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converts 7-dehydrocholesterol to previtamin D<span class="elsevierStyleInf">3</span>&#46; Then&#44; previtamin D is converted into cholecalciferol by thermal isomerization&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">5&#44;12&#44;13</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Vitamin D&#44; either from diet or endogenously synthesized&#44; is transported bound to vitamin D binding protein to the liver&#44; where it is hydroxylated into 25-hydroxyvitamin-D &#40;25&#40;OH&#41;D or calcidiol&#41;&#44; by 25-hydroxylase enzyme&#46; In turn&#44; 25&#40;OH&#41;D is transported to the kidney&#44; where it is converted into its active form&#44; calcitriol &#40;1&#44;25-dihydroxyvitamin-D or 1&#44;25&#40;OH&#41;<span class="elsevierStyleInf">2</span>D&#41; by the enzyme 1-&#945;-hydroxylase&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">5&#44;12&#8211;14</span></a> Renal hydroxylation&#44; in contrast to hepatic hydroxylation&#44; is highly regulated by serum levels of phosphorus&#44; calcium&#44; parathormone &#40;PTH&#41;&#44; FGF-23 and by active vitamin D itself&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">6</span></a> Similarly&#44; 24-hydroxylase&#44; the enzyme responsible for the calcitriol degradation&#44; is also tightly controlled by serum levels of FGF-23&#44; calcitriol itself and PTH&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">6&#44;9&#44;10&#44;15</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Calcitriol is responsible for vitamin D functions on mineral and bone metabolism&#44; but it also has a pleiotropic effect on the modulation of endothelial function&#44; immune response and regulation of the cell cycle&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">13&#44;14&#44;16&#44;17</span></a> This vitamin increases plasma concentration of calcium and phosphorus&#44; by stimulating intestinal absorption but also renal and bone resorption&#46; The resulting hypercalcemia inhibits the secretion of PTH&#44; which is also directly inhibited by vitamin D itself&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">15</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Beyond renal expression&#44; 1-&#945;-hydroxylase enzyme is also present in other cells such as parathyroid cells&#44; macrophages&#44; osteoblasts&#44; smooth muscle cells&#44; endothelial cells and tissues such as the pancreas&#44; breast&#44; prostate and colon&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">5&#44;6&#44;8&#44;9&#44;18</span></a> Peripheral hydroxylation plays a key role&#44; due to the possibility of converting 25&#40;OH&#41;D into its active form by maintaining adequate levels of 1-&#945;-hydroxylase substract&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">8</span></a> This is the rationale for native vitamin D supplementation even in patients with impaired renal function&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Vitamin D metabolism disorders in chronic kidney disease</span><p id="par0055" class="elsevierStylePara elsevierViewall">Vitamin D deficiency has a high prevalence in CKD and it is likely to worsen with kidney disease progression&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">9&#44;15&#44;19</span></a> In fact&#44; Caravaca-Font&#225;n et al&#46; demonstrated that more than 80&#37; of 367 pre-dialysis patients with a mean glomerular filtration rate &#40;GFR&#41; of 14&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;1<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#44; had plasma 25&#40;OH&#41;D concentration &#60;20<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">2</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Several factors contribute to vitamin D deficiency in these patients&#44; interfering with all phases of their metabolism&#44; respectively&#44; production&#44; activation and degradation&#46;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">2&#44;6&#44;9&#44;13&#44;15&#44;16&#44;19&#8211;26</span></a><a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarizes the possible causes of deficiency&#44; according to the respective phase of metabolism&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">In addition to these factors&#44; vitamin D concentration seems to still be influenced by body mass index&#46; Figuiredo-Dias et al&#46; reported higher storage of vitamin D in adipose tissue with increased fat mass&#44; which is no longer available for hepatic 25-hydroxylation&#46;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">27</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Since the early stages of CKD&#44; there is an increase in levels of FGF-23 and PTH in an attempt to correct the trend toward hyperphosphataemia and hypocalcemia&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">9&#44;28</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">FGF-23 inhibits renal phosphorous reabsorption and reduces serum levels of calcitriol by inhibiting renal 1-&#945;-hydroxylase enzyme and stimulating 24-hydroxylase enzyme&#44; which is responsible for vitamin D catabolism&#46; So&#44; FGF-23 contributes to phosphorus balance in pre-dialysis CKD&#44; but aggravates calcitriol deficiency&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">9&#44;10&#44;15&#44;24&#44;28</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Thus&#44; SHPT develops as an inadequate response to hyperphosphatemia&#44; hypocalcemia and progressive decline in calcitriol levels&#46; PTH increases renal calcium reabsorption and tubular phosphorus excretion&#44; also stimulating calcitriol synthesis&#44; although in CKD&#44; this process is compromised by hyperphosphatemia and functional renal mass reduction&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">6&#44;15</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">The incidence and severity of SHPT increases as renal function decreases and may significantly interfere with bone remodeling and mineralization&#44; increasing the risk of fractures and cardiovascular events&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">7&#44;15</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Despite the expected calcitriol deficiency in CKD&#44; there is evidence that even in terminal CKD&#44; there is a capability to convert 25&#40;OH&#41;D to calcitriol&#44; emphasizing the importance of extra-renal production of calcitriol&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">6&#44;8&#44;18&#44;29</span></a> So&#44; native vitamin D supplementation has a growing interest among these patients&#44; since it ensures substrate for peripheral hydroxylation&#44; in order to attenuate calcitriol deficiency&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Assessment of Vitamin D status</span><p id="par0095" class="elsevierStylePara elsevierViewall">The quantification of 25&#40;OH&#41;D is the best biomarker to evaluate the vitamin D reserve in the body&#44;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">30</span></a> because it has a long half-life &#40;approximately 3 weeks&#41; and allows to evaluate simultaneously the sources of vitamin D&#44; respectively&#44; nutritional intake and cutaneous synthesis&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">14</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Until now&#44; there is no consensus regarding 25&#40;OH&#41;D reference values due to the lack of a standardized method for quantification and the fact that the optimal level of 25&#40;OH&#41;D is based on PTH stabilization&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">11</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Concerning 25&#40;OH&#41;D measurement&#44; there are different types of assays&#46; Although the gold standard is high-performance liquid chromatography&#44; this is not widely available&#44; because it is an expensive and slow method and also requires expertise and special instrumentation&#46; Different assays have been developed&#44; but the most used in the majority of studies is Diasorin automated chemiluminescence assay&#44; which is co-specific for 25&#40;OH&#41;D<span class="elsevierStyleInf">2</span> and 25&#40;OH&#41;D<span class="elsevierStyleInf">3</span>&#44; reporting a total of 25&#40;OH&#41;D concentration&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">14</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Despite divergence in studies&#44; most consider that&#44; in general population&#44; vitamin D insufficiency corresponds to a serum 25&#40;OH&#41;D concentration between 20 and 29<span class="elsevierStyleHsp" style=""></span>ng&#47;mL and a deficiency &#60;20<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">5&#44;31</span></a> Holick concluded that the serum 25&#40;OH&#41;D level of approximately 30<span class="elsevierStyleHsp" style=""></span>ng&#47;mL corresponded to the point at which the rise in 25&#40;OH&#41;D concentration was no longer reflected in plasma PTH concentration reduction&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">In turn&#44; the Institute of Medicine&#44; for general population&#44; considered a plasma concentration of 25&#40;OH&#41;D &#60;12<span class="elsevierStyleHsp" style=""></span>ng&#47;mL as a deficiency&#44; 12&#8211;19<span class="elsevierStyleHsp" style=""></span>ng&#47;mL as a insufficiency and &#8805;20<span class="elsevierStyleHsp" style=""></span>ng&#47;mL as an adequate concentration&#44; stating that there is no benefit in concentrations &#8805;30<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">32</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">However&#44; the question remains whether these reference values are applicable to CKD patients&#46; Ennis et al&#46; after analysis of 14&#44;289 chronic kidney patients found that concentrations of 25&#40;OH&#41;D &#62;42&#8211;48<span class="elsevierStyleHsp" style=""></span>ng&#47;mL were required to achieve stable PTH levels&#44; thus concluding higher vitamin D concentration to CKD patients&#46;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">33</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Although there is evidence suggesting higher levels of vitamin D&#44; the Kidney Disease Outcomes Quality Initiative &#40;K&#47;DOQI&#41; guidelines&#44; published in 2003&#44; recommend a plasma 25&#40;OH&#41;D concentration &#8805;30<span class="elsevierStyleHsp" style=""></span>ng&#47;mL to prevent SHPT and to decrease the incidence of fractures in patients with stage 3 and 4 CKD&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">34</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">However&#44; the Kidney Disease Improvement Global Outcomes &#40;KDIGO&#41; guidelines&#44; recently published in 2017&#44; do not consider any reference value for 25&#40;OH&#41;D level&#44; recommending their evaluation&#44; when PTH levels are progressively increasing or persistently above upper normal&#44; at stages of CKD above 3&#46; This recommendation&#44; although recent&#44; represents a low level of evidence due to absence of high quality scientific studies&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">7</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Vitamin D supplementation in CKD</span><p id="par0135" class="elsevierStylePara elsevierViewall">The K&#47;DOQI guidelines recommend correcting the plasma 25&#40;OH&#41;D concentration with ergocalciferol according to a 6-month regimen&#44; as presented in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">34</span></a> However&#44; it is not yet clear in literature whether K&#47;DOQI strategy is adequate to treat vitamin D deficiency and SHPT&#46; Studies that tested the strategy suggested by K&#47;DOQI did not find improvements in serum concentration of 25&#40;OH&#41;D or PTH&#46;<a class="elsevierStyleCrossRefs" href="#bib0485"><span class="elsevierStyleSup">35&#44;36</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0140" class="elsevierStylePara elsevierViewall">Later&#44; KDIGO guidelines published in 2009&#44; recently updated in 2017&#44; recommend that deficiency and insufficiency of vitamin D in CKD with GFR &#60;60<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> should be corrected through strategies provided to general population&#46; According to the same guidelines&#44; vitamin D supplementation in pre-dialysis patients should use native forms and reserve treatment with calcitriol and its analogs for more severe or progressive phases of SHPT&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">7</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Native vitamin D supplementation has been of increasing interest in literature since there is evidence of 1-&#945;-hydroxylase enzyme activity in extra-renal cells&#44; giving the possibility of peripheral conversion of 25&#40;OH&#41;D to calcitriol&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">5&#44;6&#44;8&#44;16</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Native supplementation includes ergocalciferol or vitamin D<span class="elsevierStyleInf">2</span>&#44; cholecalciferol or vitamin D<span class="elsevierStyleInf">3</span> and calcifediol&#46; There are many trials regarding the first two&#44; being calcifediol the last agent to be studied&#46; <a class="elsevierStyleCrossRefs" href="#tbl0015">Tables 3&#8211;5</a> summarize the randomized controlled trials &#40;RCT&#41; that were performed with these three forms of native vitamin D for biochemical and clinically relevant endpoints&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><p id="par0155" class="elsevierStylePara elsevierViewall">The Italian Nephrology Society published&#44; in 2016&#44; a &#8220;position statement&#8221; about vitamin D in CKD&#44; suggesting to supplement patients in stage 3&#8211;5 CKD with a plasma 25&#40;OH&#41;D concentration &#60;30<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#44; using the scheme &#40;ergocalciferol&#44; cholecalciferol or calcifediol&#41; with which the nephrologist is more confident&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">37</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">By contrast&#44; the Spanish Society of Nephrology considered calcifediol as a more convenient option&#44; although dosage and regimen to be used is not disclosed&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">38</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">It is important to emphasize that regardless of the native form chosen&#44; the risk of toxicity should always be considered including adverse effects of hypervitaminosis D&#44; such as hypercalcemia and hyperphosphataemia&#46; Therefore&#44; native vitamin D supplementation should be discontinued when serum 25&#40;OH&#41;D concentration is greater than 100<span class="elsevierStyleHsp" style=""></span>ng&#47;mL and&#47;or when the serum calcium level exceeds 10&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#44; in the absence of administration of calcitriol&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">37</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Vitamin D supplementation and biochemical endpoints</span><p id="par0170" class="elsevierStylePara elsevierViewall">Most of studies indicate that vitamin D supplementation improves plasma 25&#40;OH&#41;D concentration&#44; with different effects on calcitriol and PTH levels&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">Reports show that ergocalciferol is less effective to the increase of 25&#40;OH&#41;D plasma concentration&#44; due to its plant origin&#44; lower half-life&#44;<a class="elsevierStyleCrossRefs" href="#bib0505"><span class="elsevierStyleSup">39&#44;40</span></a> a methyl group at C<span class="elsevierStyleInf">24</span> which confers lower conversion to 25&#40;OH&#41;D<span class="elsevierStyleInf">2</span> and also lower affinity to the binding protein<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">41</span></a> by its faster catabolism&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">42</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">In addition&#44; Armas et al&#46; demonstrated in a randomized trial that the administration of a single oral dose of 50&#44;000<span class="elsevierStyleHsp" style=""></span>IU of ergocalciferol or cholecalciferol in 20 healthy men&#44; 10 in each group&#44; produced similar initial increases in plasma 25&#40;OH&#41;D concentration &#40;mean plasma 25&#40;OH&#41;D concentration after 3 days&#44; 27&#46;5<span class="elsevierStyleHsp" style=""></span>ng&#47;mL in the ergocalciferol group <span class="elsevierStyleItalic">vs&#46;</span> 29&#46;9<span class="elsevierStyleHsp" style=""></span>ng&#47;mL in the cholecalciferol group&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41; indicating equivalent absorption&#46; However&#44; after 4 weeks&#44; cholecalciferol maintained high concentration of 25&#40;OH&#41;D for more time &#40;mean change in plasma 25&#40;OH&#41;D concentration 33&#46;7<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#41;&#44; whereas in the ergocalciferol group&#44; it had returned to the baseline level after 2 weeks&#46; Comparing the area under the curve&#44; cholecalciferol showed a more than 3-fold difference in potency&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">43</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">To evaluate the impact of ergocalciferol supplementation as recommended by K&#47;DOQI&#44; Qunibi et al&#46; performed a retrospective observational study&#44; which included 88 patients with 25&#40;OH&#41;D insufficiency or deficiency from all stages of CKD&#46; The authors concluded that the dosage strategy recommended by K&#47;DOQI is inadequate for vitamin D insufficiency or deficiency correction and treatment of SHPT&#46; In fact&#44; only 25&#37; of treated patients reached the reference value of 30<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">35</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">In a previous prospective observational paper&#44; Zisman et al&#46; used an adapted K&#47;DOQI guideline scheme in 24 stage 3 patients and 28 stage 4 CKD patients&#46; After an average period of 7 months&#44; plasma 25&#40;OH&#41;D concentration increased from 20&#46;3 to 31&#46;6<span class="elsevierStyleHsp" style=""></span>ng&#47;mL &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#41; in stage 3 patients and from 18&#46;8 to 35&#46;4<span class="elsevierStyleHsp" style=""></span>ng&#47;mL &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#41; in stage 4 patients&#46; In this study 58&#37; and 68&#37; of stage 3 and 4 patients&#44; respectively&#44; reached 30<span class="elsevierStyleHsp" style=""></span>ng&#47;mL in 25&#40;OH&#41;D level&#46; This increase was associated with increased concentrations of calcitriol in both stage 3 and stage 4&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">44</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">About plasma PTH concentration&#44; study by Qunibi et al&#46; found no significant