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Correction of 25-OH-vitamin D deficiency improves control of secondary hyperparathyroidism and reduces the inflammation in stable haemodialysis patients
La corrección del déficit de 25-OH-vitamina D mejora el control del hiperparatiroidismo secundario y el estado inflamatorio de pacientes estables en hemodiálisis
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Fresenius Medical Care, Córdoba, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author</span>." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "La corrección del déficit de 25-OH-vitamina D mejora el control del hiperparatiroidismo secundario y el estado inflamatorio de pacientes estables en hemodiálisis" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1362 "Ancho" => 2669 "Tamanyo" => 145520 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Determination of microinflammation in patients, before and after treatment, given as the percentage of activated monocytes (CD14+/CD16+) before and after treatment (A) and as the levels of C-reactive protein (CRP) (B).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The hormonal system of native vitamin D (25-OH-D) is linked to the regulation of calcium homeostasis and bone metabolism. 25-OH-D deficiency is very common not only in specific groups of patients, but also in the general population.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">1</span></a> 25-OH-D deficiency is highly prevalent in patients with chronic kidney disease in its various stages, and may be found in up to 90% of the population in CKD stage 5D patients (haemodialysis; HD).<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">2,3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Deficiency of 25-OH-D is associated to a greater prevalence of diseases such as cancer<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">4</span></a> and cardiovascular disease.<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">5,6</span></a> This is possibly explained not only by its relation with bone and mineral metabolism, but also by its pleiotropism.<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">7</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Of the pleiotropic effects of 25-OH-D, its role in the immune system and its possible association to chronic inflammation are notable. HD patients present with chronic microinflammation,<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">8</span></a> which plays an important role in the elevated morbidity and mortality of these patients. The uraemia-related inflammation can be assessed by the measurement of traditional biochemical parameters (albumin, ferritin or C-reactive protein [CRP]<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">9</span></a>), however these are not always changed, so it is necessary to use more sensitive methods. Recent studies have shown that the determination of activated monocytes (CD14+/CD16+ and CD 14++/CD16+) in the peripheral blood of patients with chronic kidney disease is more sensitive of inflammation than the conventional methods.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">10</span></a> Determination of activated monocytes may be used to evaluate inflammation in response to treatments or different dialysis techniques.<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">11–13</span></a> It is not yet known whether the repletion of 25-OH-D deficiency is capable to modify these inflammatory parameters in HD patients.</p><p id="par0020" class="elsevierStylePara elsevierViewall">It has been shown that 25-OH-D deficiency has a proinflammatory effect on HD patients,<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">14</span></a> since anaemia treatment is impaired by inflammation, the correction of 25-OH-D deficiency could lead to an improved response to the anaemia treatment.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Lastly, the relationship between 25-OH-D deficiency and the homeostasis of calcium and phosphorus is clear, but its influence in the control of secondary hyperparathyroidism (SHPT) is not well defined.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">15</span></a> Recent studies have suggested that a repletion of the vitamin could help to improve the control of hyperparathyroidism,<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">16,17</span></a> but this effect has not been found in all reports.<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">18,19</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The purpose of our study was to evaluate in stable HD patients with 25-OH-D deficiency (levels<20<span class="elsevierStyleHsp" style=""></span>ng/ml) the effect of 25-OH-D repletion on the control SHPT, anaemia and/or the chronic microinflammatory process associated to uraemia.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Patients and methods</span><p id="par0035" class="elsevierStylePara elsevierViewall">Prospective, observational single-centre study in stable HD patients. 