Original article
Protein-bound toxins: Added value in their removal with high convective volumes
Toxinas unidas a proteínas: valor añadido en su eliminación con altos volúmenes convectivos
Soraya Abad
, Almudena Vega, Borja Quiroga, David Arroyo, Nayara Panizo, Javier Eduardo Reque, Juan Manuel López-Gómez
Corresponding author
Servicio de Nefrología, Hospital General Universitario Gregorio Marañón, Madrid, Spain
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"nombre" => "Almudena" "apellidos" => "Vega" ] 2 => array:2 [ "nombre" => "Borja" "apellidos" => "Quiroga" ] 3 => array:2 [ "nombre" => "David" "apellidos" => "Arroyo" ] 4 => array:2 [ "nombre" => "Nayara" "apellidos" => "Panizo" ] 5 => array:2 [ "nombre" => "Javier Eduardo" "apellidos" => "Reque" ] 6 => array:2 [ "nombre" => "Juan Manuel" "apellidos" => "López-Gómez" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Servicio de Nefrología, Hospital General Universitario Gregorio Marañón, Madrid, Spain" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author</span>." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Toxinas unidas a proteínas: valor añadido en su eliminación con altos volúmenes convectivos" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2540 "Ancho" => 3237 "Tamanyo" => 231716 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Correlation between the protein-bound molecule reduction ratio and the total convective volume. Homocysteine reduction A); p-cresyl sulphate reduction B); and indoxyl sulphate reduction C).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The chronic kidney disease population has higher risk of fatal and non-fatal cardiovascular events than the general population, even after controlling for traditional cardiovascular risk factors.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">1</span></a> Uraemic toxins are risk factors in patients at any stages of chronic kidney disease.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Uraemic toxins have been divided according to molecular size and protein binding.<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">3</span></a> Small molecules are preferentially eliminated by diffusive transport, while mid-sized molecules are eliminated by convective transport. Recent studies demonstrate that online haemodiafiltration (OL-HDF) with volumes over 20<span class="elsevierStyleHsp" style=""></span>l are capable of decreasing mortality.<a class="elsevierStyleCrossRefs" href="#bib0180"><span class="elsevierStyleSup">4–7</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">However, there is a third group of uraemic toxins consisting of small molecules bound to proteins, including p-cresyl sulphate, indoxyl sulphate, or homocysteine, which are associated to high cardiovascular morbidity and mortality in chronic kidney disease patients.<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">8–11</span></a> Removal of these toxins with conventional haemodialysis or OL-HDF techniques remains very limited. Some authors demonstrate that both total p-cresol levels and free p-cresol levels are associated with cardiovascular events,<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">9</span></a> though other studies show that only high levels of free p-cresyl sulphate are associated with higher mortality in patients with chronic kidney disease in any stage.<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">12,13</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Furthermore, modern dialysis monitors with the ability to perform OL-HDF, through automated biocontrol systems, enable us the substitution of volumes greater than 25<span class="elsevierStyleHsp" style=""></span>l in a 4-hour session that is obtained in patients with good vascular access.</p><p id="par0025" class="elsevierStylePara elsevierViewall">The objective of this study is to assess the influence of high convective volumes in OL-HDF on removing mid-sized molecules, small molecules, and protein-bound molecules.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Material and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Population and dialysis technique</span><p id="par0030" class="elsevierStylePara elsevierViewall">This is an observational study of patients in renal replacement therapy with post-dilution OL-HDF (post-OL-HDF). Data was collected in 40 post-OL-HDF sessions in 13 prevalent patients with advanced chronic kidney disease in regular haemodialysis. Data was analysed from three weekly sessions for all the patients studied, except for one in which four sessions were collected. The patients signed an informed consent form. All the procedures were performed in accordance with the Declaration of Helsinki and its later revisions.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Before the study, all the patients were on post-OL-HDF treatment. The monitors used were Fresenius 5008 CorDiax<span class="elsevierStyleSup">®</span>, AK-200 Gambro with ultra-control<span class="elsevierStyleSup">®</span> and Artis Gambro<span class="elsevierStyleSup">®</span>, in which the substitution rate is automatically controlled. The dialyser used in all cases was the FX-1000 CorDiax (FMC<span class="elsevierStyleSup">®</span>), manufactured with a Helixone<span class="elsevierStyleSup">®</span> membrane, with an ultrafiltration coefficient of 75<span class="elsevierStyleHsp" style=""></span>ml/h x mmHg, 2.2<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> effective surface area, 35<span class="elsevierStyleHsp" style=""></span>μm wall thickness, and 210<span class="elsevierStyleHsp" style=""></span>μm internal capillary diameter. The haemodialysis sessions lasted 240<span class="elsevierStyleHsp" style=""></span>min.