decrease<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">35</span></a> and study by Zisman et al&#46; found a significant decrease only in stage 3 patients &#40;from 154&#46;1 to 130&#46;5<span class="elsevierStyleHsp" style=""></span>pg&#47;mL &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;041&#41; with no relevant changes in stage 4 patients&#44; which led the authors to conclude that ergocalciferol would be useful only for stage 3 patients with no benefit in stage 4 of CKD&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">44</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">Beyond the controversy over the efficiency of the proposed recommendations&#44; several RCTs were conducted to better evaluate the effect of ergocalciferol supplementation&#46; The RCT by Gravensen et al&#46; enrolled 43 patients with stage 4 and 5 CKD&#44; who underwent 50&#44;000<span class="elsevierStyleHsp" style=""></span>IU of ergocalciferol per week&#46; The authors found an improvement in plasma 25&#40;OH&#41;D concentration &#40;25&#46;1<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#46;4 for 51&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&#46;8<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#41;&#44; without significant improvement at PTH level&#46; Since this study lasted 6 weeks&#44; it could have been an insufficient period to promote changes in PTH&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">16</span></a> However&#44; also in the 24-month RCT by Dreyer et al&#46;&#44; it was only found plasma 25&#40;OH&#41;D concentration improvement&#44; with no statistically significant change in PTH&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">45</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">In a more recent RCT&#44; Thimachai et al&#46; evaluated the effect of high dose ergocalciferol supplementation compared to K&#47;DOQI recommendation&#46; Sixty-eight patients were randomized into 2 groups&#44; one under the conventional scheme&#44; and another had the same regimen but twice the ergocalciferol dose&#46; At 8 weeks of supplementation&#44; the authors observed a significant improvement in 25&#40;OH&#41;D levels in both groups &#91;from 20&#46;99<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#46;68 to 33&#46;41<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#46;92<span class="elsevierStyleHsp" style=""></span>ng&#47;mL &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; in the high dose group and from 20&#46;84<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;21 to 23&#46;42<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;89<span class="elsevierStyleHsp" style=""></span>ng&#47;mL &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;026&#41; in the conventional regimen group&#93;&#46; In relation to plasma PTH concentration&#44; it decreased significantly from 90&#46;75<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>67&#46;12 to 76&#46;40<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>45&#46;97<span class="elsevierStyleHsp" style=""></span>pg&#47;mL &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;024&#41; in the high dose ergocalciferol group&#44; and no significant changes were observed with the conventional group&#46; In addition&#44; the percentage of patients reaching plasma 25&#40;OH&#41;D concentration &#62;30<span class="elsevierStyleHsp" style=""></span>ng&#47;mL was significantly higher in the high dose group than in the conventional dose group &#40;60&#37; <span class="elsevierStyleItalic">vs&#46;</span> 19&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; It should be noted that although a duplicate dose of ergocalciferol was used&#44; no adverse effects were observed including hypercalcemia or hyperphosphataemia&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">36</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">Different dosages of cholecalciferol were also tested in prospective trials&#46; Oksa et al&#46; in a RCT&#44; which involved 87 chronic kidney patients&#44; stages 2&#8211;4&#44; it was compared vitamin D supplementation with two doses of cholecalciferol&#44; one low &#40;5000<span class="elsevierStyleHsp" style=""></span>IU&#47;week&#41; <span class="elsevierStyleItalic">vs&#46;</span> one high &#40;20&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;week&#41;&#44; on mineral metabolism&#44; vitamin D status and PTH plasma concentration&#46; After 12 months&#44; the authors found a significant increase in plasma 25&#40;OH&#41;D concentration in both groups &#91;from 15 to 28<span class="elsevierStyleHsp" style=""></span>ng&#47;mL &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; in the low dose group and from 16 to 37<span class="elsevierStyleHsp" style=""></span>ng&#47;mL &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; in the high dose group&#93;&#46; The increase in the high dose group was statistically higher than that observed in the low dose group &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#46; Most patients receiving low dose cholecalciferol did not reach the reference value according to K&#47;DOQI&#44; while approximately 75&#37; of the patients from high dose cholecalciferol group reached that value&#44; without significant changes in calcium and phosphorus&#46; Regarding plasma PTH concentrations&#44; the authors found significantly decrease in both groups &#91;from 63 to 48<span class="elsevierStyleHsp" style=""></span>pg&#47;mL &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; in the low dose group and from 50 to 40<span class="elsevierStyleHsp" style=""></span>ng&#47;mL &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; in the high dose group&#93;&#44; without significant differences between the groups&#46; So&#44; a high dose of cholecalciferol was only more effective at increasing plasma 25&#40;OH&#41;D level&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">46</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">The studies with cholecalciferol supplementation reproduced better results in increasing plasma 25&#40;OH&#41;D concentration&#44; and more often it reached the reference value of 30<span class="elsevierStyleHsp" style=""></span>ng&#47;mL after the supplementation scheme&#46; Wetmore et al&#46; conducted a RCT in which 44 pre-dialysis chronic kidney patients were compared with equal weekly doses of 1250<span class="elsevierStyleHsp" style=""></span>&#956;g &#40;50&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#41; ergocalciferol or 1250<span class="elsevierStyleHsp" style=""></span>&#956;g &#40;50&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#41; cholecalciferol over a period of 12 weeks&#44; assessing its influence on concentrations of 25&#40;OH&#41;D&#44; 1&#44;25&#40;OH&#41;<span class="elsevierStyleInf">2</span>D and PTH&#46; Plasma 25&#40;OH&#41;D level was further evaluated 6 weeks after completion of therapy&#46; The authors found that cholecalciferol was more effective at increasing plasma 25&#40;OH&#41;D concentration while supplementation was occurring &#91;mean change in 25&#40;OH&#41;D concentration was 45&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>16&#46;5<span class="elsevierStyleHsp" style=""></span>ng&#47;mL &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41; in the cholecalciferol group and 30&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>15&#46;3<span class="elsevierStyleHsp" style=""></span>ng&#47;mL in the ergocalciferol group&#93;&#46; At the end of supplementation&#44; concentration of 25&#40;OH&#41;D decreased with both supplements&#44; without differences between them&#46; This suggests that these patients require continued supplementation to maintain serum 25&#40;OH&#41;D level&#46; No significant differences were found in plasma concentration of 1&#44;25&#40;OH&#41;<span class="elsevierStyleInf">2</span>D in both groups&#46; The authors verified that in the cholecalciferol group&#44; there was an increase in 1&#44;25&#40;OH&#41;<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">3</span> portion and reduction of 1&#44;25&#40;OH&#41;<span class="elsevierStyleInf">2</span>D<span class="elsevierStyleInf">2</span> portion&#46; The inverse occurred in the ergocalciferol group&#44; explaining why there was balance in total plasma concentration of 1&#44;25&#40;OH&#41;<span class="elsevierStyleInf">2</span>D&#46; Regarding the change obtained in PTH levels&#44; patients in the cholecalciferol group had a greater reduction than patients treated with ergocalciferol &#40;mean change PTH &#8722;15&#46;3 <span class="elsevierStyleItalic">vs</span> 2&#46;3<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;02&#41;&#44; however&#44; a difference found in the baseline PTH values at the beginning of the study&#44; makes this interpretation more complex from statistical point of view&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">47</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">Despite these studies promising results&#44; a review published by Agarwal and Georgianos included 4 RCTs performed in pre-dialytic patients submitted to cholecalciferol supplementation and there was not any change in PTH level relative to placebo&#46; Thus&#44; the authors concluded that vitamin D supplementation in pre-dialysis CKD in order to reduce plasma concentration of PTH is not yet justified by current evidence&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">48</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">Calcifediol is a product already hydroxylated at C<span