A case of apolipoprotein E Toyonaka and homozygous apolipoprotein E2/2 showing non-immune membranous nephropathy-like glomerular lesions with foamy changes

Abstract

A 47-year-old Japanese man with mild proteinuria was treated with an ACE inhibitor and antiplatelet agent for 7 years. However, urinary protein levels increased and renal biopsy was performed. Eight out of 20 glomeruli showed global or segmental sclerosis with foamy changes or bubbles, but with a different appearance to typical foam cells or lipoprotein thrombi. "Spike" formation, as observed in membranous nephropathy (MN), was segmentally detected in methenamine silver-stained sections.In an immunofluorescence study, weak linear patterns for IgG and scanty deposits for C3 were observed in glomeruli, but were not specific for immunogenetic MN. An electron microscopy study showed highly dense deposits in the subepithelial, subendothelial, and mesangial areas, in which microbubbles appeared under a higher magnification. Since this case exhibited hypertriglyceridemia and cholesterolemia with high serum apolipoprotein E (apoE) clinically and homozygous apoE2/2 by apoE phenotype and genotype analyses, apoE2 homozygote glomerulopathy was diagnosed and various lipid-lowering agents, e.g., probucol, fenofibrate, and ezetimibe, were administered. However, renal dysfunction gradually developed and peritoneal dialysis was initiated 11 years after the diagnosis. ApoE Toyonaka (Ser197Cys) and homozygous E2/2 were recently identified by direct DNA sequencing. Therefore, non-immune MN-like lesions may develop with the combination of these apoE mutations.

APOE gene variants in primary dyslipidemia

“…Seventeen variants in the APOE gene have been reported in lipoprotein glomerulopathy (LPG) (Table 1). Several variants were reported in single cases with various disease expression from the p.Arg132Cys in a normolipidemic patient with normal levels of apoE [77] to the p.Ser215Cys-E2/E2 in a type III hyperlipidaemic patient [78]. Four variants -p.Arg43Cys, p. Lys161_Arg165del, p.Arg168Cys, p.Arg168Pro -were reported in families with a dominant transmission and a reduced penetrance [79][80][81][82].…”

Apolipoprotein E–related glomerular disorders

“…Immunoglobulin and complement depositions were not specifically obsereved in immunofluorescence studies. Unlike the case reported by Fukunaga et al, 44 foam cells characteristic of apoE2 homozygote glomerulopathy and non-lamellated lipoprotein thrombi as reported by Sakatsume et al 20 were conspicuous in the cases reported by Hirashima et al 45 and Kato et al, 46 respectively. Therefore, in carriers exhibiting both apoE2 homozygote and apoE Toyonaka, the balance of non-immune MN-like lesions and apoE2 homozygote glomerulopathy may be dependent upon the influence of apoE Toyonaka within the hinge region.…”

“…21 Membranous nephropathy-like apoE deposition disease (MN-like apoE disease). Recently, a new glomerular disease was identified in non-consanguineous carriers possessing the combination of apoE Toyonaka (Ser197Cys), a novel mutation, and apoE2 homozygote [44][45][46] (Figure 1). The first case reported by Fukunaga et al 44 was a 20-year-old female Japanese patient who underwent renal biopsy because she was found to have chance proteinuria and hematuria.…”

“…[48][49][50] When apoE Toyonaka is involved in hinge damage, type III HLP induced by defective binding to the LDL receptor in the N-terminal domain of the apoE2 homozygote may be negated due to the dysfunction of the C-terminal domain that connects with lipids. In contrast, altered apoE without lipids may accumulate within the glomerulus and induce EDD in the subepithelial region, as the apoE molecule is relatively small (34 kDa) and rich in arginine, a positively-charged amino acid 4 The other 2 cases exhibiting apoE Toyonaka and apo E2 homozygosity 45,46 were of type III HLP with marked hypertriglyceridemia, which was different from the case presented by Fukunaga et al 44 The serum apoE levels, however, were high in all 3 cases. Spike formations were recognized by light microscopy, and subepithelial and subendothelial EDDs including microbubbles were both observed by electron microscopy.…”

The Roles of Fatty Acids and Apolipoproteins in the Kidneys

“…In addition, ApoE2 homozygotes show glomerulopathy and lipoprotein thrombi [ 168 ]. ApoE2 has been associated with diabetic nephropathy with abnormal lipid metabolism.…”