. Biochem Biophys Res Commun. 1990;168:409–14. source
    • cites [3] Dong LM, Yamamura T, Tajima S, Yamamoto A. Site-directed mutagenesis of an apolipoprotein E mutant, apo E5(Glu3→Lys) and its binding to low density lipoprotein receptors. Biochem Biophys Res Commun. 1992;187:1180–6. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The apoE5 (Glu3Lys) variant, caused by substitution of lysine with glutamic acid at codon 3, has a relative frequency of approximately 0.1% in Japan.

    “The apoE5 (Glu3Lys) variant, which is caused by the substitution of lysine with glutamic acid at codon 3, has a relative frequency of 0.1% in Japan.”
    • Also stated in: § Introduction · plain
      “In Japan, an apoE5 variant caused by the substitution of lysine to glutamic acid at codon 3 has been observed, with a relative frequency of approximately 0.1% [1].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Matsunaga A, Sasaki J, Moriyama K, et al. Population frequency of apolipoprotein E5 (Glu3→Lys) and E7 (Glu244→Lys, Glu245→Lys) variants in western Japan. Clin Genet. 1995;48:93–9. source
27 of 27

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Electron microscopy is cited as the wrong Figure 1 panel

    Minor

    The pathology text cites Figure 1c for an electron-microscopy observation, whereas the figure caption identifies panel c as light microscopy and panel e as electron microscopy.

  • Direction of the apoE5 substitution is reversed

    Minor

    The abstract says lysine is replaced by glutamic acid, but the sequence description identifies the wild-type codon separately from the lysine-bearing codon, indicating a change toward lysine rather than away from it.

  • Figure 2 labels two different apoE phenotypes as the patient's

    Minor

    The text identifies the patient's phenotype as apoE3/5, but the Figure 2 caption also labels an apoE2/2 lane as belonging to the patient.

3 of 3

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Authors
Sasaki, M., Yasuno, T., Ito, K., Matsunaga, A., Hisano, S., Abe, Y., Miyake, K., Masutani, K., Nakashima, H., & Saito, T.
Affiliations
Fukuoka University (JP)
Corresponding author
Yasuno, Tetsuhiko
Venue
CEN Case Reports
Publisher
Springer Science and Business Media LLC
Published
2018-05-08
Volume
7
Issue
2
Pages
225-228
ISSN
2192-4449 (ISSN-L)
DOI
10.1007/s13730-018-0331-4
PMC
PMC6181881
OpenAlex
W2800327863
Cited by
9
References
14
Citations by year
2026: 1 · 2023: 1 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 2
FWCI
1.02
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • CEN Case Reports (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
Japan Society for the Promotion of Science (16K08955)
Topics
  • Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
  • Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
  • Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
Keywords
focal segmental glomerulosclerosis, nephrotic syndrome, dyslipidemia, lipid metabolism, podocyte hypertrophy, monoclonal gammopathy of undetermined significance, diabetes mellitus, LDL receptor binding
MeSH terms
Apolipoproteins E, Foam Cells, Glomerulosclerosis, Focal Segmental, Heterozygote, Humans, Hypertrophy, Kidney, Kidney Glomerulus, Male, Middle Aged, Monoclonal Gammopathy of Undetermined Significance, Nephrotic Syndrome, Phenotype, Sclerosis, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Asian People, Podocytes, Angiotensin Receptor Antagonists

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