Pleiotropic effects of vitamin D in chronic kidney disease

    Pleiotropic effects of vitamin D in chronic kidney disease Wen-Chih Liu, Chia-Chao Wu, Yao-Min Hung, Min-Tser Liao, Jia-Fwu Shyu, Yuh-Feng Lin, Kuo-Cheng Lu, Kun-Chieh Yeh PII: DOI: Reference:

S0009-8981(15)30066-8 doi: 10.1016/j.cca.2015.11.029 CCA 14188

To appear in:

Clinica Chimica Acta

Received date: Revised date: Accepted date:

4 October 2015 30 November 2015 30 November 2015

Please cite this article as: Liu Wen-Chih, Wu Chia-Chao, Hung Yao-Min, Liao MinTser, Shyu Jia-Fwu, Lin Yuh-Feng, Lu Kuo-Cheng, Yeh Kun-Chieh, Pleiotropic effects of vitamin D in chronic kidney disease, Clinica Chimica Acta (2015), doi: 10.1016/j.cca.2015.11.029

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ACCEPTED MANUSCRIPT Pleiotropic effects of vitamin D in chronic kidney disease

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Authors: Wen-Chih Liua,b, Chia-Chao Wuc, Yao-Min Hungd,e, Min-Tser Liaof,g, Jia-Fwu Shyuh, Yuh-Feng Lina,i, Kuo-Cheng Luj,**,1, Kun-Chieh Yeh k,*,1

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Affiliations a Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan b

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Division of Nephrology, Department of Internal Medicine, Yonghe Cardinal Tien Hospital, New Taipei City, Taiwan c Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan d Department of Emergency Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan Institute of Public Health, School of Medicine, National Yang Ming University, Taipei, Taiwan f Department of Pediatrics, Taoyuan Armed Forces General Hospital, Taoyuan,

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Taiwan Division of Pediatrics, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan h Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan i Division of Nephrology, Department of Medicine, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan j Department of Medicine, Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic

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University, New Taipei City, Taiwan Department of Surgery, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan

* Correspondence to: Dr. Kun-Chieh Yeh, Department of Surgery, Taoyuan Armed Forces General Hospital, 168, Zhongxing Road, Longtan Dist., Taoyuan City 32551, Taiwan. Tel: +886 939511532; Fax: +886 3 4799595 ** Corresponding author. E-mail addresses: [email protected] (K-C. Lu), [email protected] (K-C Yeh) 1

These authors have contributed equally to this work.

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Abstract Low 25(OH)D levels are common in chronic kidney disease (CKD) patients and are implicated in all-cause mortality and morbidity risks. Furthermore, the progression of CKD is accompanied by a gradual decline in 25(OH)D production. Vitamin D deficiency in CKD causes skeletal disorders, such as osteoblast or osteoclast cell defects, bone turnover imbalance, and deterioration of bone quality, and nonskeletal disorders, such as metabolic syndrome, hypertension, immune dysfunction, hyperlipidemia, diabetes, and anemia.

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Extra-renal organs possess the enzymatic machinery for converting 25(OH)D to 1,25(OH)2D, which may play considerable biological roles beyond the traditional roles of vitamin D. Pharmacological 1,25(OH)2D dose causes hypercalcemia and hyperphosphatemia as well as adynamic bone disorder, which intensifies vascular calcification. Conversely, native vitamin D supplementation reduces the risk of

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activity in parathyroid gland.

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hypercalcemia and hyperphosphatemia, which may play a role in managing bone and cardio–renal health and ultimately reducing mortality in CKD patients. Nevertheless, the combination of native vitamin D and active vitamin D can enhance therapy benefits of secondary hyperparathyroidism because of extra-renal 1α-hydroxylase

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This article emphasizes the role of native vitamin D replacements in CKD, reviews vitamin D biology, and summarizes the present literature regarding native vitamin D replacement in the CKD population.

ACCEPTED MANUSCRIPT Introduction Chronic inflammation persists in chronic kidney disease (CKD) patients. Most CKD patients die of CKD–mineral and bone disorder (MBD) related cardiovascular events and infectious diseases. Secondary hyperparathyroidism and hypocalcemia are other common and serious complications of CKD. All of these events are likely to be associated with vitamin D deficiency. Usually, secondary hyperparathyroidism in CKD patients is caused by hypocalcemia, hyperphosphatemia, reduced 1,25(OH)2D levels, increased fibroblast growth factor-23 (FGF-23) levels, and metabolic acidosis. Vitamin D, a group of lipid-soluble compounds with a four-ringed cholesterol

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backbone, is the only vitamin that can be synthesized by humans. Dermal synthesis and intestinal absorption are the two main vitamin D sources. Vitamin D is metabolized by 25-hydroxylase and 1-α-hydroxylase in the liver and kidneys, respectively, and converted to the active form, 1,25(OH)2D. Recent evidence suggests that the extrarenal conversion of 25(OH)D (25-hydroxyvitamin D or calcidiol) to

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1,25(OH)2D (calcitriol ) may play considerable biological roles beyond the traditionally described roles of vitamin D [1]. Vitamin D deficiency in CKD is associated with all-cause, cardiovascular, and infectious mortality risks. Activation of the vitamin D receptor (VDR) involves several