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Information about the characteristics of each session were collected: real blood flow, arterial blood pressure, venous blood pressure, substitution litres, total convective volume, defined as the sum of the substitution volume and ultrafiltration, and Kt/V, with K obtained by ionic dialysance and V analysed using bioimpedance spectroscopy (BMC<span class="elsevierStyleSup">®</span> by FMC, Bad Homburg).</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Laboratory tests</span><p id="par0045" class="elsevierStylePara elsevierViewall">The pre-dialysis and post-dialysis mid-sized molecule concentration (alpha-2 macroglobulin, beta-2 microglobulin, prolactin, myoglobin, and interleukin-6), the small molecule concentration (urea, creatinine, and phosphorus), and protein-bound molecule concentration (total p-cresyl sulphate, indoxyl sulphate, and homocysteine) were measured in each session. The post-dialysis samples were obtained from the artery once the session was completed and before the needles were removed.</p><p id="par0050" class="elsevierStylePara elsevierViewall">The samples of mid-sized molecules, homocysteine, and small molecules were sent at the time of extraction to the biochemistry laboratory and were analysed using conventional methods in an automated analyser. To determine IL-6, p-cresyl sulphate, and indoxyl sulphate, the serum samples were frozen at −35<span class="elsevierStyleHsp" style=""></span>°C and sent to an external laboratory. IL-6 was analysed using immunonephelometry. To determine the p-cresyl sulphate and indoxyl sulphate, the samples were deproteinised and analysed using high-performance liquid chromatography (HPLC).</p><p id="par0055" class="elsevierStylePara elsevierViewall">To assess the molecule clearance efficacy, the reduction ratio was calculated for each using the formula:<elsevierMultimedia ident="eq0005"></elsevierMultimedia></p><p id="par0065" class="elsevierStylePara elsevierViewall">The post-dialysis plasma concentrations of protein-bound molecules and mid-sized molecules were adjusted to the degree of haemoconcentration based on the changes in the extracellular volume as assessed by the pre- and post-dialysis weight according to the equation<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">14</span></a>:<elsevierMultimedia ident="eq0010"></elsevierMultimedia></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Statistical analysis</span><p id="par0070" class="elsevierStylePara elsevierViewall">The quantitative variables were expressed as mean and standard deviation for variables with a normal distribution and as the median and interquartile range for the rest. The qualitative variables were expressed as percentages.</p><p id="par0075" class="elsevierStylePara elsevierViewall">The means were compared using a Student's <span class="elsevierStyleItalic">t</span>-test or ANOVA when dealing with more than two samples. Pearson's correlation coefficient was used to assess the bivariate correlations between quantitative variables. It was considered statistically significant if <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.05. SPSS V.17.0 was used (Chicago, Illinois).</p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Findings</span><p id="par0080" class="elsevierStylePara elsevierViewall">The characteristics of haemodialysis session are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">The total convective volume was 28.3 (5.1) liters ranging from 16.3 to 38.0 litres. Eighty-five per cent (85%) of the patients received dialysis <span class="elsevierStyleItalic">via</span> an rteriovenous fistulae (AVF) while the remaining 15% through a permanent tunnelled catheter. The mean arterial blood flow was 426 (70) ml/min ranging from 250 to 500<span class="elsevierStyleHsp" style=""></span>ml/min.</p><p id="par0090" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> shows the molecule reduction ratio during the dialysis session and its correlation with the convective transport.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">For small molecule clearance, the mean Kt/V was 1.76 (0.64). The creatinine and urea reduction ratios showed a significant correlation with the total convective volume (<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001 and <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.050, respectively), whereas the phosphorus clearance did not show a correlation with the convective volume.</p><p id="par0100" class="elsevierStylePara elsevierViewall">The mid-sized and large molecule reduction ratios in OL-HDF were highly variable, varying between 81.3% for beta-2 microglobulin and −2.2% for alpha-2 macroglobulin. We found a significant correlation between the beta-2 microglobulin, prolactin, and myoglobin clearance rate with the total convective volume, while there was no correlation between the IL-6 and alpha-2 macroglobulin levels and the convective volume.