Nephropathy associated with the E3/E4 allelic variant of the APOE gene. Case 1

Apolipoprotein E (APOE) gene encoding apolipoprotein E is located on chromosome 19 (19q13.2). APOE is the main component of chylomicrons and lipoproteins of low and very low density, eliminated by the liver. APOE gene abnormalities lead to impairment of binding of lipoproteins to hepatocyte receptors, which cause the delay or blockade of the lipoproteins clearance and, as a result, increase of their plasma concentration [1]. Three isoforms (alleles/exons) of the APOE gene include E2, E3 and E4. Exon E3 is the most frequent (75%) and "neutral". Exon E2 is the rarest (5%). Above mentioned impairment of lipoprotein receptor binding associated mainly with exons E2 and E4 variants. Patients with homozygous allelic variants - E2/E2, E4/E4 - experience most severe manifestations [2,3]. Heterozygous allelic variants of the APOE gene with different combinations of exons E2, E3, E4 lead to lipid metabolism disorders with various severity and prognosis [4, 5]. Kidney tissue damage in patients with the APOE gene breakage is a rare condition, merging a group of nephropathies of different clinical and histological severity. The main feature of this nephropahies is the accumulation of lipoproteins in the kidney tissue, primarily in the glomeruli [6]. Patient G., 28-year-old. Family history is significant for stroke, diabetes, and malignancies in grandparents; patient’s father had morbid obesity and died early, and younger sister, 24-year-old, developed proteinuria up to 1.5 g/24 h at age of 18 years. Our patient was discovered with proteinuria in 2013. In 2018, his proteinuria increased up to 2.0 g/L, and was accompanied by moderate azotemia. Kidney biopsy was performed in 2019. At the time of biopsy, his BP was 130/90 mm Hg, and his body mass index was normal, serum creatinine was 370 μmol/L, and proteinuria was 16.0 g/24h, without edema or biochemical criteria of nephrotic syndrome. Histological examination revealed metabolic nephropathy with marked glomerulomegaly and extensive secondary segmental glomerulosclerosis, with mesangial and endocapillary lipid accumulation, with moderate tubulointerstitial fibrosis and moderate arteriolosclerosis ( Fig. 1). In addition, clinically quiescent moderate mesangial IgA-deposits were identified ( Fig. 2). Based on the pathology findings, genetic testing for the APOE gene was strongly recommended, and the APOE-E3/E4 gene polymorphism was confirmed. By February 2021, chronic kidney disease progressed to the Stage 5 with serum creatinine 736 µmol/L and eGFR 5 mL/min. Initiation of hemodialysis was advised, however the patient refused this option of kidney replacement therapy. March 2022 kidney transplantation from the relative donor (patient’s mother) was performed. The APOE gene has not been investigated in the mother or other family members. Thus, we report here the case, belonging to a rare group of genetically determined lipid metabolism disorders, associated with a breakage in the APOE gene. This metabolic disorder lead to chronic kidney disease, which progressed towards kidney failure and required kidney replacement therapy. Informed patient consent for publication of clinical information and images was obtained.

аполипопротеин E, дислипидемия, протеинурия, клиническое наблюдение, apolipoprotein E, dyslipidemia, proteinuria

1. Saito T.: Abnormal lipid metabolism and renal disorders. Tohoku J Exp Med. 1997. 181(3):321-37. doi: 10.1620/tjem.181.321

2. Ellis D., Orchard T.J., Lombardozzi S. et al: Atypical hyperlipidemia and nephropathy associated with apolipoprotein E homozygosity. J Am Soc Nephrol. 1995. 6(4):1170-7. doi: 10.1681/ASN.V641170

3. Balson K.R., Niall J.F., Best J.D.: Glomerular lipid deposition and proteinuria in a patient with familial dysbetalipoproteinemia. J Intern Med. 1996. 240(3):157-9. doi: 10.1046/j.1365-2796.1996.501855000.x

4. Eichner J.E., Dunn S.T., Perveen G. et al: Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. Am J Epidemiol. 2002. 155(6):487-95. doi: 10.1093/aje/155.6.487

5. Zhou T., Li H., Zhong H. et al: Association of apoE gene polymorphisms with lipid metabolism in renal diseases. Afri Health Sci. 2020. 20(3):1368-1381. doi: 10.4314/ahs.v20i3.43

6. Liberopoulos E., Siamopoulos K., Elisaf M.: Apolipoprotein E and renal disease. Am J Kidney Dis. 2004. 43(2):223-33. doi: 10.1053/j.ajkd.2003.10.013