Vitamin D metabolism and its role in CKD regulation Vitamin D deficiency is highly prevalent in CKD [2]. Therefore, clinicians

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pleiotropic effects, and then vitamin D plays new roles in maintaining health. Thus, achieving and maintaining an adequate vitamin D status may be essential in preventing cardiovascular events, balancing the bone–fat connection, correcting bone turnover disorders, improving endothelial function, alleviating proteinuria, and ultimately reducing morbidity and mortality in CKD patients.

prescribe native vitamin D supplements to CKD patients is crucial. However, overuse of active vitamin D for treating CKD affects extrarenal organs, tissues, and cells associated with vitamin D metabolism (Figure 1). 2.1 Vitamin D production and metabolism Vitamin D can be synthesized in the human skin or obtained through the diet. When the skin is adequately exposed to ultraviolet B radiation, 7-dehydrocholesterol in the skin is converted to pre-vitamin D3, which is further converted to vitamin D3 (cholecalciferol) because of body heat [3]. However, excess sunlight exposure destroys pre-vitamin D3, thus making it inactive [4]. The vitamin D binding protein (DBP) in blood delivers the skin-synthesized vitamin D3 to the liver through circulation.

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Vitamin D from the diet can be classified into plant vitamin D2 (ergocalciferol) and animal vitamin D3 (cholecalciferol). Cholecalciferol is identical to the skin-synthesized vitamin D3. Vitamin D synthesized from the skin or obtained through the diet is reserved in fat cells [4]. Cholecalciferol and ergocalciferol are absorbed from the gastrointestinal tract, bound to chylomicrons, and delivered to the liver through hepatic portal circulation [5]. Ergocalciferol and cholecalciferol are metabolized by the enzyme vitamin D 25-hydroxylase in the liver and converted to the 25(OH)D form of 25(OH)D2 and 25(OH)D3, respectively. Clinically, 25(OH)D is the main circulating form and determines the vitamin D status in the body.

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25(OH)D combined with DBP is delivered to the kidneys and filtrated through the glomerulus. The delivery of the 25(OH)D–DBP compound to the proximal tubular cells is facilitated by megalin receptor-mediated endocytosis [6]. Megalin is a multiligand receptor that facilitates the uptake of extracellular ligands in the renal proximal tubule. 25(OH)D is converted to its active form, calcitriol, by

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1-α-hydroxylase and transported by the intracellular vitamin D-binding protein 3; thus, 1,25(OH)2D or 25(OH)D reenters the circulation [7, 8]. 1,25(OH)2D can induce renal megalin expression, thereby generating a cycle for conserving normal systemic 25(OH)D and 1,25(OH)2D levels [9].

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Under normal renal function, high or low serum 25(OH)D levels do not adequately affect 1,25(OH)2D levels. However, in advanced kidney diseases (glomerular filtration rate [GFR] <25 mL/min), the serum 25(OH)D and 1,25(OH)2D levels exhibit strong relationships because diminished 25(OH)D can be converted to its bioactivated form 1,25(OH)2D by the residual renal 1α -hydroxylase in CKD. Higher physiological 25(OH)D levels can upregulate serum 1,25(OH)2D levels in CKD patients [9]. 2.2.1 Physiological functions of vitamin D The main physiological function of vitamin D is maintaining the serum mineral balance, obtaining bone quality, and maintaining the overall health of extrarenal organs. 1,25(OH)2D absorbs calcium and phosphate through the transient receptor potential vanilloid type 5 and type 6 channels in intestinal epithelial cells [10]. Serum parathyroid hormone (PTH) can stimulate the production of 1-α-hydroxylase in renal tissues for increasing 1,25(OH)2D synthesis [11]; however, high 1,25(OH)2D levels reduce PTH secretion because of feedback inhibition. In addition, hypocalcemia increases the serum PTH levels to enhance calcium resorption and phosphate excretion, and 1-α-hydroxylase in the renal tubule cells consequently increases 1,25(OH)2D synthesis. Therefore, serum PTH, calcium, and phosphate levels equally influence 1,25(OH)2D synthesis for maintaining the calcium and phosphate

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homeostasis. In addition, 25(OH)D is metabolized to active 1,25(OH)2D without kidney involvement because several extrarenal cells, such as cells of the brain, heart, and pancreas, possess 1-α-hydroxylation capacities [12-19] (Table 1). Approximately 85% of the circulating 25(OH)D is reportedly used in the extrarenal local production of 1,25(OH)2D through autocrine and paracrine mechanisms, and the extrarenal 1-α-hydroxylation concentration may be higher in CKD than in normal conditions [16, 20, 21]. Furthermore, the VDR is present in immune, muscular, and nervous system organs in addition to many solid organs such as the bones and kidneys [21-24]. Thus, the extraskeletal functions of vitamin D

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include renal function preservation, cardiovascular system protection, immune system regulation, cancer prevention, and so on [25-27].