45 patients were included: 27 men and 18 women with an average age of 74.08<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>12.49 (ranging from 39 to 85 years), who were in a HD programme for an average of 25<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>17 months. The aetiologies for the chronic kidney disease included: vascular nephropathy (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>12, 26.6%), chronic glomerulonephritis (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>4, 8.8%), diabetic nephropathy (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>8, 17.7%), polycystic Kidney disease (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>5, 11.1%), urological causes (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>6, 13.3%), systemic diseases (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>2, 3.6%), tubulointerstitial nephropathy (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>3, 6.6%) and a non-affiliated aetiology (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>5, 11.1%).</p><p id="par0040" class="elsevierStylePara elsevierViewall">All patients had 25-OH-D deficiency with serum levels of < 20<span class="elsevierStyleHsp" style=""></span>ng/ml. Each patient received calcifediol (Hidroferol<span class="elsevierStyleSup">®</span>), a 0.266-mcg ampoule every 2 weeks over the course of 3 months. The patients continued to take the other medications they were receiving prior to the study, which were adjusted at the discretion of the treating doctor depending on the patients’ laboratory or clinical tests; changes in treatments were documented throughout the study. The patients’ diet was not changed.</p><p id="par0045" class="elsevierStylePara elsevierViewall">The patients were dialysed three times per week with a high-flux polysulfone membrane (HF80S; Fresenius Medical Care<span class="elsevierStyleSup">®</span>, Bad Homburg, Germany). The blood flow rate was 300–400<span class="elsevierStyleHsp" style=""></span>ml/min, and the duration of the dialysis was adjusted on a patient-by-patient basis to maintain a Kt/V of greater than 1.2. All patients were dialysed in the same dialysis unit, using the same dialysate system.</p><p id="par0050" class="elsevierStylePara elsevierViewall">All samples were obtained in lithium heparin tubes and biochemistry test tubes. Haemoglobin levels were measured with an automatic analyser (Abbott Cell-Dyn 4000; Abbott Laboratories<span class="elsevierStyleSup">®</span>, Abbott Park, IL, USA). The high-sensitivity CRP levels were determined by immunoturbidimetry; the reagents were provided by Abbott Laboratories<span class="elsevierStyleSup">®</span> (Abbott Park, IL, USA). The normal range of CRP was <5<span class="elsevierStyleHsp" style=""></span>mg/l. The 25-OH-vitamin D levels were determined by the radioimmunoassay (RIA) method (Immunodiagnostic Systems IDS<span class="elsevierStyleSup">®</span>, Gamma-B kit) in nuclear medicine. The levels of intact parathyroid hormone (PTH) were determined by RIA (Nichols Institute<span class="elsevierStyleSup">®</span>, The Netherlands).</p><p id="par0055" class="elsevierStylePara elsevierViewall">The determination of activated monocytes (CD14+/CD16+ and CD14++/CD16+) in peripheral blood was carried out after incubating the blood with the monoclonal antibody M5E2 against the CD14 molecule mixed with peridinin-chlorophyll-protein, and with the 3G8 antibody against the CD16 molecule mixed with fluorescein isothiocyanate (FITC). Both antibodies and the appropriate isotype controls were provided by Becton Dickinson<span class="elsevierStyleSup">®</span> (San Jose, CA, USA). The flow cytometry analysis was conducted with a FACSCalibur flow cytometer (Becton Dickinson<span class="elsevierStyleSup">®</span>). The number of absolute CD14+ and CD16+ monocytes was obtained using BD TruCOUNT tubes (Becton Dickinson<span class="elsevierStyleSup">®</span>). To calculate the receptors’ average fluorescence intensity, the flow cytometer was calibrated using 3 BD Calibrite beads (Becton Dickinson<span class="elsevierStyleSup">®</span>) to adjust the set fluorescence compensation.</p><p id="par0060" class="elsevierStylePara elsevierViewall">In a group of patients, the FGF-23 levels were determined by enzyme-linked immunosorbent assay (ELISA).</p><p id="par0065" class="elsevierStylePara elsevierViewall">The doses of drugs taken by the patients during the study were recorded, and the dose changes during the study period were analysed.</p><p id="par0070" class="elsevierStylePara elsevierViewall">The protocol adhered to the Declaration of Helsinki and was approved by the Independent Ethics Committee of Hospital Universitario Reina Sofía (Córdoba, Spain). Informed consent was obtained from all patients before they were enrolled in the study.</p><p id="par0075" class="elsevierStylePara elsevierViewall">The statistical analysis was conducted using the SPSS statistical software, version 20.0, and the results were expressed as the arithmetic average<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>standard deviation. Student's <span class="elsevierStyleItalic">t</span>-test was used to analyse the statistical significance of the quantitative parameters for paired data. A <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.05 was considered as being statistically significant.