class="elsevierStyleInf">25</span>&#44; serving as the direct substrate for 1-&#945;-hydroxylase&#46; Calcifediol has been suggested as an effective therapy to increase 25&#40;OH&#41;D levels in general population&#44; and its application in CKD is relatively recent&#46; There are two formulations of this compound&#58; a simple one&#44; which causes a rapid increase in 25&#40;OH&#41;D concentration and a rapid catabolism by stimulated expression of FGF-23&#59; and an extended-release &#40;ER&#41; formulation which leads to a more progressive and effective increase in circulating 25&#40;OH&#41;D levels&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">49</span></a></p><p id="par0230" class="elsevierStylePara elsevierViewall">Sprague et al&#46; conducted a double-blind RCT to evaluate the effect of ER calcifediol on SHPT treatment&#44; which enrolled 78 patients with pre-dialysis CKD&#44; mean GFR of 38&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>10&#46;01<span class="elsevierStyleHsp" style=""></span>mL&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#44; serum PTH levels &#62;70<span class="elsevierStyleHsp" style=""></span>pg&#47;mL and 25&#40;OH&#41;D &#60;30<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#46; For 6 weeks&#44; patients received daily treatments of ER calcifediol doses of 30&#44; 60 and 90<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;day or placebo&#46; The authors found that plasma 25&#40;OH&#41;D concentration increased in proportion to the administered dose&#44; reaching after 6 weeks of therapy 37&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>2&#46;0<span class="elsevierStyleHsp" style=""></span>ng&#47;mL and 84&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;5<span class="elsevierStyleHsp" style=""></span>ng&#47;mL on 30 and 90<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;day groups of ER calcifediol&#44; respectively&#44; and reduced by an average of 1&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>0&#46;7<span class="elsevierStyleHsp" style=""></span>ng&#47;mL in combined placebo group&#46; Differences between 3 supplementation groups and placebo were statistically significant &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#41;&#46; Regarding the plasma PTH level&#44; it decreased from the mean baseline value &#40;140&#46;3<span class="elsevierStyleHsp" style=""></span>pg&#47;mL&#41; by about 20&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#46;2&#37;&#44; 32&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;7&#37; and 39&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>4&#46;3&#37; in groups submitted to 30&#44; 60 and 90<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;day of ER calcifediol&#44; respectively&#44; and increased 17&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;8&#37; in combined placebo group &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;005&#41;&#46; Despite a single episode of hypercalcemia&#44; no hyperphosphatemic or hypercalciuric episodes were detected&#44; therefore&#44; authors concluded that oral supplementation with ER calcifediol is a safe and effective strategy for the treatment of SHPT associated with vitamin D insufficiency&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">19</span></a></p><p id="par0235" class="elsevierStylePara elsevierViewall">Recently&#44; to further examine safety and efficacy of ER calcifediol&#44; Sprague et al&#46; published a multicenter study composed by two 26-week randomized&#44; double-blind&#44; placebo-controlled trial and a subsequent 26-week extension&#44; enrolling 429 subjects with stage 3 or 4 CKD&#44; SHPT and vitamin D insufficiency&#46; Subjects were randomized 2&#58;1 to receive oral ER calcifediol &#40;30 or 60<span class="elsevierStyleHsp" style=""></span>&#956;g&#41; or placebo once daily&#46; After treatment&#44; more than 95&#37; of patients receiving ER calcifediol achieved serum 25&#40;OH&#41;D concentration &#62;30<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#46; The ER calcifediol replacement also reduced plasma PTH by at least 10&#37; in 72&#37; of the patients&#44; and reductions &#8805; 30&#37; increased progressively with treatment extension&#44; achieving 50&#37; at 52 weeks&#46; The authors concluded that lowering PTH with ER calcifediol was independent of CKD stage and not associated to adverse events&#44; making ER calcifediol a safe and effective treatment for these patients&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">50</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Vitamin D supplementation and cardiovascular endpoints</span><p id="par0240" class="elsevierStylePara elsevierViewall">Cardiovascular disease &#40;CVD&#41; is the most common cause of mortality in patients with CKD and has been associated with vitamin D deficiency&#46; In a meta-analysis&#44; Pilz et al&#46; verified that it occurs an increase of 14&#37; in risk of all-cause mortality in patients with CKD by each 10<span class="elsevierStyleHsp" style=""></span>ng&#47;mL of reduction in vitamin D level&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">51</span></a> In another meta-analysis&#44; Duranton et al&#46; suggested that vitamin D replacement reduces cardiovascular mortality risk in 27&#37; when administered CKD patients&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">52</span></a></p><p id="par0245" class="elsevierStylePara elsevierViewall">Endothelial dysfunction happens early in patients with CKD and is associated with origination of atherosclerosis and future cardiovascular events&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">53</span></a> Vascular calcification is a common complication in CKD and promotes an increase on cardiovascular morbidity and mortality rates&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">Chitalia et al&#46; investigated the relationship between vitamin D levels and endothelial function in nondiabetic with mild to moderate CKD patients&#46; Endothelial function was evaluated by endothelium-dependent brachial artery flow mediated dilation &#40;FMD&#41;&#44; defined as the maximum percent increase in vessel diameter during reactive hyperaemia&#46; The authors showed that patients with serum 25&#40;OH&#41;D level &#8804;15<span class="elsevierStyleHsp" style=""></span>ng&#47;mL had lower FMD when compared to patients with 25&#40;OH&#41;D level &#62;15<span class="elsevierStyleHsp" style=""></span>ng&#47;mL &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;007&#41;&#46; A direct association between vitamin D deficiency and low FMD was found &#40;<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;44&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; A multivariate regression analysis indicated an independent association between low vitamin D levels and low FMD&#44; even after adjustments for traditional cardiovascular risk factors&#44; such as age&#44; gender&#44; smoking&#44; hypertension and hyperlipidaemia&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">53</span></a> Also&#44; Capusa et al&#46; in their recent cross-sectional study concluded&#44; in 87 clinically stable CKD patients&#44; that hypovitaminosis D is associated with subclinical peripheral arterial disease&#44; independently of other traditional or non-traditional risk factors for atherosclerosis&#46; A univariate analysis identified a correlation between serum concentration of 25&#40;OH&#41;D &#60;15<span class="elsevierStyleHsp" style=""></span>ng&#47;mL and increased aortic calcifications scores &#40;<span class="elsevierStyleItalic">r</span>s<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;23&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;03&#41;&#59; and through a multivariate binomial logistic regression models adjusted for cardiovascular risk factors&#44; lower levels of 25&#40;OH&#41;D were considered an independent predictor for pathological ankle-brachial index &#40;beta 0&#46;84&#59; 95&#37; CI of beta 0&#46;71&#8211;1&#46;00&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">54</span></a></p><p id="par0255" class="elsevierStylePara elsevierViewall">There are few studies about vitamin D supplementation and endothelial dysfunction&#46; Recently&#44; Kumar et al&#46; published a randomized&#44; double-blinded&#44; placebo-controlled clinical trial in which 120 adult subjects with nondiabetic CKD stage 3&#8211;4 and serum 25&#40;OH&#41;D level &#8804;20<span class="elsevierStyleHsp" style=""></span>ng&#47;mL were randomized to receive either two directly observed oral doses of cholecalciferol &#40;300&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#41; or matching placebo at baseline and after 8 weeks&#46; Cholecalciferol treatment significantly improved vascular function as increased FMD in this group <span class="elsevierStyleItalic">vs&#46;</span> sustained in the placebo group &#40;between-group difference in mean change 5&#46;49&#37;&#59; 95&#37; CI 4&#46;34&#37; to 6&#46;64&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and changes were correlated with 25&#40;OH&#41;D levels&#46; In addition&#44; endothelium-independent nitroglycerine mediated dilatation &#40;NMD&#41; and pulse wave velocity &#40;PWV&#41; also improved after intervention &#91;between-group difference in mean change&#58; 2&#46;85&#37; &#40;95&#37; CI 1&#46;41&#37; to 4&#46;84&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; and &#8722;1&#46;24<span class="elsevierStyleHsp" style=""></span>m&#47;s &#40;95&#37; CI &#8722;2&#46;16 to &#8722;0&#46;74&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41; for NMD and PWV&#44; respectively&#93;&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">55</span></a></p><p id="par0260" class="elsevierStylePara elsevierViewall">The NMD has been used as a control test for FMD&#46; The PWV is a marker of arterial stiffness&#44; atherosclerotic transformation and an independent predictor of CVD and mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">55</span></a></p><p id="par0265" class="elsevierStylePara elsevierViewall">Kumar et al&#46; at the end of this study&#44; tested the same intervention in placebo group and concluded that even in this group there were an improvement in endothelial function and vascular stiffness after cholecalciferol supplementation &#40;mean change in FMD&#37;&#58; 5&#46;8&#37;&#59; 95&#37; CI 4&#46;0&#37; to 7&#46;5&#37;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; NMD&#44; PWV&#44; PTH&#44; FGF-23 and interleukin-6 also showed favorable changes&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">56</span></a></p><p id="par0270" class="elsevierStylePara elsevierViewall">Levin et al&#46; also assessed the vitamin D supplementation effect on PWV&#46; In a randomized&#44; placebo-controlled trial&#44; the authors compared fixed doses of calcifediol &#40;5000<span class="elsevierStyleHsp" style=""></span>IU&#41;&#44; calcitriol &#40;0&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;g&#41; or placebo thrice weekly on PWV&#44; in 119 stable patients with CKD stage 3b-4&#46; In spite of randomization&#44; there were differences in baseline PWV values&#44; so analysis took adjustments into account&#46; After 6 months&#44; PWV decreased in the calcifediol group &#40;mean change&#58; &#8722;1&#46;1&#59; 95&#37; CI &#8722;2&#46;2 to 0&#46;1<span class="elsevierStyleHsp" style=""></span>m&#47;s&#41;&#44; remained similar in the calcitriol group &#40;mean change&#58; 0&#46;2&#59; 95&#37; CI &#8722;0&#46;9 to 1&#46;4<span class="elsevierStyleHsp" style=""></span>m&#47;s&#41; and increased in the placebo group &#40;mean change&#58; 1&#46;1&#59; 95&#37; CI &#8722;0&#46;1 to 2&#46;2<span class="elsevierStyleHsp" style=""></span>m&#47;s&#41;&#46; The results of calcifediol <span class="elsevierStyleItalic">versus</span> placebo groups were statistically different &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; However&#44; when baseline PWV was included as a covariate&#44; there were not significant differences&#46; Observationally&#44; patients in the highest 25&#40;OH&#41;D tertile at the end of the trial had significant decreases in PVW &#40;mean change&#58; &#8722;1&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>1&#46;0<span class="elsevierStyleHsp" style=""></span>m&#47;s&#41; compared with the middle and lower tertiles &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#41;&#46; These results suggest that vitamin D supplementation decrease PWV in CKD patients&#44; but more trials are needed to confirm these findings&#44; because of attenuated effects when adjustments were done&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">57</span></a></p><p id="par0275" class="elsevierStylePara elsevierViewall">Vitamin D may have a protective effect over arterial wall because it reduces smooth muscle cell proliferation and decreases vascular inflammation &#40;by reduction of pro-inflammatory cytokines such as interleukin-6 and tumor necrosis factor and increases secretion of the anti-inflammatory cytokine&#44; like interleukin-10&#41;&#46; Thus&#44; vitamin D seems to be crucial in the atherosclerotic process and an important target for treatment in the context of CKD&#44; not only for bone and mineral regulation&#44; but also for cardiovascular benefit&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">54</span></a></p><p id="par0280" class="elsevierStylePara elsevierViewall">In contrast to these papers&#44; Kendrick et al&#46; promoted an RCT whose aim was to compare the effects of oral cholecalciferol and calcitriol on FMD&#46; A total of 128 patients were enrolled with CKD 3b-4 and serum 25&#40;OH&#41;D levels &#60;30<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#46; They were randomized to receive either oral cholecalciferol &#40;4000<span class="elsevierStyleHsp" style=""></span>IU daily for 1 month&#44; then 2000<span class="elsevierStyleHsp" style=""></span>IU daily&#41; or calcitriol &#40;0&#46;25<span class="elsevierStyleHsp" style=""></span>&#956;g daily for 1 month&#44; then 0&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;g daily&#41;&#46; The authors found no differences in FMD or NMD after 6 months of treatment and neither changes in total vascular endothelial cell expression of NFkB or in inflammation markers&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">58</span></a></p><p id="par0285" class="elsevierStylePara elsevierViewall">In fact&#44; these recent RCTs were of extreme importance&#44; persisting uncertainty about the effectiveness of vitamin D replacement on cardiovascular endpoints in CKD patients&#46;</p><p id="par0290" class="elsevierStylePara elsevierViewall">Regarding vascular calcification&#44; subjacent factors remain under investigation&#44; but it seems to result from an imbalance between factors that promote and inhibit calcification&#44; under some pathological circumstances&#44; such as uremia&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">59</span></a> Hyperphosphatemia and excess of calcitriol accelerates an ostegenic transformation of vascular smooth muscle&#46; Vitamin D has a paradoxal effect over vascular calcification&#46; Its action on regulation of mineral metabolism may promote calcification&#44; but other functions&#44; such as cell cycle regulation and inflammatory response modulation may have a preventive effect&#46;<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">60</span></a> Because of this good effect&#44; some authors defend that reasonable doses of vitamin D could provide a survival benefit for patients with CKD&#46;<a class="elsevierStyleCrossRefs" href="#bib0585"><span class="elsevierStyleSup">55&#44;60</span></a> Also KDIGO guidelines recommend the use of calcitriol or vitamin D analogs not routinely in pre-dialysis patients&#44; but reserve them for treatment of severe and progressive SHPT to prevent episodes of hypercalcemia and vascular calcifications&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">7</span></a></p><p id="par0295" class="elsevierStylePara elsevierViewall">More investigation about vitamin D supplementation is needed to understand the best supplement and recommended doses to avoid adverse events like vascular calcifications&#46;</p><p id="par0300" class="elsevierStylePara elsevierViewall">Concerning hard clinical outcomes&#44; to our knowledge&#44; only a retrospective study of Lishmanov et al&#46; was conducted to analyze if vitamin D replacement can decrease the incidence of cardiovascular events&#46; The study enrolled 126 men&#44; average age of 70 years&#44; CKD stages 3&#8211;4 with serum 25&#40;OH&#41;D level &#60;30<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#46; After 6 months of ergocalciferol supplementation&#44; according to modified K&#47;DOQI guidelines&#44; the patients whose serum 25&#40;OH&#41;D level was increased by 25&#37; from baseline were included in treatment group &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>90&#41;&#46; Others patients who did not respond to treatment were considered as controls &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>36&#41;&#46; At 27&#46;2 months&#44; the treatment group had fewer CVD events compared to the control group &#40;21&#37; <span class="elsevierStyleItalic">vs</span>&#46; 44&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#41;&#46; A multivariate logistic regression analysis estimated an odds ratio for 25&#40;OH&#41;D replacement status of 0&#46;37 &#40;95&#37; CI&#58; 0&#46;14&#8211;1&#46;0&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#44; after adjusting by age&#44; baseline PTH&#44; statin use&#44; CVD history&#44; diabetes and GFR&#46; Both overall survival and CVD-specific survival were higher in the treatment group compared to control with Kaplan&#8211;Meier survival curves statistically different &#40;Log rank <span class="elsevierStyleItalic">P</span> values of 0&#46;008 and 0&#46;02&#44; respectively&#41;&#46; Although there were some limitations&#44; as a retrospective study&#44; a relatively small group of patients&#44; possibility of unmeasured confounders and the fact of treatment group having a lower history of diabetes compared to controls &#40;53&#37; <span class="elsevierStyleItalic">vs</span>&#46; 73&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;02&#41;&#44; the authors concluded that vitamin D supplementation with ergocalciferol seems to be associated with significant reduction in cardiovascular events in patients with moderate CKD&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">61</span></a></p><p id="par0305" class="elsevierStylePara elsevierViewall">Of importance&#44; there are no controlled or observational prospective studies demonstrating that native vitamin D supplementation decreases mortality or hospitalizations&#46; Other outcomes such as fractures&#44; infections and neoplasias have also been proposed but remain to be confirmed&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusion</span><p id="par0310" class="elsevierStylePara elsevierViewall">Vitamin D insufficiency or deficiency are common in CKD&#44; in spite of lack of reference levels of serum 25&#40;OH&#41;D&#46; Vitamin D replacement has improved serum 25&#40;OH&#41;D and PTH levels&#44; and it was thought to guarantee vitamin D pleiotropic functions&#44; due to extra-renal hydroxylation&#46; Despite these advantages&#44; there was no consensus about the optimal threshold that must be achieved&#44; and which supplement and dosage must be chosen&#46; Uncertainty remains about effectiveness of vitamin D supplementation on endothelial dysfunction&#46; Several guidelines exist on the topic&#44; but also highlight the need of further investigation&#44; because data is often poor and inconsistent&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conflicts of interest</span><p id="par0315" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span></span>"