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2.2.2 The regulation of vitamin D and its receptor The biological actions of 1,25(OH)2D act on its high-affinity VDR [28]. There are

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four major parts (ligand binding domain, retinoid X receptor/RXR, DNA-binding domain/DBD and regulating proteins) of the VDR structures which control the target gene transcription [12]. The ligand binding domain can influence the whole VDR conformation and can promote activation of the VDR complex. The RXR is a

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co-receptor of VDR which heterodimerizates with VDR. The DBD is a conserved nuclear steroid receptor which can affect the VDR interaction with specific DNA sequences in the promoter region of 1,25(OH)2D target genes, vitamin D-responsive elements (VDREs). The VDR positively and negatively regulating proteins, naming co-activators (CoAs: SRC1, CBP/p300, DRIP-TRAP, etc.) [12, 29] and co-repressors (CoRs: NCoR, SMRT, etc.) [12, 30] respectively. CoAs act as the connector of the VDR-RXR complex, which are assembled on the transcription start site to promote the transcription of the target gene. In contrast, CoRs play the role of down-regulation of gene transcription and are known as one of the mechanisms by which VDR inhibit transcription of its primary target genes [31]. 2.3 25(OH)D dysregulation in CKD The international Kidney Disease Outcomes Quality Initiative (KDOQI) [32] and Kidney Disease: Improving Global Outcomes (KDIGO) guidelines [33] recommend that vitamin D be prescribed to stage 3–5 CKD patients with low 25(OH)D and high serum PTH levels because vitamin D deficiency is observed in almost all CKD patients [34]. Therefore, native vitamin D is a common routine medication administered to CKD patients. Usually, the circulatory 25(OH)D levels can indicate the amount of vitamin D reserves in CKD patients. The normal 25(OH)D level in blood is 30–80 ng/mL (75-200 nmol/L). Although there is no consistent conclusion, most

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professionals identify vitamin D deficiency levels as 20 to 30 ng/ml (50-75 nmol/L) [4]. Vitamin D supplement is generally accepted at levels under 30 ng/mL (75 nmol/L) in CKD patients. Several studies revealed that the lower 25(OH)D levels are related to an increased risk of ESRD [35] and mortality [36]. The association between 25(OH)D levels and mortality was attenuated in dialysis patients receiving VDRA [36]. However, there is still no sufficient RCTs on the effect of nutritional vitamin D supplementation on survival in ESRD cohorts [1]. The low 25(OH)D levels of CKD patients have several potential causes. We discuss the major causes in the following sections.

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2.3.1 Low 25(OH)D levels in CKD Cholecalciferol production in the skin is impaired in CKD and dialysis patients because of low exposure to sunlight, impaired response, malnutrition. Renal mass, GFR, and megalin expression are reduced in patients with CKD as well; hence, the

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amount of 25(OH)D entering the renal tubules and the subsequent uptake in the circulation are limited. Furthermore, proteinuria limits 25(OH)D binding to the megalin receptor, and fewer receptors are available to reabsorb 25(OH)D–DBP compound in CKD, particularly, in diabetic nephropathy. In addition, consequent to

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proteinuria, proximal tubular cells are damaged and hence, fewer megalin receptors are available [9]. Therefore, CKD patients have low 1,25(OH)2D levels in a substrate–product relationship [37].

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2.3.2 Low 1-α-hydroxylase activity and high 24-hydroxylase activity The renal tubular epithelial cells possess two enzymes, 1-α-hydroxylase, converting 25(OH)D into 1,25(OH)2D, and 24-hydroxylase, converting 25(OH)D into 24,25(OH)2D. In addition, elevated 1,25(OH)2D lowers the activity of 1-α-hydroxylase in renal cells [9, 38] and promotes the activity of the 24-hydroxylase gene in enhancing its inactivation [39]. Furthermore, CKD, diabetes mellitus, reduce the activity of 1-α-hydroxylase and 25-hydroxylase and increase the activity of 24-hydroxylase, causing prominent reduction of endogenous 25(OH)D and 1,25(OH)2D product and increasing their decay [38, 40]. 2.3.3 Effects of FGF-23 FGF-23, a phosphaturic hormone, is secreted by osteocyte for keeping serum phosphate homeostasis in early renal dysfunction and is markedly elevated in patients with deterioration of renal function [41]. FGF-23 inhibits 1-α-hydroxylase activity in the renal proximal tubule to reduce 1,25(OH)2D production and stimulates 24-hydroxylase to produce 24,25(OH)2D [42].

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2.3.4 Pharmacological 1,25(OH)2D dose The normal serum physiological 1,25(OH)2D concentration is approximately 20–30 pg/mL (50-75 pmol/L) [43]. The therapeutic dose of 1,25(OH)2D (usual dose in micrograms) plays a crucial role in treating secondary hyperparathyroidism in CKD patients. However, 1,25(OH)2D, is the end product of the vitamin D pathway and inhibits 1-α-hydroxylase and 25-hydroxylase through feedback inhibition. A pharmacological dose of 1,25(OH)2D may downregulate 25(OH)D levels, thus reducing 25(OH)D availability in extrarenal tissues and organs and increasing

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25(OH)D deficiency [44]. Furthermore, 1-α-hydroxylase activity and the 25(OH)D concentration exhibit a substrate–product relationship in CKD patients, in which a higher 25(OH)D concentration elicits stronger 1-α-hydroxylase activity and vice versa [45].