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Results</span><p id="par0080" class="elsevierStylePara elsevierViewall">After 3 month treatment with calcifediol, 27 out of the 45 patients (60%) attained the desired 25-OH-D levels (>20<span class="elsevierStyleHsp" style=""></span>ng/ml) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">Regarding the effect of 25-OH-D repletion and the control of SHPT, 32 patients (71%) showed a decrease in PTH levels after treatment, with 23 (50% of the total number of patients and 71% of those who reached levels above 20<span class="elsevierStyleHsp" style=""></span>ng/ml) showed a reduction in PTH of more than 30% from the baseline PTH levels. The average PTH levels before and after treatment is seen in <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">The better control of PTH allowed a reduction in the doses vitamin D analogue (paricalcitol), with no changes made in the dose of calcimimetics throughout the study (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). The average calcium levels increased during the study, but it was not statistically significant. Serum phosphorus levels decreased without reaching statistically differences (the average calcium and phosphorus levels are presented in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). The decrease in phosphataemia was attained without changing the doses of phosphate binders. A greater decrease in serum phosphate was noted in patients whose dose of vitamin D analogues was reduced during the study. However, there was no significant correlation between the decrease in phosphataemia and the reduction in the dose of vitamin D analogues. This greater control of phosphorus levels may be attributed to a better control of SHPT.</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">Soluble levels of FGF-23, a molecule related to phosphorus homeostasis and SHPT control, were determined from the findings of our study regarding greater control of SHPT. These levels were much higher in HD patients than in healthy patients. In HD patients, the average FGF-23 levels did not change before and after the 25-OH-D repletion (pre-treatment average of 432.157361 vs. 541.852406 post-treatment, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.47). The same results had been observed in earlier studies.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">20</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">The results obtained in this study regarding chronic microinflammation in HD patients were determined using conventional biochemical parameters such as CRP, albumin and ferritin, and also using parameters obtained through flow cytometry, such as the percentage of activated monocytes (CD14+/CD16+ and CD14++/CD16+).</p><p id="par0105" class="elsevierStylePara elsevierViewall">The level of CRP significantly decreased after vitamin D replacement (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>B), indicating less patient inflammation. No changes were noted in other parameters related to inflammation, such as albumin or ferritin. The data are presented in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">The percentage of activated monocytes (CD14+/CD16+ and CD14++/CD16+) did not change during the study (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>A).</p><p id="par0115" class="elsevierStylePara elsevierViewall">Regarding anaemia, haemoglobin levels remained stable throughout the study (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>), and the doses the darbepoetin were maintained (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>), however the weekly dose of iron dose was reduced (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>), which may be related to the improvement in patient inflammation as determined by the significant decrease in CRP.</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">The drugs taken by the patients and the doses thereof were recorded during the study, with the changes being registered down.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Discussion</span><p id="par0125" class="elsevierStylePara elsevierViewall">After three months of treatment with native vitamin D (calcifediol), 60% of the patients had adequate 25-OH-D levels (>20<span class="elsevierStyleHsp" style=""></span>ng/ml). This was achieved without any drug-related adverse effect during the treatment period and with a high tolerance to the treatment.</p><p id="par0130" class="elsevierStylePara elsevierViewall">In this group of patients, the correction of 25-OH-D deficiency was associated with a better control of SHPT, which was accompanied by a lower requirement for vitamin D analogues (paricalcitol). The doses of other commonly used drugs in SHPT treatment, such as calcimimetics or phosphate binders, was not changed during the study. These data have already been published previously,<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">16,17</span></a> but with different treatment regimens. As with earlier studies,<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">20</span></a> no significant decrease in FGF-23 plasma levels were seen in our patients.</p><p id="par0135" class="elsevierStylePara elsevierViewall">Regarding chronic microinflammation, it should be noted that there was a significant decrease in CRP levels after treatment, which is a parameter correlated to microinflammation in HD patients.