</p><p id="par0105" class="elsevierStylePara elsevierViewall">The protein-bound molecule reduction ratio was significantly correlated with the total convective volume in all analysed molecules (<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>). Likewise, the clearance of the three molecules was correlated with the Kt/V (<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.425, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.014 for homocysteine; <span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.554, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.009 for p-cresyl sulphate, and <span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.579, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.006 for indoxyl sulphate). Furthermore, the percentage of protein binding the analysed molecules (70% for homocysteine,<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">15</span></a> 90% for indoxyl sulfate,<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">16</span></a> and 95% for p-cresol<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">16</span></a>) showed an inverse relationship with the reduction ratio of these molecules (<span class="elsevierStyleItalic">r</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>−0.996, <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.058). The linear relationship between the analysed protein-bound molecules and the total convective volume is presented in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Discussion</span><p id="par0110" class="elsevierStylePara elsevierViewall">Our study demonstrates that high-volume convective transport in OL-HDF is associated with higher protein-bound toxin clearance and confirms a high small- and mid-sized molecule clearance, as demonstrated in other studies.</p><p id="par0115" class="elsevierStylePara elsevierViewall">The importance of removing these protein-bound toxins has increased in recent years, as we have been learned about the association between high serum levels of these molecules and increased cardiovascular risk.<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">11,13,17</span></a> Two of the most studied protein-bound molecules, in both metabolism and action, are p-cresol and indoxyl sulphate.</p><p id="par0120" class="elsevierStylePara elsevierViewall">P-cresol is generated in the intestinal flora and is subsequently metabolised into p-cresyl sulphate and p-cresyl glucuronide. Both molecules are strongly bound to proteins.<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">18</span></a> Free p-cresyl sulphate (not protein-bound) appears to be associated with overall and cardiovascular mortality in patients with chronic kidney disease and in dialysis.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">10</span></a> Free p-cresyl glucuronide, the other p-cresol metabolite, is also associated with cardiovascular mortality in chronic kidney disease patients.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">19</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">Indoxyl sulphate belongs to the indol family and is also a protein-bound toxin that has been associated with endothelial damage and overall and cardiovascular mortality, as well as vascular calcification.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">10</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">The problem with protein-bound toxins is the difficulty to remove them with conventional dialysis techniques. Several studies have been conducted with different clearance techniques showing non-uniform results. Meert et al. compared pre- and post-dilution OL-HDF with pre-dilution haemofiltration. They found a higher protein-bound toxin clearance in the two OL-HDF modalities than in pre-dilution haemofiltration, but no differences between pre- and post-dilution OL-HDF.<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">20</span></a> In contrast, Bammens et al. shoed greater protein-bound toxin clearance in post-dilution OL-HDF, with convective transport equivalent to 20<span class="elsevierStyleHsp" style=""></span>l (substitution flux of 87<span class="elsevierStyleHsp" style=""></span>ml/min over 230<span class="elsevierStyleHsp" style=""></span>min per session), than with high-flux haemodialysis.<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">21</span></a> Nevertheless, other authors found, in only eight patients, that mean substitution volumes of 21.5<span class="elsevierStyleHsp" style=""></span>l have little significance on removing these solutes,<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">22</span></a> our results demonstrate that a 40% higher substitution volumes manage to significantly increase clearance of this type of toxin.</p><p id="par0135" class="elsevierStylePara elsevierViewall">The three protein-bound solutes studied have a similar molecular weight, but different protein-binding rates, 70%, 90% and 95% for homocysteine, indoxyl sulphate and p-cresyl sulphate respectively.