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3. Effects of vitamin D on bone 3.1 Effect of vitamin D on bone cells: osteoblasts and osteoclasts The VDR is localized in osteoblasts and its expression can be regulated by 1,25(OH)2D, PTH, glucocorticoids, transforming growth factor-β, and the epidermal

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growth factor [46-48]. Human and mouse osteoblasts contain 1-α-hydroxylase, which is crucial to osteoblast differentiation., In addition, this enzyme enhances 25(OH)D-induced 1,25(OH)2D production through an autocrine or paracrine mechanism; increases the expression of osteopontin, osteocalcin, the matrix Gla protein, and alkaline phosphatase; and enhances bone mineralization [49]. 1,25(OH)2D upregulates the Wnt signaling cascade and β-catenin signaling to induce osteoblast differentiation [50]. 1,25(OH)2D and the VDR bind together in osteoblasts to promote the activities of the LRP5 and Frizzled coreceptor-initiated canonical Wnt signaling pathway, thus increasing the LRP5 mRNA levels [51]. The elevated LRP5 promotes the performance of a crucial component of the Wnt signaling pathway, thus influencing osteogenesis [51]. In addition, the 1,25(OH)2D–VDR association promotes RUNX2, a key transcription factor in osteoblast differentiation, to increase the expression of osteocalcin and osteopontin in osteoblasts [52, 53]. Therefore, 1,25(OH)2D has been observed to stimulate osteogenic differentiation from mesenchymal stem cells (MSCs) [49, 54-56]. In osteoblasts, the VDR level enhances the 24-hydroxylase activity and downregulates 1,25(OH)2D levels [57, 58]. During bone remodeling, osteoclast differentiation and function are also regulated by osteoblasts. 1,25(OH)2D is one of the most critical bone resorption-stimulating factors in osteoblasts that induce the expression of RANKL and M-CSF. Osteoclast precursors express RANK and c-Fms. When M-CSF binds to c-Fms,

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osteoclast precursors identify osteoblast RANKL expression through cell–cell interaction and promote their differentiation. Moreover, RANKL in osteoblasts couples with RANK in activated osteoclasts to stimulate the bone resorption process [59].

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3.2 Vitamin D and bone turnover 3.2.1 Role of native vitamin D in high bone turnover disorders (secondary hyperparathyroidism) CKD patients receive high 1,25(OH)2D doses that suppress 25-hydroxylase in the

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liver and 1-α-hydroxylase in the kidney through feedback inhibition. Thus, the greater the 1,25(OH)2D dose is, the lower the 25(OH)D production. Consequently, administering a high 1,25(OH)2D dose exacerbates the 25(OH)D shortage in kidney, pancreas, bone, prostate, breast, and immune cells (Figure 2). In CKD patients with secondary hyperparathyroidism, the proliferation of oxyphil

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cells in the parathyroid gland elevates 1-α-hydroxylase production, facilitating the 25(OH)D to 1,25(OH)2D conversion [4]. In addition, 24-hydroxylase expression is elevated in the uremic kidney [60]. Therefore, native vitamin D (cholecalciferol) supplements convert to 25(OH)D, then occupy 24-hydroxylase. In addition, native

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vitamin D supplements increase 1,25(OH)2D production in the PTH gland through an autocrine or paracrine mechanism to suppress PTH production by chief cells [4].

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3.2.2 Role of native vitamin D in low bone turnover disorders (adynamic bone disorder) 1,25(OH)2D overuse, total parathyroidectomy, and immunosuppression after kidney transplantation lower serum PTH levels and lead to low bone turnover disorders or adynamic bone disorder. The characteristic feature of adynamic bone disorder is the low viability of osteoblasts and osteoclasts. Therefore, providing native vitamin D may recover the viability of osteoblasts and improve bone turnover and bone quality [61]. 3.2.3 Vitamin D in CKD patients with acceptable PTH levels The KDOQI guidelines recommended that 25(OH)D be measured once a year in CKD patients at all stages, and the levels should be >30 ng/mL [12, 62-64]. Furthermore, early vitamin D supplementation can prevent or delay the onset of secondary hyperparathyroidism [65]. The KDOQI [62] and KDIGO guidelines [66] recommended that patients with low 25(OH)D and high PTH serum levels at CKD stage 3–5 should be prescribed native vitamin D. The Institute of Medicine (IOM) suggested the recommended dietary

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allowance of vitamin D to be 600 and 800 IU/day for people aged <70 and >70 years, respectively. The therapy goal is to reach adequate 25(OH)D levels of >20 ng/mL (or 50 nmol/L) [67]. In addition, the IOM states that the upper level of intake is 4000 IU/day [68]. However, in 2010, the International Osteoporosis Foundation recommended that 25(OH)D levels >30 ng/mL (75 nmol/L) are optimal for preventing falls and fractures. The vitamin D dosage should reach 800–1,000 IU/day [69], although a higher dosage was suggested by other authors [70]. 3.3 Vitamin D effects on bone quality