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">9</span></a> This decrease in CRP is therefore attributed to a decrease of inflammation. Parameters such as ferritin and albumin, which are also linked to microinflammation, did not change during the study.</p><p id="par0140" class="elsevierStylePara elsevierViewall">Regarding the correction of anaemia, no differences were noted in haemoglobin levels before and after repletion with 25-OH-D, and no changes were seen in the doses of erythropoiesis-stimulating agents. However, the weekly requirements for intravenous iron were decreased, which was possibly related to the reduced inflammation after repletion of the 25-OH-D deficiency. These data are similar to those found in previous studies,<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">14</span></a> which relate 25-OH-D deficiency to inflammation and, therefore, to a worse response to anaemia treatment.</p><p id="par0145" class="elsevierStylePara elsevierViewall">Our study has limitations such as the moderate response rate (60%) at the end of the study which may be the main limiting factor. This rate of response to the treatment is lower than in other published studies, even though treatment completion was guaranteed because it was administered at the end of dialysis sessions. This relatively low response rate is possibly related to the average age of the patients (74 years), which is higher than that of other published studies. Alternatively, it may be related to treatment duration; perhaps to obtain an optimal drug response rate, the duration of treatment should have been longer.</p><p id="par0150" class="elsevierStylePara elsevierViewall">Nevertheless, and regardless of the study's limitations, the results obtained in terms of SHPT control and inflammation in this group of patients are encouraging, because both processes are closely linked to the high morbidity and mortality rates in this group of patients. The correction of 25-OH-D deficiency in HD patients is associated with a greater control of SHPT using lower doses of vitamin D analogues, and with an improvement in the inflammation experienced by these patients. Our results therefore support the current recommendations of good clinical practice guidelines for determining 25-OH-D levels and for correcting the deficiency in HD patients.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Funding</span><p id="par0155" class="elsevierStylePara elsevierViewall">This study was funded by <span class="elsevierStyleGrantSponsor" id="gs1">Amgen<span class="elsevierStyleSup">®</span> España S.A. Amgen</span> had no role in the study design, the collection, analysis or interpretation of the data, the drafting of the report, or the decision to publish the study results.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Conflicts of interest</span><p id="par0160" class="elsevierStylePara elsevierViewall">The authors declare that they have no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:11 [ 0 => array:3 [ "identificador" => "xres985581" "titulo" => "Abstract" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objective" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Patients and methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec953232" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres985580" "titulo" => "Resumen" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivos" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Pacientes y métodos" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec953231" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Patients and methods" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Results" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "Funding" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Conflicts of interest" ] 10 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2017-01-21" "fechaAceptado" => "2017-05-22" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec953232" "palabras" => array:4 [ 0 => "Hypovitaminosis D" 1 => "Haemodialysis" 2 => "Secondary hyperparathyroidism" 3 => "Inflammation" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec953231" "palabras" => array:4 [ 0 => "Hipovitaminosis D" 1 => "Hemodiálisis" 2 => "Hiperparatiroidismo secundario" 3 => "Inflamación" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Patients on haemodialysis (HD) have a high prevalence of 25-OH-vitamin D (25-OH-D)deficiency. Secondary hyperparathyroidismis a common condition in these patients, which is very important to control. 25-OH-D is involved in regulating calcium homeostasis. As such, appropriate levels of this vitamin could help to control bone mineral metabolism.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Objective</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">To evaluate the effect 25-OH-D repletion in HD patients with 25-OH-D deficiency (<20<span class="elsevierStyleHsp" style=""></span>ng/ml) on the control of secondary hyperparathyroidism and microinflammation status.