Introduction
Vitamin D is a group of fat-soluble steroids, which are essential for intestinal calcium absorption and for metabolic regulation of calcium and phosphates [
1]. Vitamin D is either synthesized in the skin (vitamin D
3) or ingested in the diet (vitamin D
2) and is transported to the liver, where vitamin D 25-hydroxylase mediates D
2/D
3 to change into 25-hydroxyvitamin D (25(OH)D). 25(OH)D is the main storage form of vitamin D, which is a quantifiable form mostly used to determine vitamin D level in serum. The main physiologic function of vitamin D is to ensure adequate mineralization and bone growth [
2]. The influence of vitamin D on the immune system is one of its another most important roles. Recent evidence show that vitamin D plays important role in metabolic syndrome (MetS), cardiovascular disease (CVD) [
3], diabetes mellitus [
4], and inflammation [
5]. Prior studies have shown that 25(OH)D is negatively associated with markers of inflammation (interleukin [IL]-6, IL-10, high sensitivity C-reactive protein [hsCRP]) [
6,
7]. Olsziwiec-Chlebna et al. reported that both the analogues of VitD (cholecalciferol and calcitriol) suppressed the proinflammatory cytokines (IL-17A and IL-23) in the airway of patients with Cystic Fibrosis [
8]. However, an increasing number of authorities believed that chronic inflammation could lead to low 25(OH)D conversely [
9]. Robert L. Modlin et al. found that cytokines, interferon-gamma and IL-4, stimulated conversion and catabolism of 25(OH)D respectively, resulting in low 25(OH)D in human monocytes [
9,
10]. Another study showed that the extra-renal conversion of 25(OH)D by cytokines (TNF-α, IL-1, IL-2, IFN-γ, etc.) could result in depletion and low levels of 25(OH)D [
10].
Chronic kidney disease (CKD) is a progressive loss of kidney function over time. The pathophysiological process of CKD is characterized by low-grade chronic inflammation [
11]. Inflammation, together with coagulation disorders and neutrophil-endothelium interaction, are believed to play a role in the development of kidney injury, which may lead to chronically impaired function [
12]. Compared to the healthy population, patients with CKD present more severe vitamin D deficiency and insufficiency [
13]. Multiple observational studies have shown low levels of low 25(OH)D levels in patients with CKD and end-stage renal disease (ESRD) have been associated with a faster progression of kidney disease and a higher risk of all-cause mortality [
14‐
16]. Many factors may account for low levels of 25(OH)D in CKD patients, including the loss of vitamin D binding protein in the urine [
17], insufficient nutritonal intake, inadequate sun exposure and so on. In addition, inflammatory status might be an important factor contributing to the low low levels of 25(OH)D in CKD patients.
Diet play a central role in the regulation of chronic inflammation [
18] and thus in kidney health. Anti-inflammation nutrients are associated with better kidney function [
19,
20]. Conversely, pro-inflammation nutrients may be linked with worsening of kidney function [
21]. Until 2009, there was no tool that could take into account the entire diet and determine its inflammatory potential. Researchers from University of South Carolina have developed a dietary tool called the Dietary Inflammatory Index (DII). DII, a literature-derived and population-based scoring system, was designed by assigning a score for each dietary parameter found to positively or negatively impact concentration of six specific inflammatory biomarkers: IL-1
β, IL-4, IL-6, IL-10, TNF-
α and CRP [
22]. Forty-five pro and anti-inflammatory food parameters are included to calculate the DII score. A positive value for DII is assigned to an pro-inflammatory diet, and a negative value for DII is assigned to an anti-inflammatory diet. The higher total DII score indicate a more proinflammatory effect, and the lower total DII score suggest a more anti-inflammatory effect. The strength of the DII was that it evaluated the composite effects of multiple dietary components, rather than a single nutrient or individual food item. Recent studies have demonstrated that an increased DII not only affects the physical health of the patients such as cancer incidence [
23,
24], all-cause and caner-specific mortality [
25,
26] and respiratory conditions [
27], but also has a significant effect on mental health [
28]. Mazidi et al. has found that greater DII was associated with higher likelihood of chronic kidney disease [
29]. However, the association between the dietary inflammatory potential and 25(OH)D has not been reported before. We hypothesized that increased intake of proinflammatory diets with increased levels of IL-1 β, IL-4, IL-6, IL-10, TNF- α and CRP was associated with decreased 25(OH)D levels in CKD patients.
In the present study, we aimed to assess the effect of DII on 25(OH)D in patients with CKD. We used the data from the National Health and Nutrition Examination Survey (NHANES), and estimated the negative relationship between DII and 25(OH)D levels. In addition, we further investigated this association in subgroups stratified by renal function, gender and age.
Discussion
This cross-sectional analysis documented the association between DII and 25(OH)D in patients with CKD. Our results demonstrated that higher consumption of pro-inflammatory diet leaded to lower 25(OH)D in CKD patients, even after adjustment for a range of extraneous factors. Moreover, we found that this negative association was remained in subgroup analysis stratified by low eGFR, gender, age, and diabetes, suggesting this relationship could be applicable to population with different condition. What's particularly interesting was that pro-inflammatory food constituents (such as protein, total saturated fatty acids, and total monounsaturated fatty acids, which were the main sources of 25(OH)D), were negatively associated with 25(OH)D.
