Relation between 25-Hydroxyvitamin D, Systemic Inflammation and Endothelial Function Biomarkers in Diabetic Nephropathy

Background: Diabetic nephropathy (DN) is a microvascular diabetic complications that leads to renal failure worldwide. However, vitamin D is essential to maintain health of vascular system. Objective:The target of this study was to measure the association between 25-hydroxyvitamin D, systemic inflammation and endothelial function biomarkers in patients with type 2 diabetic nephropathy. Material and Methods: Two hundred Saudi obese type 2 diabetes mellitus (T2DM) patients (114 males and 86 females), their body mass index (BMI) was 31-35Kg/m2and the chronicity of diabetes was 11.87±2.95 year enrolled in the present study. Smokers and patients with renal insufficiency, congestive heart failure, pregnancy, respiratory failure and hepatitis were excluded. Participants were enrolled into three equal groups: group (A) 25-OHD<20ng/ml (deficiency of vitamin D), group (B): 25-OHD=20-30 ng/ml (insufficiency of vitamin D) and group(C) 25-OHD >30ng/ml (normal vitamin D). Consent from was signed by participants. Results: Mean values of VCAM-1, ICAM-1, E-selectin, TNF-α, IL-6 and CRP were significantly greater in group(A) compared to group(B) and group(C). However, vitamin D showed a strong inverse relationship with these parameters in the three groups (P<0.05). Conclusion: Level of vitamin D closely related to systemic inflammation and endothelial function biomarkers in Saudi patients with diabetic nephropathy


Introduction
Diabetic nephropathy (DN) is a common metabolic disorder with progressive rate of morbidity and mortality worldwide [1]. However, DN is a global diabetic microvascular complication leads to renal failure [2][3][4][5]. While, DN occur in 20-40% of type 2 diabetes mellitus (T2DM) patients and the principal etiology of renal failure [6,7]. Patients with DN suffer from high rate of morbidity and mortality. In fact, a rapid kidney function decline is a predictor for both cardiovascular disorders as well as all-cause mortality [8][9][10]. Risk factors of DN include poor metabolic control, diabetes duration, race, heredity, lifestyle, diet composition, aging and hypertension. On the other hand, systemic inflammation and endothelial dysfunction are 2 serious elements in promoting DN [11][12][13]. Vitamin D is essential for the function and health of the heart, blood vessels and kidney [14][15][16][17]. However, deficiency of vitamin D affects about 50% of worldwide population and induce many vascular complications among T2DM patients [18][19][20]. Therefore, this study aimed to detect the association between vitamin D, systemic inflammation and endothelial function biomarkers in patients with T2DM nephropathy.

Statistical analysis
SPSS (Chicago, IL, USA) version 23 was used for statistical analysis of data. Descriptive statistics for quantitative variables were presented as mean±SD, while qualitative variables were presented as percentage and numbers. Analysis of variance (ANOVA) was used to compare between the three groups, P<0.05. While Pearson's correlation coefficients (r) used to detect the degree of correlation between level of vitamin D and VCAM-1, ICAM-1, E-selectin, TNF-α, IL-6 & CRP.

Results
Participants baseline criteria of the three groups presented in (Table 1). Mean values of HDL-c, LDL-c, TC, TG, HbA1C and Creatinine revealed significant differences among the three groups. While, mean values of age and BMI revealed no significant differences among the three groups (Table 1). Mean values of VCAM-1, ICAM-1, E-selectin, TNF-α, IL-6 and CRP were significantly greater in vitamin D deficiency group (A) compared to vitamin D insufficiency group (B) and normal vitamin D group(C) ( Table 2). Moreover, vitamin D showed a strong inverse relationship with these parameters in the three groups (Table 3) (P<0.05).

Discussion
Diabetic nephropathy (DN) considered as the most serious T2DM complication [21,22].While, vitamin D deficiency among T2DM patients is common [23]. Vitamin D share in regulation of insulin sensitivity and secretion and ameliorates systemic inflammation [24]. Limited information is available about relation between cardiovascular dysfunction and D deficiency among DN patients [25,26]. Therefore, this study aimed to detect the association between vitamin D, systemic inflammation and endothelial function among T2DM patients nephropathy.
Results of this study indicated that vitamin D deficiency group (A) had greater significant mean values of TNF-α, IL-6 and CRP than group (B) and group (C) in addition to a negative relation between these systemic inflammatory parameters and vitamin D level. These findings agreed with many previous studies [27,28]. Moreover, several researches proved that vitamin D deficiency related to higher inflammatory cytokines levels [29][30][31][32]. In the other hand, many previous trails on different pathological conditions stated that administration of supplemental vitamin D for different durations resulted in highly significant down regulation of inflammatory cytokines which prove the ameliorating effect of vitamin D upon the systemic inflammation [33][34][35].
Concerning results of endothelial function parameters, vitamin D deficiency group (A) had greater significant mean values of VCAM-1, ICAM-1 and E-selectin than group (B) and group (C) in addition to a inverese relation between these parameters and vitamin D level. These findings approved by proved that low vitamin D was related to endothelial dysfunction [36][37][38]. In the other hand, many previous trails on different pathological conditions stated that administration of supplemental vitamin D for different durations resulted in highly significant improvement in endothelial function [39][40][41][42][43]. Renin-angiotensin system inhibition [44], vascular resistance reduction [45], inflammatory cytokines amelioration [46] and reduction of platelet aggregation [47][48][49] & oxidative stress are the mechanisms that link of vitamin D and endothelial function.

Conclusion
Level of vitamin D closely related to systemic inflammation and endothelial function biomarkers in Saudi patients with diabetic nephropathy.