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Patients and methods</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Prospective observational study in which stable patients on HD with 25-OH-D deficiency (<20<span class="elsevierStyleHsp" style=""></span>ng/ml) were treated with oral calcifediol 0.266<span class="elsevierStyleHsp" style=""></span>mcg/every 2 weeks for three months. Dialysis characteristics, biochemical parameters and drug doses administered were analysed before and after the correction of the deficiency.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Forty-five stable HD patients with a mean age of 74.08<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>12.49 years completed treatment. Twenty-seven patients (60%) achieved 25-OH-D levels above 20<span class="elsevierStyleHsp" style=""></span>ng/ml (23 with levels<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>ng/ml and 4 between 20 and 30<span class="elsevierStyleHsp" style=""></span>ng/ml). Parathyroid hormone levels decreased in 32 of the 45 patients, 23 of which (51%) achieved a >30% decrease from baseline. In terms of concomitant treatment, we observed a significant reduction in the selective vitamin D receptor activator dose, but no changes in calcimimetic or phosphate binders administration. In terms of malnutrition–inflammation status, a decrease in C-reactive protein was noted, although other microinflammation parameters, such as activated monocytes (CD14+/CD16+ and CD 14++/CD16+) were unchanged. No changes were observed in the levels of FGF-23.</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Correcting 25-OH-D deficiency in HD patients is associated with better secondary hyperparathyroidism control with lower doses of vitamin D analogues, as well as an improvement in inflammatory status. Our results support the recommendation to determine 25-OH-D levels and correct its deficiency in these patients.</p></span>" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Objective" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Patients and methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Introducción</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">El déficit de 25-OH-vitamina D (25-OH-D) es común en los pacientes en hemodiálisis (HD). Por otra parte, es bien conocida la elevada incidencia de hiperparatiroidismo secundario en este grupo de pacientes, y lo importante que es su adecuado control. La 25-OH-D está implicada en la regulación de la homeostasis del calcio, por lo que tener niveles adecuados puede contribuir en el control del metabolismo óseo-mineral.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Objetivos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Evaluar el efecto de la repleción de 25-OH-D en pacientes en HD con déficit vitamínico (niveles<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>20<span class="elsevierStyleHsp" style=""></span>ng/ml), en el control del hiperparatiroidismo secundario y en el estado de microinflamación.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Pacientes y métodos</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Estudio observacional, prospectivo en el que se trataron pacientes estables en HD con déficit de 25-OH-D (<20<span class="elsevierStyleHsp" style=""></span>ng/ml), con calcifediol 0,266<span class="elsevierStyleHsp" style=""></span>mcg/15 días vía oral durante 3 meses. Los datos de HD, parámetros bioquímicos y las dosis de fármacos administrados fueron analizados antes y después de la corrección del déficit.</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Resultados</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Un total de 45 pacientes estables en HD con edad media 74,08<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>12,49 años completaron el tratamiento. Del total, 27 pacientes (60%) alcanzaron niveles de 25-OH-D<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>20<span class="elsevierStyleHsp" style=""></span>ng/ml (en 23 fueron<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>ng/ml, y 4 entre 20-30<span class="elsevierStyleHsp" style=""></span>ng/ml). Las cifras de hormona paratiroidea descendieron en 32 de los 45 pacientes, alcanzando en 23 (51% de tratados) un descenso<span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>30% respecto al valor basal. En cuanto al tratamiento concomitante, se objetivó un descenso significativo de la dosis de activador selectivo del receptor de vitamina D; sin evidenciarse cambios en la dosis de calcimimético ni de quelantes. Respecto al estado de malnutrición-inflamación, destaca un descenso de la proteína C reactiva, aunque no se modificaron otros parámetros de microinflamación como los monocitos activados (CD14+/CD16+ y CD 14++/CD16+). Tampoco se observaron cambios en los niveles de FGF-23.</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusiones</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">La corrección del déficit de 25-OH-D en pacientes en HD se asocia a un mejor control del hiperparatiroidismo secundario con menores dosis de análogos de vitamina D y a una mejoría en el estado inflamatorio de estos pacientes. Nuestros resultados apoyan la recomendación de determinar niveles de 25-OH-D y corregir el déficit en pacientes en HD.