Herein, we report the case of a patient with LPG with markedly increased arterial stiffness at the time of diagnosis, in whom combination therapy with fenofibrate and losartan successfully improved both proteinuria and arterial stiffness. To the best of our knowledge, this is the first case report of LPG in which the CVD risk was assessed using arterial stiffness.

LPG is histologically characterized by dilated glomerular capillaries with lamellated lipoprotein thrombi that lack foam cells [2, 3]. In the present case, the glomerular lesions, such as dilated capillary lumens with lipoprotein thrombi showed a laminated appearance without foamy macrophage infiltration and membranous nephropathy-like lesions. These findings were consistent with the known histologic features of LPG among ApoE-related glomerular diseases. Subsequent phenotype analysis by IEP, genotype analysis, DNA sequencing, and proteomics by LC–MS/MS revealed that the patient harbored a heterozygous ApoE-Sendai mutation.

No standard treatment regimen has been established for patients with LPG. However, LPG is typically associated with type III hyperlipidemia, and hypertriglyceridemia exacerbates LPG in humans and animal models [3]. Although different types of ApoE mutations have been reported [3], the efficacy of lipid-lowering agents, including fibrates, has been evaluated for each type of LPG mutation. Ieiri et al. reported a case of LPG with heterozygous ApoE Sendai mutation in which proteinuria was not detected 11 months after the initiation of a combined intensive lipid-lowering therapy comprising fenofibrate (300 mg/day), niceritrol (750 mg/day), ethyl-icosapentate (1800 mg/day), and probucol (500 mg/day) [14]. Arai et al. reported a marked improvement in nephrotic syndrome and disappearance of intraglomerular lipoprotein thrombi after two years of treatment with bezafibrate (400 mg/day) after switching from one year of pravastatin in a patient with LPG with a heterozygous ApoE2 Kyoto mutation [15]. Furthermore, Kinomura et al. reported the case of a patient with LPG with a heterozygous ApoE Okayama mutation whose proteinuria remarkably reduced within six weeks of commencing combined intensive lipid-lowering therapy with bezafibrate (400 mg/day) and ethylicosapentate (1800 mg/day) after substituting one month of pravastatin therapy [16]. As mentioned above, various therapeutic regimens, including fibrates, improve both clinical manifestations and histopathological lesions [14, 15]; therefore, fibrates are considered to play a central role in the treatment of LPG. Thus, treatment with fenofibrate and losartan was initiated in our case to improve the lipid abnormalities and reduce proteinuria. Shortly after initiation (three months later), improvements in TG and RLP-C levels along with a significant reduction in proteinuria were achieved. Moreover, these effects were maintained despite the lack of a decrease in serum ApoE levels (Fig. 3). The mechanisms responsible for the marked reduction in proteinuria in patients with LPG are currently unknown; however, the reduction in blood very-low-density lipoprotein levels by acting on the peroxisomal proliferator-activated receptor and activating lipoprotein lipase by fenofibrate [5], resulting in the reduction in renal lipid accumulation can be contemplated to be the primary mechanism. Furthermore, once the lipoprotein thrombi are reduced with fenofibrate, the antiproteinuric effect of losartan can be more effective.

Recently, the clinical course of his younger brother, an identical twin in this case, was reported [17]. The same ApoE mutation was observed in both cases. However, in contrast to the younger brother, the proteinuria was milder, and no vacuolated areas in the peritubular capillaries of the tubulointerstitium were observed in our case. Differences in serum ApoE levels at the time of kidney biopsy and/or in the non-genetic pathogenic mechanisms involved may underlie the differences in clinical and histopathological findings between the two cases.

Nevertheless, at the time of kidney biopsy, a marked increase in baPWV for his age was observed (14.3 m/s, equivalent to that of a 56-year-old man) (Fig. 3). However, to the best of our knowledge, there are no reports on the relationship between LPG and CVD risk, as assessed by arterial stiffness. Therefore, it may be difficult to discuss this issue from the perspective of ApoE mutation alone.

Arterial stiffness has been recognized as an indicator of arteriosclerosis and a predictor of cardiovascular events [9, 10]. Factors that increase arterial stiffness include age, BP, heart rate, diabetes mellitus, lipid metabolism, smoking, uric acid (UA) level, obesity, inflammation, and oxidative stress [9, 10]. In contrast to CAVI, baPWV is influenced by the BP at the time of measurement; however, our patient’s BP was normal at initial baPWV assessment, even without antihypertensive medication. Therefore, in our case, the factors responsible for markedly increased arterial stiffness may have been factors other than BP. Furthermore, the patient had never smoked, and his blood glucose, UA levels and BMI were within normal ranges. Therefore, the following mechanisms are considered to potentially underlie the markedly increased arterial stiffness observed at the time of kidney biopsy.

First, among the risk factors for baPWV [9], dyslipidemia may have contributed to the markedly increased baPWV at the time of kidney biopsy. In the context of lipid profile and its effects on baPWV, some studies have reported an association between serum TG levels rather than serum cholesterol levels and baPWV [9]. In addition, serum TG levels were an independent predictor of endothelial function [18], and Ryan et al. reported that fenofibrate reduced inflammation, improved markers of endothelial function and reduced arterial stiffness [19]. In our case, in addition to LDL, TG and RLP-C levels were higher at the time of kidney biopsy. Although the patient had no apparent history of dyslipidemia and his TG and RLP-C levels were not extremely high, after initiation of fenofibrate, baPWV improved with a decrease in TG and RLP-C, suggesting close involvement of hyperlipidemia in his markedly increased baPWV for his age at the time of kidney biopsy.

Second, the presence of the ApoE ε4 allele, which our patient carried, may be another factor contributing to his dyslipidemia and markedly increased arterial stiffness. Numerous studies have reported the relationship between ApoE genotype and CVD. The ApoE ε4 allele has specifically been associated with CVD risk [20]. The mechanisms underlying the associations between ApoE genotypes and CVD events are considered to include the variations in serum lipid concentration and inflammatory responses to different ApoE alleles [21]. As for ApoE genotype and plasma levels of major lipids, both ε2 and ε4 alleles are associated with unfavorable lipid profiles [22]. In the context of inflammation-related mechanisms, ApoE ε4 carriers reportedly have significantly lower and ApoE ε2 carriers have significantly higher levels of C-reactive protein than ApoE ε3/ε3 carriers [23]. Contrastingly, Gungor et al. reported significantly higher levels of lipoprotein-associated phospholipase A2 index, a vascular inflammation marker, in Apo E4 isoform carriers [24]. In addition, Tziakas et al. reported that ApoE ε4 carriers had lower levels of atheroprotective IL-10 [25]. These findings may support the possibility in patient carrying the ApoE ε4 allele that the net effect of the underlying disease status may contribute to future CVD via advanced arterial stiffness. The present case suggests that the CVD risk in patients with LPG can be reduced by therapeutic intervention, including the use of fenofibrate.

In conclusion, we describe the first case of LPG with markedly increased arterial stiffness at the time of diagnosis, in whom combination therapy with fenofibrate and losartan successfully improved both proteinuria and arterial stiffness. However, the significance of arterial stiffness and response to treatment in patients with LPG may vary according to the ApoE variant, and further case studies are needed.