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Vitamin D deficiency is well known to lead to rickets in children and osteomalacia or osteoporosis in adults. Previous studies approve that vitamin D supplement cures weakened bone mineralization. Osteoporosis is a systemic metabolic bone disease of multiple causes, which have the characters of impaired bone strength and increasing fragility fracture risk. Bone strength is reflected equally

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by both BMD, which is determined by peak bone mass and amount of bone loss and bone quality, which refers to architecture, turnover, and mineralization [71, 72]. Mounting evidence indicates most bone cells possess 1α-hydroxylase to perform the intracrine/paracrine activities of vitamin D [73]. 1,25(OH)2D produced by

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bone cells can diminish bone resorption through an intracrine/paracrine function resulting in increased bone mass [74]. Vitamin D deficiency will increase the risks of fracture, which not only impairs bone mineralization but also numerous pathological alterations. Vitamin D deficiency increases both the beginning and extension of fragility fracture. Thus, vitamin D deficiency is associated with both diminished bone mass and worsen bone quality. Appropriate vitamin D levels are the key to preserve the structural integrity of bone [75]. Although several meta-analyses show no influence of vitamin D treatment alone on fracture risk [76, 77], the emerging evidence shows that cholecalciferol combined with calcium has the greatest advantage to reduce the risk of nonvertebral and hip fractures [78]. 4. Nonskeletal effects of vitamin D 4.1 Vitamin D in bone–fat connection Low 25(OH)D3 levels are associated with metabolic syndromes, such as overweight, hypertension, high blood glucose, and hyperlipidemia [79]. Obesity exacerbates CKD and osteoporosis, and these two disorders frequently induce severe bone loss. Bone loss is more severe in CKD patients with vitamin D deficiency than in patients without vitamin D deficiency [80] (Figure 3). Adipocytes are formed from MSCs, which can differentiate into different cells,

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such as osteoblasts, chondrocytes, and myocytes [81] (Figure 3). MSCs differentiate in a complicated manner into osteoblasts or adipocytes and are influenced by several growth factors, C/EBP-δ, C/EBP-α, and peroxisome proliferator-activated receptor-γ (PPAR-γ) in the bone marrow. Adipogenesis and osteoblastogenesis have an inverse association and are delicately balanced [82]. Obesity and aging are clearly associated with greater adipogenesis potential and less osteoblastogenesis from MSCs in the bone marrow [83, 84]. In elderly people with severe bone loss conditions such as osteoporosis, MSCs tend to undergo adipogenesis in the bone marrow [83, 84]. Noggin, a glycosylated protein that inhibits bone morphogenetic protein signaling,

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directly induces adipogenesis from MSCs. Thus, high noggin levels may be used as a potential therapeutic target, and noggin may serve as a potential substitute biomarker in the obese population [85]. By contrast, the Wnt signaling pathway promotes osteogenesis and inhibits adipogenesis synchronously [86, 87]. Furthermore, these two pathways can influence

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each other. The canonical Wnt signaling in bone can prevent the phosphorylation of β-catenin and its proteosomal degradation, and several reports have consistently stated that the Wnt/β-catenin activity is essential for bone development [88]. In addition, Wnt10b is crucial to bone formation because it inhibits PPAR-γ expression,

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enhances osteoblastogenesis, and increases the bone density in the bone marrow [89, 90]. Therefore, use of vitamin D supplements improves osteoblast differentiation and function and induces adipocyte apoptosis, resulting in increased bone mass in the bone marrow and reducing the likelihood of obesity development.

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4.2 Vitamin D and blood pressure Low vitamin D levels have been associated with increased vascular stiffness, endothelial dysfunction, inflammatory cytokines, and higher coronary artery calcium scores [91]. In a previous study on patients with hypertension exposed to sufficient sunlight, the 25(OH)D levels were upregulated by approximately 180%, and subsequently the blood pressure was normal [92]. In an animal experiment, VDR-knockout mice had enhanced renin-angiotensin-aldosterone system (RAAS) signaling in the blood, which led to significant sodium retention, vascular resistance, and hypertension [93]. 1,25(OH)2D produced from the kidney enters the circulation and reduces renin production in the kidneys to control the blood pressure [4]. Another study reported that weekly native vitamin D supplementation (cholecalciferol; 50,000 units for 12 weeks) in type 2 diabetic patients may improve hypertension [94]. 4.3 Vitamin D and immune function

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More and more researches state that vitamin D deficiency not only causes dysregulation of the innate and adaptive immune systems, but also promotes microinflammation in CKD [95]. Owing to immune cells carrying VDR and 1α-hydroxylase, which can produce the active metabolite 1,25(OH)2D through local synthesis. In innate immunity, vitamin D promotes macrophages to produce cathelicidin and β-defensin 2 and enhance the capacity for autophagy via toll-like receptor activation as well as affects complement concentrations [96]. Therefore, 1,25(OH)2D was proved to heighten the effects of macrophages and monocytes against pathogens by stimulating monocytes change into mature phagocytic

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macrophages [97]. In addition, in adaptive immunity, vitamin D suppresses the maturation of dendritic cells (DCs) and weakens antigen presentation. Vitamin D will increase T helper (Th) 2 cytokine production and the efficiency of Treg lymphocytes [98] but diminish the secretion of Th1 and Th17 cytokines to decrease autoimmune disease [99].