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          "identificador" => "xres1134871"
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        1 => array:2 [
          "identificador" => "xpalclavsec1066988"
          "titulo" => "Keywords"
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          "titulo" => "Resumen"
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            0 => array:1 [
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            ]
          ]
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          "titulo" => "Palabras clave"
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        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        5 => array:2 [
          "identificador" => "sec0010"
          "titulo" => "Vitamin D metabolism"
        ]
        6 => array:2 [
          "identificador" => "sec0015"
          "titulo" => "Vitamin D metabolism disorders in chronic kidney disease"
        ]
        7 => array:2 [
          "identificador" => "sec0020"
          "titulo" => "Assessment of Vitamin D status"
        ]
        8 => array:2 [
          "identificador" => "sec0025"
          "titulo" => "Vitamin D supplementation in CKD"
        ]
        9 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Vitamin D supplementation and biochemical endpoints"
        ]
        10 => array:2 [
          "identificador" => "sec0035"
          "titulo" => "Vitamin D supplementation and cardiovascular endpoints"
        ]
        11 => array:2 [
          "identificador" => "sec0040"
          "titulo" => "Conclusion"
        ]
        12 => array:2 [
          "identificador" => "sec0045"
          "titulo" => "Conflicts of interest"
        ]
        13 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2018-04-11"
    "fechaAceptado" => "2018-07-12"
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          "clase" => "keyword"
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          "palabras" => array:6 [
            0 => "Chronic renal disease"
            1 => "Native vitamin D"
            2 => "Ergocalciferol"
            3 => "Cholecalciferol"
            4 => "Calcifediol"
            5 => "Secondary hyperparathyroidism"
          ]
        ]
      ]
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palabras clave"
          "identificador" => "xpalclavsec1066989"
          "palabras" => array:6 [
            0 => "Enfermedad renal cr&#243;nica"
            1 => "Vitamina D nativa"
            2 => "Ergocalciferol"
            3 => "Colecalciferol"
            4 => "Calcifediol"
            5 => "Hiperparatiroidismo secundario"
          ]
        ]
      ]
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      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Chronic kidney disease patients have a high prevalence of vitamin D insufficiency&#47;deficiency&#46; Vitamin D deficiency has been associated with a variety of bone&#44; metabolic and cardiovascular disorders&#46; However&#44; the role of native vitamin D supplementation &#40;ergocalciferol&#44; cholecalciferol or calcifediol&#41; remains unclear in chronic kidney disease &#40;CKD&#41;&#44; particularly in the pre-dialytic phase&#46; Several international guidelines have been developed on CKD&#8211;Mineral and Bone Disorder&#44; but the optimal strategy for native vitamin D supplementation and its clinical benefit remains a subject of debate in the scientific community&#46; This paper aims to review the available literature&#44; including randomized clinical trials that evaluated the effects of native vitamin D supplementation on pre-dialysis CKD on biochemical and clinically relevant outcomes&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Los pacientes renales cr&#243;nicos tienen una elevada prevalencia de insuficiencia&#47;deficiencia de vitamina D&#46; El d&#233;ficit de vitamina D se ha asociado con una serie de cambios &#243;seos&#44; metab&#243;licos y cardiovasculares&#46; Sin embargo&#44; contin&#250;a por aclarar el papel de la suplementaci&#243;n con vitamina D nativa &#40;ergocalciferol&#44; colecalciferol o calcifediol&#41; en la enfermedad renal cr&#243;nica &#40;ERC&#41;&#44; especialmente en la fase pre-dial&#237;tica&#46; Varias pautas internacionales se han desarrollado sobre la enfermedad mineral y &#243;sea relacionada con la ERC&#44; pero la estrategia ideal de suplementaci&#243;n con vitamina D nativa y su beneficio cl&#237;nico contin&#250;an siendo objeto de debate en la comunidad cient&#237;fica&#46; Este trabajo pretende revisar la literatura disponible&#44; incluyendo ensayos cl&#237;nicos aleatorizados que evaluaron los efectos de la suplementaci&#243;n con vitamina D nativa en la ERC pre-di&#225;lisis en resultados bioqu&#237;micos y cl&#237;nicamente relevantes&#46;</p></span>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Production</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Insufficient sunlight exposure<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">21</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Low dietary vitamin D intake<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">22</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Impaired intestinal absorption<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">20&#44;26</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Impaired hepatic 25-hydroxylation<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">23</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Loss of 25&#40;OH&#41;D-DBP&#44; in case of severe proteinuria<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">2&#44;9&#44;20</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Activation</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Reduced glomerular filtration of 25&#40;OH&#41;D-DBP as a consequence of low GFR<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">9&#44;13&#44;62</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Impaired re-uptake of 25&#40;OH&#41;D&#44; due to reduced renal megalin expression<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">9&#44;25</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Reduced 1-&#945;-hydroxilase activity due to loss in the functional kidney mass&#44; high FGF-23 level&#44; progressive retention of &#8220;uremic toxins&#8221; and suppressive effect of N-terminally truncated PTH fragments<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">9&#44;15&#44;16&#44;24&#44;61</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleItalic">Degradation</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top"><span class="elsevierStyleHsp" style=""></span>Increased degradation of 1&#44;25&#40;OH&#41;<span class="elsevierStyleInf">2</span>D induced by high FGF-23 level<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">9&#44;16&#44;24</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Factors contributing to impaired vitamin D metabolism&#46;</p>"
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " colspan="4" align="center" valign="top" scope="col">Ergocalciferol dose supplementation</th></tr><tr title="table-row"><th class="td" title="table-head  " colspan="2" align="center" valign="top" scope="col">Serum 25&#40;OH&#41;D &#60;5<span class="elsevierStyleHsp" style=""></span>ng&#47;mL</th><th class="td" title="table-head  " align="center" valign="top" scope="col">Serum 25&#40;OH&#41;D 5&#8211;15<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col">Serum 25&#40;OH&#41;D 16&#8211;30<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">50&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;wk orally<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>12<span class="elsevierStyleHsp" style=""></span>weeks&#59; then monthly&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">50&#44;000<span class="elsevierStyleHsp" style=""></span>IU as single I&#46;M&#46; dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">50&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;wk<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>4<span class="elsevierStyleHsp" style=""></span>weeks&#59; then 50&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;month orally&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">50&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;month orally&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Ergocalciferol supplementation regimen for vitamin D insufficiency or deficiency in patients with CKD stage 3&#8211;4&#44; according to K&#47;DOQI&#46;</p>"
        ]
