4. Discussion

The present study discovered that a higher intake of water-soluble vitamins and fat-soluble vitamins, especially niacin, vitamin C, and α-tocopherol, was independently associated with lower CKD tendency in the Japanese population minor homozygote of rs883484 located upstream of PTGS1 gene. In contrast, the participants with the C allele showed no significant effect of vitamins on CKD status. In addition, the association between the intake of fat-soluble vitamins (except for α-tocopherol), vitamin B2, and vitamin B12 and kidney function was not observed in both groups of rs883484 genotypes. Unexpectedly, the salt intake in the CKD group was lower than that in the non-CKD group. Hence, the effect of elevated blood pressure by consuming salt on CKD might be excluded.

The present results for vitamins intake are consistent with previous studies indicating the protective effect of dietary vitamins intake and CKD. Vitamin C, niacin, and α-tocopherol significantly affected CKD status. Moreover, the lower intake of vitamins B1, B6, pantothenic acid, and folate were borderline significantly associated with higher CKD prevalence. Niacin (nicotinic acid, vitamin B3) is the oldest drug to treat dyslipidemia [27,28] and hyperphosphatemia [29]. Niacin reduces serum phosphorus levels and oxidative stress, including inflammation and endothelial dysfunction, and improves the CKD outcome [30]. Vitamin C is vital for many biological functions and attenuates reactive oxygen species, and renal oxidative damage preserves hydroxylase and monooxygenase enzymes and endothelium and vascular function in renal injury patients [31]. However, vitamin C deficiency is common among CKD patients due to dialytic vitamin C clearance, high vitamin C food restriction, and escalated vitamin C catabolism in vivo from inflammation [14,15]. α-Tocopherol, which belonged to the vitamin E group, was inversely associated with CKD in middle-aged and older-aged Japanese women [26]. The intake of vitamins C and E alone or in combination lessened kidney function damage, renal injury, and arterial pressure in rats with salt-sensitive hypertension [32]. Even though vitamins have been reported to be protective against CKD because of their antioxidant and anti-inflammatory [14], the results were not statistically significant [27].

In the CC + CT group, the intake of vitamins did not alter the outcome of CKD, while in the TT group, it drastically changed the CKD status. Yoshida et al. showed that the rs883484 (C/T) located upstream of the PTGS1 gene was associated with CKD in the general population [12] and individuals with metabolic syndrome [10] as well as hypertension [11] patients. The SNP is located in the 5′ flanking region [8], which contains the promoter and may contain enhancers or other protein binding sites. Polymorphisms in this region can induce changes in the regulation of transcription. Helmersson et al. displayed that the TT genotype of rs883484 was associated with the increased formation of PGF2α, a product of COX [8]. PTGS1 gene encodes COX-1, which synthesizes PG and thromboxane (Tx), which leads to inflammatory damage to the kidney [33]; thus, the COX pathway might be the mechanism for developing CKD in the case of TT genotype for rs883484. The previous findings suggested that the minor homozygote (TT genotype) of rs883484 increased the PTGS1 gene expression and the amount of COX-1, which worsened renal function. COX-1 is the primary target of nonsteroidal anti-inflammatory drugs (NSAIDs). Inhibition of PGs by pharmacological medicine enhances immunocompetence in animals and humans. Likewise, the supplement of vitamins has a similar effect on PGs. Vitamins C and E inhibited PGE2 production by human gingival fibroblasts and SCC-25 oral squamous carcinoma cells [34]. Plasma PGE2 concentrations decreased in men and women after 14 days of using vitamin C-rich vegetable soup [35]. Niacin regulates PGF2α [36], PGE2 [37], and PGD2 [38] through COX-1 and COX-2. Because of the enhanced expression of COX-1, individuals with TT genotype of rs883484 might become more sensitive to the antioxidant and anti-inflammatory effects of vitamins. Thus, the TT genotype of rs883484 seemed to be more susceptible to dietary intake of vitamins against kidney failure.

This study has several limitations. First, this cross-sectional study cannot establish a causal relationship, which means we cannot determine that the dietary intake of antioxidant vitamins can prevent CKD development in the general population with minor homozygotes of rs883484. Second, the estimated GFR was used instead of directly measured GFR to define CKD. Third, the self-administered dietary history questionnaire (BDHQ) cannot accurately determine the nutrition intake due to a limited number of food and beverage items. Moreover, there is a lack of objective markers of daily vitamin intake and energy intake.