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Interestingly, vitamin D plays a role in the crosstalk between innate and adaptive immunity because it has a significant impact on macrophages and DCs [96]. DCs are the important connector between innate and adaptive immune systems. Local production of 1,25(OH)2D in paracrine responses also seems to have an effect on

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monocytes and immature DCs. Thus, local 1,25(OH)2D is assumed to enhance a tolerogenic immune response and possess immunosuppressive properties.

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4.4 Vitamin D and diabetes mellitus nephropathy Because of secondary hyperparathyroidism, inflammation, and oxidative stress, CKD patients have impaired insulin secretion and enhanced insulin resistance, which alter glucose metabolism [100]. Active vitamin D (1,25(OH)2D) directly enhances insulin secretion by interacting with the 1,25(OH)2D3-RXR-VDR complex, which binds to vitamin D responsive elements, thus enhancing the transcriptional activation of the insulin gene, increasing insulin synthesis, and indirectly increasing the calcium concentration within the β islet cells of the pancreas. In addition, native vitamin D augments insulin sensitivity by stimulating the insulin receptor and activating PPAR-γ [101]. In a previous study on people with prediabetes, vitamin D and calcium upregulated insulin sensitivity [102]. 4.5 Vitamin D in the endothelium The vascular endothelial function of CKD patients is dysregulated. Active vitamin D inhibits vascular calcification through two possible mechanisms. First, increased Klotho secretion can alleviate phosphaturia and restrict phosphate uptake by the vascular smooth muscles. Second, upregulating the expression of the calcification

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inhibitor osteopontin in aortic medial cells and increasing matrix G1A protein synthesis can improve vascular endothelial function [103, 104]. Chitalia et al. reported that oral vitamin D (cholecalciferol) improves endothelial vasomotor and secretory functions in CKD patients without significant adverse effects on the arterial stiffness [105]. In addition, vitamin D3 administration (cholecalciferol, 4000 IU/day) enhanced vascular regeneration by inducing stromal cell–derived factor 1 expression in the healthy population. Therefore, native vitamin D3 is a new approach for promoting vascular endothelial repair [106].

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4.6 Vitamin D and albuminuria As CKD progresses, albuminuria, including microalbuminuria, increases [107, 108]. Therefore, albuminuria is a critical indicator of kidney deterioration and subsequent cardiovascular diseases, thus serving as a potential treatment target [109]. Traditionally, using RAAS blockers, reducing salt intake, and controlling blood

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pressure can reduce albuminuria. However, the effects of these methods on preventing kidney damage are limited. Vitamin D deficiency is related to albuminuria and CKD progression [35, 110-112]. Furthermore, vitamin D deficiency independently predicts the 5-year

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incidence of albuminuria [113]. Activation of the VDR is essential in reducing proteinuria [114, 115]. Molina et al. reported that vitamin D supplements may effectively reduce albuminuria at CKD stages 3–4 [116]. Massart et al. reported that oral administration of 25,000 IU/week of cholecalciferol for 13 weeks increases 25(OH)D and 1,25(OH)2D levels in patients on hemodialysis [43]. Hence, vitamin D supplementation is indicated in CKD. 4.7 Vitamin D and anemia Chronic inflammation and a reduced GFR in CKD patients cause iron imbalance and increased hepcidin production [117] (Figure 4). Vitamin D deficiency alters innate and adaptive immune function, which will increase inflammatory cytokine production (IL-6, IFN-γ, TFN-α) which will stimulate canonical janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, and phosphorylation of JAKs and STAT3 to stimulate hepcidin expression in liver [118, 119] . Hepcidin limits iron absorption from the intestine or iron release from macrophages and liver reserves by inducing ferroportin degradation for maintaining the systemic iron balance [120]. Under iron deficiency, anemia or hypoxia prohibits hepcidin production, increasing iron usability in the liver; however, inflammation and the use of excess iron supplements stimulate hepcidin production, thus inhibiting ferroportin activity and limiting iron usability [121]. Several factors, such as the use of

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phosphate binders and antacids, loss of blood during hemodialysis, and intake of erythropoiesis-stimulating agents (ESA), cause iron deficiency [122]. In addition, secondary hyperparathyroidism will directly inhibit erythroid progenitors, endogenous EPO synthesis, and RBC survival [123]. It also indirectly promotes bone marrow fibrosis, hyperphosphataemia, and increase serum alkaline phosphatase. All of them will lead to ESA hyporesponsivenes [124]. According to recent studies, vitamin D deficiency, low hemoglobin levels, and ESA resistance constitute a pathophysiological cofactor of renal anemia [125, 126]. Providing vitamin D or active vitamin D is associated with improving anemia and

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reducing ESA requirements [127, 128]. Therefore, vitamin D levels and ESA requirements exhibit an inverse relationship in CKD patients [129]. In addition, vitamin D application promotes anti-inflammation and erythroid proliferation [13, 130].