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        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; ns&#44; not significant&#59; 1&#44;25&#40;OH&#41;<span class="elsevierStyleInf">2</span>D&#44; calcitriol&#59; CKD&#44; chronic kidney disease&#59; FGF-23&#44; fibroblast growth factor 23&#59; K&#47;DOQI&#44; Kidney Disease Outcomes Quality Initiative&#59; LVMI&#44; left ventricular mass index&#59; PWV&#44; pulse wave velocity&#59; PTH&#44; parathyroid hormone&#59; RCT&#44; randomized controlled trial&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Author&#44; year&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Type of study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Participants&#44; CKD stage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Type of supplementation&#44; dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Follow-up&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">25 &#40;OH&#41;D &#40;ng&#47;ml&#41;<br>Change &#91;baseline-post&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">PTH &#40;pg&#47;ml&#41;<br>Change &#91;baseline-post&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Other outcomes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Gravesen et al&#46;&#44; 2013&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">43 CKD 4&#8211;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A&#58; 50&#46;000<span class="elsevierStyleHsp" style=""></span>IU&#47;week&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">26&#46;5 &#91;25&#46;1&#8211;51&#46;6&#93;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">a</span></a><br><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;12 &#91;180&#8211;168&#93;<br>ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8596; FGF-23<br>&#8596; 1&#44;25&#40;OH&#41;<span class="elsevierStyleInf">2</span>D&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">B&#58; Control&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;5 &#91;23&#46;7&#8211;24&#46;2&#93;<br>ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">11 &#91;168&#8211;179&#93;<br>ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Dreyer et al&#46;&#44; 2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">22 CKD 3<br>16 CKD 4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A&#58; 50&#44;000<span class="elsevierStyleHsp" style=""></span>IU weekly for one month followed by 50&#44;000<span class="elsevierStyleHsp" style=""></span>IU monthly for 5 months&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">24 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">21 &#91;14&#8211;35&#93;<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">b</span></a><br><a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;6 &#91;103&#8211;97&#93;<br>ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8593; Flux<br>&#8595; Autofluorescence<br>&#8596;PWV<br>&#8596;LVMI&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">B&#58; Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0 &#91;10&#8211;10&#93;<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">b</span></a><br>ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#43;17 &#91;119&#8211;136&#93;<br>ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Thimachai et al&#46;&#44; 2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">68 CKD 3&#8211;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A&#58; Double dose of K&#47;DOQI regimen&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12&#46;4 &#91;21&#8211;33&#46;4&#93;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">a</span></a><br><a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">&#42;&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;15 &#91;91&#8211;76&#93;<br><a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">&#42;&#42;&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">B&#58; K&#47;DOQI regimen<br>- If 25&#40;OH&#41;D &#60;5<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#44; 50&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;week<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>8 weeks&#59;<br>- If 25&#40;OH&#41;D 5&#8211;15<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#44; 50&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;week<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>4 weeks then 50&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;month<br>- If 25&#40;OH&#41;D 16&#8211;30<span class="elsevierStyleHsp" style=""></span>ng&#47;mL 50&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;month&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">2&#46;6 &#91;20&#46;8&#8211;23&#46;4&#93;<br><a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">&#42;&#42;&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">4 &#91;97&#8211;101&#93;<br>ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Abbreviation&#58; ns&#44; not significant&#59; 1&#44;25&#40;OH&#41;<span class="elsevierStyleInf">2</span>D&#44; calcitriol&#59; Ca&#44; calcium&#59; CKD&#44; chronic kidney disease&#59; CV&#44; cardiovascular&#59; FGF-23&#44; fibroblast growth factor 23&#59; FMD&#44; flow mediated dilation&#59; PWV&#44; pulse wave velocity&#59; PTH&#44; parathyroid hormone&#59; RCT&#44; randomized controlled trial&#59; &#40;&#8211;&#41;&#44; <span class="elsevierStyleItalic">p</span>-value not presented&#46;</p><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">&#42;</span><span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;0001&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Author&#44; year&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Type of study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Participants&#44; CKD stage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Type of supplementation&#44; dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Follow-up&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">25 &#40;OH&#41;D &#40;ng&#47;ml&#41;<br>Change<br>&#91;baseline-post&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">PTH &#40;pg&#47;ml&#41;<br>Change<br>&#91;baseline-post&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Other outcomes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Oksa et al&#46;&#44; 2008&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25 CKD 2<br>45 CKD 3<br>17 CKD 4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A&#58; Cholecalciferol<br>5000<span class="elsevierStyleHsp" style=""></span>IU&#47;wk &#40;714<span class="elsevierStyleHsp" style=""></span>IU&#47;day&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">52 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A&#58; 13 &#91;15&#8211;28&#93;<br><a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">&#42;&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A&#58; &#8722;15 &#91;63&#8211;48&#93;<br><a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">&#42;&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8593;1&#44;25&#40;OH&#41;<span class="elsevierStyleInf">2</span>D&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">B&#58; Cholecalciferol<br>20&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;wk &#40;2857<span class="elsevierStyleHsp" style=""></span>IU&#47;day&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">B&#58; 21 &#91;16&#8211;37&#93;<a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">a</span></a><br><a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">&#42;&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">B&#58; &#8722;10 &#91;50&#8211;40&#93;<br><a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">&#42;&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Marckmann et al&#46;&#44; 2012<br>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">25 CKD 1&#8211;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A&#58; Cholecalciferol<br>40&#44;000<span class="elsevierStyleHsp" style=""></span>IU&#47;wk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">51&#46;1 &#91;15&#46;8&#8211;66&#46;9&#93;<a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">a</span></a><br><a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">&#42;&#42;&#42;</span></a><br>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;29 &#91;79&#8211;50&#93;<a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">a</span></a><br><a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">&#42;&#42;&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8593;1&#44;25&#40;OH&#41;<span class="elsevierStyleInf">2</span>D<br>&#8593; Ca<br>&#8593; FGF-23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">B&#58; Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;2&#46;8 &#91;11&#46;5&#8211;8&#46;7&#93;<br>&#40;&#8211;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">41 &#91;120&#8211;161&#93;<br>&#40;&#8211;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Wetmore et al&#46;&#44; 2016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">44 CKD 3&#8211;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A&#58; Cholecalciferol 50&#46;000<span class="elsevierStyleHsp" style=""></span>IU&#47;wk &#40;1250<span class="elsevierStyleHsp" style=""></span>&#956;g ou 7142<span class="elsevierStyleHsp" style=""></span>IU&#47;day&#41;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">12 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A&#58; 45&#46;0 &#91;20&#46;9&#8211;65&#46;9&#93;<a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">a</span></a><br><a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">&#42;&#42;&#42;</span></a><br>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A&#58; &#8722;15&#46;3 &#91;76&#46;6&#8211;61&#46;3&#93;<br><a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">&#42;&#42;&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8596; 1&#44;25&#40;OH&#41;<span