Hyperlipoproteinemia Type V

Glomerular lipidosis is a rare histological feature presenting the extensive glomerular accumulation of lipids with or without histiocytic infiltration, which develops under various conditions. Among its various etiologies, macrophage activation syndrome (MAS) is a condition reported to be associated with histiocytic glomerular lipidosis. Here we describe the first case of glomerular lipidosis observed in a renal allograft that histologically mimicked histiocytic glomerulopathy owing to MAS.

A 42-year-old man underwent successful living-donor kidney transplantation. However, middle-grade proteinuria and increased serum triglyceride levels indicative of type V hyperlipidemia developed rapidly thereafter. An allograft biopsy performed 6 months after the transplantation showed extensive glomerular infiltration of CD68⁺ foam cells (histiocytes) intermingled with many CD3⁺ T-cells (predominantly CD8⁺ cells). Furthermore, frequent contact between glomerular T-cells and histiocytes, and the existence of activated CD8⁺ cells (CD8⁺, HLA-DR⁺ cells) were observed by double immunostaining. There was no clinicopathological data suggesting lipoprotein glomerulopathy or lecithin cholesterol acyltransferase deficiency, both of which are well-known causes of glomerular lipidosis. The histological findings were relatively similar to those of histiocytic glomerulopathy caused by MAS. As systemic manifestations of MAS, such as fever, pancytopenia, coagulation abnormalities, hyperferritinemia, increased liver enzyme levels, hepatosplenomegaly, and lymphadenopathy were minimal, this patient was clinicopathologically diagnosed as having renal-limited MAS. Although optimal treatment strategies for MAS in kidney transplant patients remains unclear, we strengthened lipid-lowering therapy using pemafibrate, without modifying the amount of immunosuppressants. Serum triglyceride levels were normalized with this treatment; however, the patient's extensive proteinuria and renal dysfunction did not improve. Biopsy analysis at 1 year after the transplantation demonstrated the disappearance of glomerular foamy changes, but the number of glomerular infiltrating cells remained similar.

To our knowledge, this is the first reported case of glomerular lipidosis in a transplanted kidney. Increased interaction-activation of histiocytes (macrophages) and CD8⁺ T-cells, the key pathogenic feature of MAS, was observed in the glomeruli of this patient, who did not demonstrate overt systemic manifestations, suggesting a pathological condition of renal-limited MAS. The clinical effects of triglyceride-lowering therapy were limited, suggesting that hypertriglyceridemia was not the cause of but rather may be a consequence of renal-limited MAS.

Hypertriglyceridemia (HTG) remains a risk-enhancing factor of atherosclerotic cardiovascular disease. We aimed to report real-world data on the management of patients with type V hyperlipoproteinemia (HLP5), an uncommon phenotype of dyslipidemia characterized by fasting chylomicronemia and severe HTG. Between July 2018 and May 2021, 90 patients with HTG, including 83 patients with type IV hyperlipoproteinemia (HLP4) and 7 patients with HLP5, were identified by plasma apolipoprotein B (apoB) and lipoprotein electrophoresis. Patients with HLP5 were younger, had higher total cholesterol (TC) (264.9 ± 26.7 mg/dL vs. 183.9 ± 26.1 mg/dL; p < 0.01) and higher triglyceride (TG) (1296.7 ± 380.5 mg/dL vs. 247.6 ± 96.1 mg/dL; p < 0.01), and had lower high-density lipoprotein cholesterol (HDL-C) (30.6 ± 4.8 mg/dL vs. 40.5 ± 8.7 mg/dL; p < 0.01) and lower low-density lipoprotein cholesterol (LDL-C) (62.9 ± 16.4 vs. 103.0 ± 21.1 mg/dL; p < 0.01) compared with patients with HLP4. Despite an aggressive use of statin and fenofibrate with greater reductions in TG (-65.9 ± 13.7% vs. -27.9 ± 30.5%; p < 0.01) following 6 months of treatment, patients with HLP5 had persistent HTG (440.1 ± 239.0 mg/dL vs. 173.9 ± 94.8 mg/dL; p < 0.01) and an increase in LDL-C (28.3 ± 57.2% vs. -19.5 ± 32.0%; p < 0.01) compared with patients with HLP4. Our findings highlight that the lack of novel TG-lowering medications and management guidelines remains an unmet medical need in patients with HLP5. Closely monitoring lipid profiles, full assessment of individual's risk of cardiovascular disease, and emphasis on medication adherence are of clinical importance.

Hypertriglyceridemia is caused not only by environmental factors but also by genetic factors. Severe hypertriglyceridemia is prone to complications of acute pancreatitis. Here, we report a whole-exome sequencing (WES) analysis for a young hypertriglyceridemic patient with recurrent acute pancreatitis and the patient's mother. A 28-year-old hypertriglyceridemic female was admitted to our hospital. At 23 years old, a health checkup clarified her hypertriglyceridemia. At the age of 26 and 27, she had repeated acute pancreatitis with severe hypertriglyceridemia (serum triglyceride level were 3,888 mg/dL and 12,080 mg/dL, respectively). The patient's BMI was 29.0 kg/m², and blood samples under fibrate medication showed triglyceride 451 mg/dL and HbA1c 7.2%. Type V dyslipidemia became more apparent at postprandial state. The WES analysis showed that the patients had two heterozygous variants in Apolipoprotein A5 (APOA5) gene (p.G185C and p.V153M), a heterozygous variant in Apolipoprotein E (APOE) gene (p.R176C), three heterozygous variants in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene (p.T1220I, p.R1453W and p.V470M). On the other hand, her mother, who had moderate hypertriglyceridemia without acute pancreatitis, had a heterozygous variant in APOA5 gene (p.G185C) and two heterozygous variants in CFTR gene (p.T1220I and p.V470M). These results suggest that the more severe pathology of the patient than her mother might be due to the possible compound heterozygous APOA5 variants, the heterozygous APOE variant, and the possible compound heterozygous CFTR variants. In this case, WES analyses were useful to evaluate not only the causative genes of hypertriglyceridemia (APOA5 and APOE) but also the genes involved in the development of acute pancreatitis (CFTR) simultaneously.