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4.8 Vitamin D and lipid metabolism The VDR affects bile acid synthesis and reduces cholesterol levels in hepatocytes and serum. Activation of the VDR by 1,25(OH)2D reduces liver and serum cholesterol because it suppresses the expression of small heterodimer partner (SHP) and the

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activation of cholesterol 7-α-hydroxylase (CYP7A1) [131]. SHP combines with the liver receptor homolog-1, a positive regulator of CYP7A1, for to blocking the activation of the CYP7A1 gene [132]. CYP7A1 is the rate-limiting enzyme in bile acid synthesis, and its expression controls serum cholesterol levels [133, 134]. In addition, the hepatic farnesoid X receptor (FXR) can enhance SHP activity to inhibit CYP7A1 [135, 136]. A study showed that VDR activation downregulated FXR and SHP expression [135], which are responsible for increasing CYP7A1 expression to lower cholesterol. 5. Combination of native and active vitamin D therapy in CKD 25(OH)D deficiency is widespread in the general and CKD populations [137]. Native vitamin D supplementation prevents secondary hyperparathyroidism in early CKD; KDOQI suggests its use is not beneficial in advanced CKD because of the lack of 1-α-hydroxylase in the kidneys [62, 138]. However, another recent study indicated that 1,25(OH)2D levels were increased after supplementation with native vitamin D in hemodialysis patients and suggested that there was enough extra-renal 1-α-hydroxylase activity to produce serum levels of 1,25(OH)2D even in ESRD [139]. Physicians should prescribe native vitamin D (cholecalciferol, ergocalciferol, or calcidiol) to all patients whose 25(OH)D levels are <30 ng/mL, irrespective of whether they belong to the general, CKD, or ESRD population. Desirable calcidiol targets and

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their treatment applications are receiving ongoing attention [140-142]. Active 1,25(OH)2D causes hypercalcemia, hyperphosphatemia [143], and adynamic bone disorder. However, in CKD patients, 1-α-hydroxylase can convert vitamin D to its active form in extrarenal cells such as monocytes/macrophages and parathyroid cells [144]. Kandula et al. analyzed the data from several independent studies and reported that native vitamin D administration can reduce PTH levels in CKD and ESRD patients [145]. Tassin et al. conducted an observational study, which demonstrated that PTH levels continually decreased as the dosage of cholecalciferol and calcidiol was increased in dialysis patients [146].

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Vitamin D has only a minor effect in hypercalcemia and hyperphosphatemia. In a 6-month study on 149 dialysis patients, vitamin D (calcidiol) was associated with a significant PTH reduction and a reduced dose (from 66% to 43%) of the vitamin D receptor analog (VDRA) alfacalcidol [147]. In addition, vitamin D supplements increased the 25(OH)D levels in the blood and osteogenesis markers with a reduction

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in the active calcitriol dosage in ESRD patients [148]. Therefore, for stage 5 CKD patients, a combination therapy of native vitamin D and VDRA supplementation is affordable and safe, and has health benefits.

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6. The risks of excessive vitamin D The most common complication of excessive vitamin D intake is hypercalcemia but the serum concentration of 25(OH)D at which hypercalcemia happens is ambiguous, many experts consider the serum level of vitamin D intoxication is more than 150 mg/mL (374 nmol/L) [4]. The Institute of Medicine (IOM) stated the "tolerable upper intake level" for vitamin D is 4000 IU daily for healthy adults [149]. The adverse event analysis identified increased hypercalcemia risk with loading doses >400,000 IU and loading doses ≤ 300 000 IU should be advocated [150]. The symptoms of hypercalcemia induced by vitamin D intoxication include confusion, polyuria, polydipsia, anorexia, vomiting, and muscle weakness. The hypercalcemia of long term vitamin D intoxication may cause nephrocalcinosis, bone demineralization, pain, and [151]. In addition, vitamin D intoxication can induce acute renal failure [152]. 7.

Conclusion Several studies have recently reported the advantages of vitamin D in treating CKD-MBD. Vitamin D, a hormone with pleiotropic functions, is a critical substance that provides nourishment essential for bone health and growth. Native vitamin D use has fewer hypercalcemia- and hyperphosphatemia-associated complications than active vitamin D use does. In addition, vitamin D exerts beneficial quality on

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bone cells and enhances osteoblast cell production, thereby alleviating osteoporosis. Reducing adipogenesis, alleviating metabolic syndrome, maintaining regular blood pressure, improving insulin resistance and alleviating diabetes mellitus, lowering cholesterol levels, increasing vascular endothelial cell function, and managing renal anemia are other functions of vitamin D. For early-stage CKD patients, adequate native vitamin D supplementation decelerates the decline of kidney function by slowing the progression to the ESRD stage, relieves proteinuria caused by CKD, and reduces the occurrence of hyperparathyroidism. In advance-stage CKD patients with high bone turnover, a

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combination therapy of native vitamin D and active vitamin D can reduce the dosage of active vitamin D and vascular calcification. In addition, native vitamin D supplementation will enhance the function of osteoblasts and improve the bone quality, and increase the viability of osteoblasts in patients with low bone turnover. In summary, native vitamin D promotes bone remodeling and enhances the health of

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nonskeletal organs. Therefore, its role is extremely valuable for bone metabolism and maintaining bone quality in CKD. Conflict of interests

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The authors declare that there is no conflict of interests regarding the publication of this paper.