<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">15,16</span></a> We found that the reduction ratio in these molecules is usually inversely proportional to the protein-binding, such that p-cresyl sulphate, which is the solute with the tightest protein bond, is the hardest to remove by convection, whereas homocysteine is the one that shows the greatest reduction ratio. Nevertheless, it is important to point out that the clearance of the three toxins studied show a direct correlation with the convective volume, with a higher correlation coefficient for p-cresyl sulphate. It has been suggested that protein-bound toxins are removed nearly exclusively by removing the free fraction, such that the protein-bound fraction is displaced into its free form during the dialysis session, enabling these toxins to cross the membrane.<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">21</span></a> It is clear that in our study, small molecule clearance is high, as the sum resulting from the convective and diffusive transport. The result may be that more of the free fraction of the protein-bound toxins are removed, which may increase the displacement of the protein-bound fraction to the free fraction, thereby enabling their continued clearance. However, this hypothesis would need to be confirmed.</p><p id="par0140" class="elsevierStylePara elsevierViewall">Encouraging studies have recently appeared which demonstrate that incorporating resins with the ability to remove protein-bound molecules by adsorption may have an additive effect on the efficacy of conventional techniques. Thus, haemodiafiltration using resin adsorption to regenerate the ultrafiltrate (HFR, Bellco<span class="elsevierStyleSup">®</span>), which combines adsorption with convective transport and reinfusion of the patient's own ultrafiltrate, has been shown to be effective in removing protein-bound toxins.<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">23–25</span></a> Nevertheless, more studies are necessary to assess the amount of resin that needs to be incorporated into the technique to prevent premature saturation.</p><p id="par0145" class="elsevierStylePara elsevierViewall">Studies have also been conducted with absorbents, which have been demonstrated to decrease the levels of these toxins<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">26</span></a> although not significantly, and especially not in <span class="elsevierStyleItalic">in vitro</span> studies. Moreover, using probiotics and symbiotics has been demonstrated to be able to reduce the levels of protein-bound toxins.<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">26,27</span></a> More recently it has been demonstrated that it is also possible to decrease the levels of indoxyl sulphate and possibly p-cresyl sulphate by increasing the fibre content in the diets of haemodialysis patients.<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">28</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Three randomised, controlled studies conducted in recent years have demonstrated increased survival in patients treated with post-OL-HDF with substitution volumes greater than 17.4, 20.7, and 22<span class="elsevierStyleHsp" style=""></span>l, respectively,<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">5–7</span></a> possibly in relation to a higher uraemic toxin clearance, especially mid-sized toxins, although with the findings from our study, it is possible that this decrease in morbidity and mortality is also partly due to greater protein-bound toxin clearance.</p><p id="par0155" class="elsevierStylePara elsevierViewall">Modern dialysis monitors with the possibility of performing OL-HDF incorporate automatic biomonitoring systems, which enable substitution volumes over 25<span class="elsevierStyleHsp" style=""></span>l to be obtained in four-hour sessions. This requires good vascular access, and preferably using 14G needles to increase blood flow. In our study, the mean blood flow was 426<span class="elsevierStyleHsp" style=""></span>ml/min, which enabled more than 100<span class="elsevierStyleHsp" style=""></span>l of blood to be dialysed in a 4-hour session, reaching a convective volume over 28<span class="elsevierStyleHsp" style=""></span>l on average with no technical problems (approximate filtration fraction was 28%). However, one of the largest bottlenecks for increasing convective transport is that not all the potentially beneficial substances that may be removed with the ultrafiltrate have been quantified, such as amino acids, minerals, vitamins, antioxidants, and other nutrients, whose clinical relevance is still unknown.</p><p id="par0160" class="elsevierStylePara elsevierViewall">The possible albumin loss is one of the most studied aspects. These losses occur especially during the first 30<span class="elsevierStyleHsp" style=""></span>min of each session.<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">29,30</span></a> Nevertheless, recent studies demonstrate that the losses are higher in haemodiafiltration than in haemodialysis and depend on the type of dialyser chosen.