</p></span>" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivos" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Pacientes y métodos" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Ojeda López R, Esquivias de Motta E, Carmona A, García Montemayor V, Berdud I, Martín Malo A, et al. La corrección del déficit de 25-OH-vitamina D mejora el control del hiperparatiroidismo secundario y el estado inflamatorio de pacientes estables en hemodiálisis. Nefrologia. 2018;38:41–47.</p>" ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1306 "Ancho" => 1566 "Tamanyo" => 82876 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">25-OH-D data before and after treatment with calcifediol.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1364 "Ancho" => 1417 "Tamanyo" => 64791 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Control of hyperparathyroidism, levels of parathyroid hormone (PTH) before and after treatment.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1399 "Ancho" => 2678 "Tamanyo" => 164162 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Average drug (paricalcitol and cinacalcet) doses taken to control secondary hyperparathyroidism, before and after treatment.</p>" ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1362 "Ancho" => 2669 "Tamanyo" => 145520 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">Determination of microinflammation in patients, before and after treatment, given as the percentage of activated monocytes (CD14+/CD16+) before and after treatment (A) and as the levels of C-reactive protein (CRP) (B).</p>" ] ] 4 => array:7 [ "identificador" => "fig0025" "etiqueta" => "Fig. 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 1437 "Ancho" => 2667 "Tamanyo" => 153018 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Control of patients’ anaemia; average doses of iron and darbepoetin taken by the patients before and after taking calcifediol.</p>" ] ] 5 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">CRP: C-reactive protein; PTH: parathyroid hormone; 25-OH-D: 25-OH-vitamin D.</p>" "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <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"><span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>45 \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">Pre-calcifediol \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">Post-calcifediol \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"><span class="elsevierStyleItalic">p</span> \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">25-OH-D (ng/ml) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">12.88<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3.49 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">39.43<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>29.25 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.001 \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">Haemoglobin (g/dl) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11.36<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">11.2<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.56 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.145 \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">LnFerritin \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.96<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.79 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.1<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.75 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.093 \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">Darbepoetin (mcg/week) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">24.33<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>18.51 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">23.88<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>21.12 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.85 \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">Iron (mg/week) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">78.88<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>83.24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">62.22<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>74.92 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.006 \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">Calcium (mg/dl) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9.05<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.86 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9.27<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.79 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.058 \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">Phosphorus (mg/dl) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4.45<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.28 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4.12<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.36 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.161 \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">Cinacalcet mg/week \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">23.86<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>59.5 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">22.84<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>59.95 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.581 \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">Paricalcitol (mcg/week) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">2.45<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>4.63 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.70<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3.66 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.042 \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">LnPTH \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.59<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.61 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.13<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.11 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.002 \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">Albumin (g/dl) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3.48<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.28 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3.45<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.48 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.870 \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">LnCRP \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.6<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>0.88 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.16<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>1.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.001 \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">CD14+/CD16+ (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3.94 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">6.93<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>3.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.648 \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">CD14++/CD16+ (%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">3.59<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>2.55 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4.16<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>2.88 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.458 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1672100.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">Main findings determined before and after the correction of 25-OH-D deficiency.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:20 [ 0 => array:3 [ "identificador" => "bib0105" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Vitamin D deficiency" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "M.F. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 8 | 10 | 18 |
| 2024 October | 74 | 50 | 124 |
| 2024 September | 94 | 41 | 135 |
| 2024 August | 86 | 59 | 145 |
| 2024 July | 65 | 26 | 91 |
| 2024 June | 106 | 48 | 154 |
| 2024 May | 93 | 42 | 135 |
| 2024 April | 94 | 49 | 143 |
| 2024 March | 85 | 26 | 111 |
| 2024 February | 65 | 37 | 102 |
| 2024 January | 49 | 29 | 78 |
| 2023 December | 45 | 26 | 71 |
| 2023 November | 84 | 43 | 127 |
| 2023 October | 72 | 25 | 97 |
| 2023 September | 73 | 37 | 110 |
| 2023 August | 55 | 35 | 90 |
| 2023 July | 73 | 33 | 106 |
| 2023 June | 76 | 19 | 95 |
| 2023 May | 86 | 34 | 120 |
| 2023 April | 76 | 20 | 96 |
| 2023 March | 108 | 24 | 132 |
| 2023 February | 90 | 29 | 119 |
| 2023 January | 66 | 31 | 97 |
| 2022 December | 116 | 39 | 155 |
| 2022 November | 128 | 48 | 176 |
| 2022 October | 146 | 43 | 189 |
| 2022 September | 103 | 56 | 159 |
| 2022 August | 108 | 50 | 158 |
| 2022 July | 89 | 52 | 141 |
| 2022 June | 84 | 51 | 135 |
| 2022 May | 80 | 29 | 109 |
| 2022 April | 101 | 53 | 154 |
| 2022 March | 110 | 55 | 165 |
| 2022 February | 110 | 54 | 164 |
| 2022 January | 131 | 39 | 170 |
| 2021 December | 112 | 43 | 155 |
| 2021 November | 95 | 36 | 131 |
| 2021 October | 141 | 50 | 191 |
| 2021 September | 135 | 30 | 165 |
| 2021 August | 167 | 40 | 207 |
| 2021 July | 150 | 34 | 184 |
| 2021 June | 131 | 32 | 163 |
| 2021 May | 176 | 64 | 240 |
| 2021 April | 443 | 60 | 503 |
| 2021 March | 256 | 34 | 290 |
| 2021 February | 375 | 52 | 427 |
| 2021 January | 263 | 19 | 282 |
| 2020 December | 236 | 27 | 263 |
| 2020 November | 231 | 25 | 256 |
| 2020 October | 172 | 20 | 192 |
| 2020 September | 332 | 27 | 359 |
| 2020 August | 200 | 21 | 221 |
| 2020 July | 187 | 17 | 204 |
| 2020 June | 195 | 25 | 220 |
| 2020 May | 229 | 28 | 257 |
| 2020 April | 297 | 26 | 323 |
| 2020 March | 264 | 19 | 283 |
| 2020 February | 268 | 27 | 295 |
| 2020 January | 286 | 38 | 324 |
| 2019 December | 256 | 30 | 286 |
| 2019 November | 234 | 25 | 259 |
| 2019 October | 234 | 29 | 263 |
| 2019 September | 264 | 34 | 298 |
| 2019 August | 188 | 23 | 211 |
| 2019 July | 861 | 33 | 894 |
| 2019 June | 175 | 34 | 209 |
| 2019 May | 171 | 23 | 194 |
| 2019 April | 179 | 32 | 211 |
| 2019 March | 127 | 39 | 166 |
| 2019 February | 78 | 36 | 114 |
| 2019 January | 89 | 46 | 135 |
| 2018 December | 217 | 39 | 256 |
| 2018 November | 343 | 23 | 366 |
| 2018 October | 352 | 16 | 368 |
| 2018 September | 195 | 24 | 219 |
| 2018 August | 171 | 26 | 197 |
| 2018 July | 64 | 14 | 78 |
| 2018 June | 53 | 18 | 71 |
| 2018 May | 77 | 18 | 95 |
| 2018 April | 115 | 11 | 126 |
| 2018 March | 206 | 28 | 234 |
| 2018 February | 61 | 9 | 70 |
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