Glomerulopathy with homozygous apolipoprotein e2: a report of three cases and review of the literature
Open accessAbstract
Most cases of type III hyperlipoproteinemia are accounted for by apolipoprotein E2 (apoE2) homozygotes, a genetic mutation of apoE (Arg158Cys). Glomerulopathy with homozygous apoE2 is rare and characterized by marked foam cell infiltration in the glomerular capillaries and mesangium. Here, we report 3 cases of apoE2 homozygote glomerulopathy diagnosed by renal biopsy and DNA analysis. All 3 cases were middle-aged or elderly males complicated with diabetes for at least a decade. The kidney biopsies showed massive foam cell infiltration in the glomerular capillaries and expanded mesangium accompanied by histological findings of diabetic glomerulosclerosis. The lipid profiles showed type III hyperlipoproteinemia and phenotypic/genetic analyses revealed homozygosity of apoE 2. Two of the cases showed nephrotic proteinuria and progressed to renal failure in 3 and 8 years after the diagnosis of kidney disease.
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Very rare cases of glomerulopathy, different from LPG because they are characterized by marked glomerular foam cell infiltration, have been reported in homozygotes for the apoE2 isoform and in most cases have been associated with type III hyperlipoproteinemia.
“Very rare cases of glomerulopathy, which are different from that of LPG, because they are characterized by marked glomerular foam cell infiltration, have been reported in homozygotes for the apoE2 isoform and, in most of the cases, have been associated with type III hyperlipoproteinemia (41,42).”
From Thermodynamic destabilization and aggregation propensity as the mechanism behind the association of apoE3 mutants and lipoprotein glomerulopathy (2018) · cites this paper as [42]
The Introduction and Discussion describe apoE2-homozygote glomerulopathy as very rare and distinguish its marked glomerular foam-cell infiltration from LPG. The Abstract reports type III hyperlipoproteinemia in all three new cases, but the passages do not establish that it was present in most of the previously reported cases. No page numbers are available in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredApoE2 is not expected to lead to LPG, explaining the distinct-to-LPG phenotype of glomerulopathy rarely reported in apoE2 homozygotes.
“Therefore, apoE2 is not expected to lead to LPG, explaining the distinct-to-LPG phenotype of glomerulopathy rarely reported to apoE2 homozygotes (41,42).”
From Thermodynamic destabilization and aggregation propensity as the mechanism behind the association of apoE3 mutants and lipoprotein glomerulopathy (2018) · cites this paper as [42]
The Introduction and Discussion describe apoE2 homozygote glomerulopathy as rare and histologically distinct from LPG. But the Discussion also reports LPG lesions in patients with an apoE2 homozygote phenotype and suggests apoE2 homozygosity may contribute to LPG; it does not support ruling out an LPG role for apoE2. (LLM, conf=0.86)
Experimental — accuracy not yet measuredLPG 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]”
From Membranous Nephropathy-Like Apolipoprotein E Deposition Disease with Apolipoprotein E Toyonaka (Ser197Cys) and a Homozygous Apolipoprotein E2/2 (2018) · cites this paper as [5]
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 measuredHomozygotic 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.”
From Focal segmental glomerulosclerosis with heterozygous apolipoprotein E5 (Glu3Lys) (2018) · cites this paper as [12]
Several cases are reported to have glomerular lesions called ApoE2 homozygote glomerulopathy, characterized by foam cell infiltration and different from LPG.
“Additionally, several cases are reported to have glomerular lesions as called ApoE2 homozygote glomerulopathy, which is characterized by foam cell infiltration and different from LPG [16].”