It has been well documented that Vitamin D played a major role in bone metabolism. Over the past years, considerable pieces of evidence have demonstrated its effects on inflammation and immunity. Cherrie MPC et al. found an atopic dependent trend in the association between 25(OH)D levels and asthma [
33]. Various studies have emphasized the association between low level of vitamin D with increased risk of respiratory disease symptoms [
33,
34]. A cross-sectional study proposed that lower VitD levels might cause severity and more complications in treatment in asthmatic adults [
35]. Rabih Halwani et al. revealed that VitD plays immunomodulatory role during COVID – 19 infection [
36]. Studies have found that 25(OH)D is negatively associated with markers of inflammation (interleukin [IL]-6, and high sensitivity C-reactive protein (hsCRP) in Autism Spectrum Disorders [
6,
7]. Vitamin D actions on inflammatory mechanisms depends on its biologically active form, 1,25(OH)2D. Generally, 1,25(OH)2D enhance the innate immune system and inhibit the adaptive immune system [
33,
37]. As for innate immune system, 1,25(OH)2D binds to the vitamin D receptor (VDR), which is present in most immune cell types particularly in antigen-presenting cells (APCs) (monocytes, macrophages and dendritic cells) [
38], and activates the VDR to express antimicrobial peptides (AMPs) such as cathelicidin and beta defensins to attack pathogens [
39,
40]. For adaptive immune responses, 1,25(OH)2D binds to the VDR and modulates the balance of T-helper subsets by inhibiting Th1 and Th17 effector cells, and enhancing the development of Treg cells. 1,25(OH)2D suppressed the release of pro-inflammatory cytokines (e.g., IL-2, IL-6, IL-12, INFr, TNFa, etc.) from both innate and adaptive immune response [
41].
Extensive research has been done to estimate the effect of inflammation on the 25 (OH) D level. In the present study, we concluded an inverse association between the pro-inflammation nutrients and 25 (OH) D level in patients with CKD. This cannot be fully explained by the above-mentioned mechanisms for dietary parameter as a invariable factor. Opposing reasoning can be used to explain this contradiction. One explanation reasons is that chronic inflammation can result in low level of 25(OH)D. Kelly Fincher et al. considered that after nucleated cells parasitized by intracellular bacteria, extra-renal production of 1,25 (OH)2D increased, and 25(OH)D decreased due to rapid conversion to 1,25 (OH) 2D for CYP27B1 activation [
9]. Multiple mechanisms are thought to be involved in the pathogenesis: a. inflammatory cytokines (e.g., TNF-α, IL-1, IL-2 and IFN-γ) activates CYP27B1, an enzyme that converts 25(OH)D into its active form 1,25(OH)2D [
42], which is expressed in most immune cell types such as macrophages [
9,
10]; b. elevated 1,25(OH)2D binds to the PXR (pregnane X receptor) and inhibits conversion of Vitamin D
3 to 25(OH)D [
43]; c. excess 1,25(OH)2D inhibits the hepatic synthesis of 25(OH)D [
44]. The hypothesis was confirmed by Waldronn et al. who found a reduction of the serum 25(OH)D following an acute inflammatory insult (i.e., orthopedic surgery) [
45]. The DII was designed based on the impaction of dietary parameter on the inflammatory biomarkers (IL-1 β, IL-4, IL-6, IL-10, TNF- α and CRP), which might stimulate the activation of CYP27B1.
Regarding the negative association between DII scores and the 25(OH)D level, we observed significant dependence on gender (P for interation = 0.001), age (P for interation = 0.003) and diabetes status (P for interation < 0.001), but not on low eGFR (P for interation = 0.464), which indicated that the magnitude of these associations did not differ by renal function (Pinteraction > 0.1). It was worth noting that there was higher 25(OH)D level in patients with low eGFR than those without low eGFR. We speculated that vitamin D supplementation was more common among population with low eGFR for serious disorders of calcium and phosphorus metabolism, which was contributed to this inconsistent result. Additionally, no significant difference was found in 25(OH)D level across increasing DII tertiles in the population with CKD stage 4 (P for trend = 0.464) and CKD stage 5 (P for trend = 0.82). Small sample may be contributed to these results (162 patients for CKD stage 4; 83 for CKD stage 5).
Some limitations of this study should be considered. Firstly, a causal inference on the relationship between DII and 25(OH)D in CKD patients was limited because of a cross-sectional nature of this study. Second, the DII score was calculated using 24-h recall data instead of long-term dietary exposure, leading to some nutrients that have effects on 25(OH)D excluded. Thirdly, We calculated DII based on 26 dietary items and data regarding 19 other dietary items were not available in this study. Fourthly, small sample size of patients with CKD stage 4 and 5 was used to analysis, although most of the participants with CKD were in stage 1–3. It may affect the accuracy. In addition, some potential confounders, such as drug use, hemodialysis condition, were not available in NHANES data, which may influence this association. Another limitation was that 25(OH)D was only assayed at a single time point, and no repeat measurements of 25(OH)D were conducted. At last, the serum level of 25(OH)D may not accurately reflects the serum level of active form 1,25(OH)2D, which was not available in the database.
The strength of our study was that we performed subgroup analysis stratified by different setting and found similar association, suggesting that this negative association could be appropriate for different population settings. Importantly, our study was based on large sample size with more representative.
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