<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">22,31</span></a> Incorporating nanotechnology into the manufacture of more modern dialysers has enabled the membrane pore characteristics to be modified, such that these losses are much smaller<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">30</span></a> with low clinical significance. In a previous study, we found that the albumin losses with the dialyser used in this study are limited, although with significant differences between the 20- and 30-l substitution volumes per session.</p><p id="par0165" class="elsevierStylePara elsevierViewall">In our results, we found that the reduction ratio of the alpha-2 macroglobulin levels, with a molecular weight of 72,000<span class="elsevierStyleHsp" style=""></span>Da, is slightly negative despite having adjusted the post-dialysis levels to the haemoconcentration, which indicates that it is hardly removed or not removed at all.</p><p id="par0170" class="elsevierStylePara elsevierViewall">This study has some limitations such as the small number of sessions analysed, that we only determined the reduction rate in protein-bound toxins without measuring the losses by the dialyser and that we used a single type of dialyser, although we chose a dialyser with suitable characteristics for the technique used.<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">32</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">In summary, our study demonstrates that with high-volume convective transport can achieve higher protein-bound toxin removal. Nevertheless, more studies with the ability to confirm our hypothesis are needed to analyse the possible effect that this behaviour may have in the longer term on the progression of patients thus treated.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Conflicts of interest</span><p id="par0180" class="elsevierStylePara elsevierViewall">The authors declare that there are no conflicts of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres803795" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:1 [ "identificador" => "abst0005" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec801988" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres803794" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:1 [ "identificador" => "abst0025" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec801989" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Material and methods" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Population and dialysis technique" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Laboratory tests" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Statistical analysis" ] ] ] 6 => array:2 [ "identificador" => "sec0030" "titulo" => "Findings" ] 7 => array:2 [ "identificador" => "sec0035" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflicts of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-05-27" "fechaAceptado" => "2016-05-04" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec801988" "palabras" => array:5 [ 0 => "Online haemodiafiltration" 1 => "Protein-bound toxins" 2 => "High convective volumes" 3 => "p-Cresyl sulphate" 4 => "Indoxyl sulphate" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec801989" "palabras" => array:5 [ 0 => "Hemodiafiltración on-line" 1 => "Toxinas unidas a proteínas" 2 => "Alto volumen convectivo" 3 => "p-cresyl sulfato" 4 => "Indoxyl sulfato" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Chronic kidney disease is associated with an increased risk of cardiovascular events. In recent years, protein-bound toxins have become more important due to their association with increased morbidity and mortality, characterised by inadequate clearance during dialysis. The purpose of this study is to assess the influence of high convective volumes on postdilution online haemodiafiltration (OL-HDF) on the removal of medium-sized molecules, small molecules and protein-bound molecules.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">In forty postdilutional OL-HDF sessions, the reduction rates of toxins of different molecular weights were measured in 13 patients, including protein-bound molecules such as p-cresyl sulphate, indoxyl sulphate and homocysteine.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Total convective volume was 28.3 (5.1)<span class="elsevierStyleHsp" style=""></span>l (range 16.3–38.0<span class="elsevierStyleHsp" style=""></span>l). Mean reduction rate of protein-bound molecules was 44.4% (15.7%), 48.7% (14.1%) and 58.6% (8.8%) for p-cresyl sulphate, indoxyl sulphate and homocysteine, respectively. Moreover, a statistically significant direct association was found between the reduction rates of all three molecules, the replacement volume and the Kt/V.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">High convective volumes during postdilution OL-HDF are associated with increased removal of protein-bound uraemic toxins.</p></span>" "secciones" => array:4 [ 0 => array:1 [ "identificador" => "abst0005" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusion" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La enfermedad renal crónica tiene mayor riesgo de eventos cardiovasculares. En los últimos años, han ido adquiriendo mayor importancia las toxinas unidas a proteínas, que han sido asociadas a mayor morbimortalidad y que se caracterizan por la dificultad para su depuración en diálisis. El objetivo de este estudio es valorar la influencia de altos volúmenes convectivos en HDF-OL posdilucional sobre la eliminación de medianas moléculas, pequeñas moléculas y moléculas unidas a proteínas.