From A case report of youth-onset lipoprotein glomerulopathy with APOE Chicago mutation (2024) · cites this paper as [16]
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 [98]
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 [98]
The Introduction and Case Reports describe three patients with homozygous apoE2 (Arg158Cys), not first and fourth reported cases of APOE Toyonaka. I searched for Toyonaka and nonimmune membranous nephropathy-like features, but our copy does not address those cases; findings from its different patients cannot verify or contradict the claim about them. (LLM, conf=0.76)
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Research works printed but not linked: 17
- [1]Mahley RW Huang Y Rall SC Pathogenesis of type III hyperlipoproteinemia (dysbetalipoproteinemia). Questions, quandaries, and paradoxes J Lipid Res 1999 40 1933 1949 10552997
- [2]Eto M Saito M Nakata H Iwashima Y Watanabe K Ikoda A Kaku K Type III hyperlipoproteinema with apolipoprotein E2/2 genotype in Japan Clin Genet 2002 61 416 422 12121348
- [3]Henneman P van der Sman-de Beer F Moghaddam PH Huijts P Stalenhoef AF Kastelein JJ van Duijn CM Havekes LM Frants RR van Dijk KW Smelt AH The expression of type III hyperlipoproteinemia: involvement of lipolysis genes Eur J Hum Genet 2009 17 620 628 19034316 PMC2986263
- [4]McKenzie IF Kincaid-Smith P Foam cells in the renal glomerulus J Pathol 1969 97 151 154 5783631
- [5]Amatruda JM Margolis S Hutchins GM Type 3 hyperlipoproteinemia with mesangial foam cells in renal glomeruli Arch Pathol 1974 98 51 54 4829776
- [6]Suzaki K Kobori S Ueno S Effects of plasmapheresis on familial type III hyperlipoproteinemia associated with glomerular lipidosis, nephrotic syndrome and diabetes mellitus Atherosclerosis 1990 80 181 189 2310424
- [7]Ongkingco JR Mann WA Ruley EJ Gregg RE Severe hyperlipidemia due to multiple factors in a child with nephrotic syndrome Child Nephrol Urol 1991 11 107 110 1756519
- [8]Ellis D Orchard TJ Lombardozzi S Yunis EJ McCauley J Agostini R Diamond JR Atypical hyperlipidemia and nephropathy associated with apolipoprotein E homozygosity J Am Soc Nephrol 1995 6 1170 1177 8589283
- [9]Balson KR Niall JF Best JD Glomerular lipid deposition and proteinuria in a patient with familial dysbetalipoproteinaemia J Intern Med 1996 240 157 159 8862125
- [10]Joven J Vilella E The influence of apoprotein epsilon 2 homozygosity on nephrotic hyperlipidemia Clin Nephrol 1997 48 141 145 9342484
- [11]Sakatsume M Kadomura M Sakata I Imai N Kondo D Osawa Y Shimada H Ueno M Miida T Nishi S Arakawa M Gejyo F Novel glomerular lipoprotein deposits associated with apolipoprotein E2 homozygosity Kidney Int 2001 59 1911 1918 11318963
- [12]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 16431249
- [13]Amenomori M Haneda M Morikawa J Nishigaki I Maeda S Hidaka H Kikkawa R Shigeta Y A case of lipoprotein glomerulopathy successfully treated with probucol Nephron 1994 67 109 113 8052351
- [14]Zhao YY Weir MA Manno M Cordy P Gomes T Hackam DG Juurlink DN Mamdani M Moist L Parikh CR Paterson JM Wald R Yao Z Garg AX New fibrate use and acute renal outcomes in elderly adults: a population-based study Ann Intern Med 2012 156 560 569 22508733
- [15]Kinomura M Sugiyama H Saito T Matsunaga A Sada KE Kanzaki M Takazawa Y Maeshima Y Yanai H Makino H A novel variant apolipoprotein E Okayama in a patient with lipoprotein glomerulopathy Nephrol Dial Transplant 2008 23 751 756 18045818
- [16]Cautero N Di Benedetto F De Ruvo N Novel genetic mutation in apolipoprotein E2 homozygosis and its implication in organ donation: a case report Transplant Proc 2010 42 1349 1351 20534298
- [17]Araki S Koya D Makiishi T Sugimoto T Isono M Kikkawa R Kashiwagi A Haneda M APOE polymorphism and the progression of diabetic nephropathy in Japanese subjects with type 2 diabetes: results of a prospective observational follow-up study Diabetes Care 2003 26 2416 2420 12882872
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A case report of youth-onset lipoprotein glomerulopathy with APOE Chicago mutation
Liu, Y., Cheng, Y., Wen, Y., Li, C., Chen, G., & Li, M. (2024) · BMC Nephrology · doi:10.1186/s12882-024-03515-z · Cited by 2 · see citing works
- Authors
- Kawanishi, K., Sawada, A., Ochi, A., Moriyama, T., Mitobe, M., Mochizuki, T., Honda, K., Oda, H., Nishikawa, T., & Nitta, K.
- Affiliations
- Tokyo Women's Medical University (JP)
- Corresponding author
- Kawanishi, Kunio
- ORCID
- Venue
- Case Reports in Nephrology and Dialysis
- Publisher
- S. Karger AG
- Published
- 2013-11-28
- Volume
- 3
- Issue
- 2
- Pages
- 128-135
- ISSN
- 2296-9705 (ISSN-L)
- PMC
- PMC3924710
- OpenAlex
- W2025286502
- Cited by
- 19
- References
- 0
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 2 · 2022: 1 · 2021: 2 · 2019: 2 · 2018: 4 · 2017: 1 · 2015: 2
- FWCI
- 0.51
- Type
- journal article
- Language
- en
- Open access
- hybrid
- 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)
- Topics
- Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- glomerular disease, apolipoprotein E2, type III hyperlipoproteinemia, diabetic glomerulosclerosis, nephrotic-range proteinuria, renal failure, diabetes mellitus, renal biopsy, genetic mutations
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