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Figure 1. Vitamin D metabolism and its regulation Dermal synthesis of vitamin D (cholecalciferol) from cholesterol depends on UV exposure (UV-B radiation), which is the major natural source of vitamin D. Because vitamin D from the diet or dermal synthesis is biologically inactive, it must be converted to its active form 1,25(OH)2D or calcitriol by the liver enzyme 25-hydroxylase and renal enzyme 1-α-hydroxylase. The mitochondrial protein 24-hydroxylase initiates the degradation of 25(OH)D and 1,25(OH)2D through hydroxylation of the side chain to form calcitroic acids. CKD, diabetes mellitus, increased FGF-23, and active vitamin D supplementation reduce the activity of

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25-hydroxylase and 1-α-hydroxylase and increase the activity of 24-hydroxylase. This reduces endogenous 25(OH)D and 1,25(OH)2D production and enhances their degradation. CKD patients with secondary hyperparathyroidism on high doses of active vitamin-D may have aggravated 25(OH)D deficiency, which may also reduce the availability of 25(OH)D in extrarenal tissues, organs, and cells such as the skin,

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prostate, colon, brain, breast, lungs, placenta, osteoblasts, parathyroid gland, pancreas, muscles, monocytes, and T/B cells.

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Figure 2. Native vitamin D and bone turnover disorders In patients with secondary hyperparathyroidism (high bone turnover), native vitamin D supplements increase the production of 1,25(OH)2D in the parathyroid gland through autocrine or paracrine mechanisms that suppress the activity of the chief cells producing the parathyroid hormone. The combination therapy of native vitamin D and active vitamin D supplements has fewer adverse effects of hypercalcemia and hyperphosphatemia and can improve bone quality efficiently. In patients with adynamic bone disorder (low bone turnover), the viability of osteoblasts and osteoclasts is low. Providing native vitamin D or intermittent PTH supplements may rescue the function of osteoblasts, improve bone turnover, and promote bone health.

Figure 3. Influence of vitamin D on bone–fat connection Adipocytes and osteoblasts originate from a common mesenchymal precursor (MSCs) that can differentiate into other cell types; however, among the various cell fates, differentiation into adipocytes or osteoblasts is of particular relevance because the factors that enable osteoblastogenesis inhibit adipogenesis and vice versa. Noggin

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induces adipogenic differentiation of MSCs through a novel mechanism. People with a high body mass index have elevated circulating noggin levels in plasma. In addition to inhibiting the osteoblast differentiation of MSCs, noggin may induce adipogenesis. Alternatively, activation of PPAR-γ promotes the differentiation of MSCs into adipocytes over osteoblasts. By contrast, the Wnt signaling pathway inhibits adipogenesis while supporting osteogenesis. These two pathways can also influence each other. Wnt signaling negatively regulates adipogenesis through β-catenin, which inhibits PPAR-γ-induced genes. Wnt10b, one of the Wnt family members, plays a key role in bone formation. The induction of Wnt10b-mediated osteogenesis

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is caused by its ability to inhibit PPAR-γ expression. Adequate vitamin D supplements not only enhance osteoblast differentiation and function but also induce adipocyte apoptosis, resulting in increased bone mass and a reduced likelihood of osteoporosis development.

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Figure 4. Vitamin D deficiency and anemia in CKD CKD patients often present with increased serum markers of inflammation, anemia

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and EPO resistance. 25(OH)D and 1,25 (OH)2D deficiencies alter innate and adaptive immune function, which will increase inflammatory cytokine production (IL-6, IFN-γ, TFN-α) which will stimulate canonical janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, and phosphorylation of JAKs and STAT3. Phosphorylated-STAT3 homodimers enter the nucleus and bind to the hepcidin promoter to stimulate hepcidin expression in liver. The liver is the major source of hepcidin production. Inflammation stimulates, whereas erythropoiesis and growth factors decrease, hepcidin production. Hepcidin downregulates ferroportin in macrophages, enterocytes, and hepatocytes, leading to decreased iron release into the serum that is subsequently bound to transferrin for erythropoiesis. In addition, secondary hyperparathyroidism will directly inhibit erythroid progenitors, endogenous EPO synthesis, and RBC survival. It also indirectly promotes bone marrow fibrosis, hyperphosphataemia, and increase serum alkaline phosphatase. All of them will lead to ESA hyporesponsiveness.

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Brain cells

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Decidual stromal cells

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Dendritic cells

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Macrophages

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T or B cells

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Fetal trophoblasts

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Osteoblasts

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Osteoclasts

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Keratinocytes

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Breast cells

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Prostate cells

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Pancreas cells

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Colon cells

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Renal tubular cells

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Enterocytes

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Vascular endothelial cells

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Human cells containing 1-α-hydroxylase and vitamin D receptor

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Highlights  CKD patients are prone to deficiencies in both 25(OH)D and 1,25(OH)2D.  Circulating 25(OH)D can convert to 1,25(OH)2D in the extra-renal tissues.  Native vitamin D improves skeletal quality and quantity in CKD patients.  Native vitamin D promotes extra-skeletal health in CKD patients.  The benefit of combination of native and active vitamin D therapy in CKD.