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Material y métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se realizaron 40 sesiones de HDF-OL posdilucional en 13 pacientes y se midió el porcentaje de reducción de toxinas de distinto peso molecular y entre ellas, moléculas unidas a proteínas como el p-cresyl sulfato, indoxyl sulfato y homocisteína.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">El volumen convectivo total fue de 28,3(5,1) litros con un rango entre 16,3 y 38,0 litros. La reducción media de moléculas unidas a proteínas fue de 44,4(15,7) % para el p-cresyl sulfato, de 48,7(14,1) % para el indoxyl sulfato y de 58,6(8,8) % para la homocisteína. Además, se encontró una relación directa y estadísticamente significativa entre el porcentaje de reducción de las tres moléculas con el volumen de sustitución y con el Kt/V.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Conclusión</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Altos volúmenes convectivos totales en HDF-OL en posdilución se asocian a una mayor eliminación de toxinas urémicas unidas a proteínas.</p></span>" "secciones" => array:4 [ 0 => array:1 [ "identificador" => "abst0025" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusión" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Abad S, Vega A, Quiroga B, Arroyo D, Panizo N, Reque JE, et al. Toxinas unidas a proteínas: valor añadido en su eliminación con altos volúmenes convectivos. Nefrología. 2016;36:637–642.</p>" ] ] "multimedia" => array:5 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2540 "Ancho" => 3237 "Tamanyo" => 231716 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Correlation between the protein-bound molecule reduction ratio and the total convective volume. Homocysteine reduction A); p-cresyl sulphate reduction B); and indoxyl sulphate reduction C).</p>" ] ] 1 => 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:1 [ "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=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Arterial flow (ml/min) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">426(70) \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">Arterial blood pressure (mmHg) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−190(21) \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">Venous blood pressure (mmHg) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">170(21) \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">Total convective volume (l) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">28.3(5.1) \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">Ultrafiltration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">1.9(1.0) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1349370.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Haemodialysis session characteristics, represented as the mean (standard deviation).</p>" ] ] 2 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "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">Molecules (MW Da) \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-dialysis serum levels \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">% Reduction \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">Pearson coefficient of correlation \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" title="table-entry " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">Low-molecular-weight molecules</span></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>Phosphorus (31) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">4.2(1.5)<span class="elsevierStyleHsp" style=""></span>mg/dl \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">57.1(17.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−0.004 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.981 \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>Urea (60) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">121(40)<span class="elsevierStyleHsp" style=""></span>mg/dl \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">79.0(23.12) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.320 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><0.050 \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>Creatinine (113) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">9.6(3.7) mg/dl \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">75.9(7.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.678 \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" title="table-entry " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">Mid- and high-molecular-weight molecules</span></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>Beta-2 microglobulin (11,800) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">23(7)<span class="elsevierStyleHsp" style=""></span>mg/l \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">81.3(6.4) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.607 \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"><span class="elsevierStyleHsp" style=""></span>Myoglobin (17,000) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">236(114)<span class="elsevierStyleHsp" style=""></span>ng/ml \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">60.0(11.