class="elsevierStyleInf">2</span>D in both groups&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">B&#58; Ergocalciferol 50&#46;000<span class="elsevierStyleHsp" style=""></span>IU&#47;wk &#40;1250<span class="elsevierStyleHsp" style=""></span>&#956;g ou 7142<span class="elsevierStyleHsp" style=""></span>IU&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">B&#58; 30&#46;7 &#91;20&#46;5&#8211;51&#46;2&#93;<br><a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">&#42;&#42;&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">B&#58; 2&#46;3 &#91;149&#46;0&#8211;151&#46;3&#93;<br>ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Kendrick et al&#46;&#44; 2017&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">128 CKD 3b-4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A&#58; Cholecalciferol<br>2000<span class="elsevierStyleHsp" style=""></span>IU&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">24 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A&#58; 11&#46;8 &#91;23&#46;0&#8211;34&#46;8&#93;<a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">a</span></a><br><a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">&#42;&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A&#58; 2&#46;5 &#91;99&#46;5&#8211;102&#93;<a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">a</span></a><br>ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8596; FMD<br>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">B&#58; Calcitriol 0&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">B&#58; &#8722; 0&#46;5 &#91;21&#46;7&#8211;21&#46;2&#93;<br>ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">B&#58; &#8722;36&#46;8 &#91;93&#46;8&#8211;57&#93;<br><a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">&#42;&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8596; FMD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Kumar et al&#46;&#44; 2017&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">120 CKD 3&#8211;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A&#58; Cholecalciferol 300&#46;000<span class="elsevierStyleHsp" style=""></span>IU at baseline and 8 weeks later&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">16 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A&#58; 24&#46;91 &#91;13&#46;40&#8211;38&#46;31&#93;<a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">a</span></a><br><a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">&#42;&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A&#58; &#8722;10&#46;073 &#91;139&#8211;38&#46;27&#93;<a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">a</span></a><br><a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">&#42;&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " rowspan="2" align="left" valign="top">&#8593; FMD and PWV<br><a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">&#42;&#42;</span></a><br>&#8593;1&#44;25&#40;OH&#41;<span class="elsevierStyleInf">2</span>D<br><a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">&#42;&#42;</span></a><br>&#8593;endothelial function<br>&#8595; CV risk&#63;</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">B&#58; Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">B&#58; 1&#46;51 &#91;13&#46;21&#8211;14&#46;72&#93;<br>ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">B&#58; 47&#46;36 &#91;146&#8211;193&#46;36&#93;<br>ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Abbreviations&#58; ns&#44; not significant&#59; 1&#44;25&#40;OH&#41;<span class="elsevierStyleInf">2</span>D&#44; calcitriol&#59; Ca&#44; calcium&#59; CKD&#44; chronic kidney disease&#59; PWV&#44; pulse wave velocity&#59; P&#44; phosphorus&#59; PTH&#44; parathyroid hormone&#59; RCT&#44; randomized controlled trial&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Author&#44; year&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Type of study&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Participants&#44; CKD stage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Type of supplementation&#44; dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Follow-up&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">25 &#40;OH&#41;D &#40;ng&#47;ml&#41; Change &#91;baseline-post&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">PTH &#40;pg&#47;ml&#41; Change &#91;baseline-post&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="center" valign="top" scope="col" style="border-bottom: 2px solid black">Other outcomes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sprague et al&#46;&#44; 2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">78 CKD&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A&#58; ER Calcifediol in 3 groups&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">6 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">30<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;daily&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">16&#46;2 &#91;21&#46;1&#8211;37&#46;3&#93;<a class="elsevierStyleCrossRef" href="#tblfn0050"><span class="elsevierStyleSup">a</span></a><br><a class="elsevierStyleCrossRef" href="#tblfn0045"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;32&#46;7 &#91;156&#46;3&#8211;123&#46;6&#93;<a class="elsevierStyleCrossRef" href="#tblfn0050"><span class="elsevierStyleSup">a</span></a><br><a class="elsevierStyleCrossRef" href="#tblfn0045"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8593;1&#44;25&#40;OH&#41;<span class="elsevierStyleInf">2</span>D proportionally in all groups of calcifediol<br>&#8596; P&#44; Ca&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">60<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;daily&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">43&#46;3 &#91;23&#46;6&#8211;66&#46;9&#93;<a class="elsevierStyleCrossRef" href="#tblfn0050"><span class="elsevierStyleSup">a</span></a><br><a class="elsevierStyleCrossRef" href="#tblfn0045"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;39&#46;7 &#91;118&#46;5&#8211;78&#46;8&#93;<a class="elsevierStyleCrossRef" href="#tblfn0050"><span class="elsevierStyleSup">a</span></a><br><a class="elsevierStyleCrossRef" href="#tblfn0045"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">90<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;daily&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">63&#46;7 &#91;21&#46;1&#8211;84&#46;8&#93;<a class="elsevierStyleCrossRef" href="#tblfn0050"><span class="elsevierStyleSup">a</span></a><br><a class="elsevierStyleCrossRef" href="#tblfn0045"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;62&#46;5 &#91;155&#46;9&#8211;93&#46;4&#93;<a class="elsevierStyleCrossRef" href="#tblfn0050"><span class="elsevierStyleSup">a</span></a><br><a class="elsevierStyleCrossRef" href="#tblfn0045"><span class="elsevierStyleSup">&#42;</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">B&#58; Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;1&#46;2 &#91;19&#46;7&#8211;18&#46;5&#93;<br>ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20 &#91;145&#46;7&#8211;165&#46;7&#93;<br>ns&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Levin et al&#46;&#44; 2017&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">119 CKD 3&#8211;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">A&#58; Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">24 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;2&#46;9 &#91;29&#46;1&#8211;26&#46;2&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">0&#46;1 &#91;4&#46;9&#8211;5&#46;0&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8593; PWV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">B&#58; Calcitriol 0&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;g<br>3&#215;&#47;wk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;2&#46;9 &#91;26&#46;7&#8211;23&#46;8&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;0&#46;3 &#91;4&#46;6&#8211;4&#46;4&#93;<a class="elsevierStyleCrossRef" href="#tblfn0050"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8596; PWV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">C&#58; Calcifediol 5&#46;000<span class="elsevierStyleHsp" style=""></span>IU 3&#215;&#47;wk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">68&#46;3 &#91;25&#46;8&#8211;94&#46;1&#93;<a class="elsevierStyleCrossRef" href="#tblfn0050"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8722;0&#46;5 &#91;4&#46;6&#8211;4&#46;1&#93;<a class="elsevierStyleCrossRef" href="#tblfn0050"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8595; PWV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Sprague et al&#46;&#44; 2016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">429 CKD 3&#8211;4&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">52 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Group 1&#58; 12<span class="elsevierStyleHsp" style=""></span>weeks 30<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;daily<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>14 weeks 30 or 60<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;daily&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">48 &#91;20&#8211;68&#93;<a class="elsevierStyleCrossRef" href="#tblfn0050"><span class="elsevierStyleSup">a</span></a><a class="elsevierStyleCrossRef" href="#tblfn0055"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Group 2&#58; 26<span class="elsevierStyleHsp" style=""></span>weeks placebo&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td><td class="td" title="table-entry  " align="" valign="top">&nbsp;\t\t\t\t\t\t\n
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