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.431 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><0.010 \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>Prolactin (22,000) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">28(22)<span class="elsevierStyleHsp" style=""></span>μg/l \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">60.1(14.3) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.395 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><0.050 \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>Interleukin-6 (26,000) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">5.6(3.0)<span class="elsevierStyleHsp" style=""></span>pg/ml \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">28(17.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.113 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.613 \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>Alpha-2 macroglobulin (72,000) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">153(30)<span class="elsevierStyleHsp" style=""></span>mg/dl \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">−2.2(12.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.270 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.960 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="5" align="left" valign="top"><span class="elsevierStyleItalic">Protein-bound molecules</span></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>Homocysteine (135) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">26.8(9.5)<span class="elsevierStyleHsp" style=""></span>μmol/l \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">58.6(8.8) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.492 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><0.005 \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>P-cresyl-sulphate (187) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">13.7(3.7)<span class="elsevierStyleHsp" style=""></span>mg/dl \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">44.4(15.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.630 \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"><span class="elsevierStyleHsp" style=""></span>Indoxyl-sulphate (212) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">42.2(14.9)<span class="elsevierStyleHsp" style=""></span>mg/l \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">48.7(14.1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top">0.461 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="char" valign="top"><0.050 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1349369.png" ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Bivariate correlations between the total convective transport and the molecule reduction ratio, represented as the mean (standard deviation).</p>" ] ] 3 => array:5 [ "identificador" => "eq0005" "tipo" => "MULTIMEDIAFORMULA" "mostrarFloat" => false "mostrarDisplay" => true "Formula" => array:5 [ "Matematica" => "100*(predialysis plasma concentration−postdialysis plasma concentration (corrected by hemoconcentration)/predialysis plasma concentration" "Fichero" => "STRIPIN_si1.jpeg" "Tamanyo" => 8874 "Alto" => 72 "Ancho" => 416 ] ] 4 => array:5 [ "identificador" => "eq0010" "tipo" => "MULTIMEDIAFORMULA" "mostrarFloat" => false "mostrarDisplay" => true "Formula" => array:5 [ "Matematica" => "corrected post dialysis concentration=postdialysis concentration/[1+((predialysis dry weight−post dialysis dry weight)/(postdialysis weight*0.2))]" "Fichero" => "STRIPIN_si2.jpeg" "Tamanyo" => 9185 "Alto" => 72 "Ancho" => 420 ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:32 [ 0 => array:3 [ "identificador" => "bib0165" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Epidemiology of cardiovascular disease in chronic renal disease" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "R.N. 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| 2024 August | 81 | 63 | 144 |
| 2024 July | 44 | 18 | 62 |
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| 2024 May | 58 | 42 | 100 |
| 2024 April | 48 | 47 | 95 |
| 2024 March | 33 | 23 | 56 |
| 2024 February | 27 | 34 | 61 |
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| 2023 December | 18 | 20 | 38 |
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| 2023 August | 37 | 23 | 60 |
| 2023 July | 31 | 25 | 56 |
| 2023 June | 27 | 23 | 50 |
| 2023 May | 46 | 36 | 82 |
| 2023 April | 22 | 23 | 45 |
| 2023 March | 58 | 17 | 75 |
| 2023 February | 43 | 15 | 58 |
| 2023 January | 26 | 25 | 51 |
| 2022 December | 53 | 28 | 81 |
| 2022 November | 48 | 26 | 74 |
| 2022 October | 46 | 41 | 87 |
| 2022 September | 43 | 29 | 72 |
| 2022 August | 46 | 47 | 93 |
| 2022 July | 29 | 41 | 70 |
| 2022 June | 43 | 29 | 72 |
| 2022 May | 40 | 25 | 65 |
| 2022 April | 34 | 43 | 77 |
| 2022 March | 45 | 36 | 81 |
| 2022 February | 39 | 44 | 83 |
| 2022 January | 39 | 43 | 82 |
| 2021 December | 32 | 32 | 64 |
| 2021 November | 28 | 45 | 73 |
| 2021 October | 34 | 47 | 81 |
| 2021 September | 63 | 38 | 101 |
| 2021 August | 36 | 48 | 84 |
| 2021 July | 31 | 42 | 73 |
| 2021 June | 26 | 38 | 64 |
| 2021 May | 80 | 48 | 128 |
| 2021 April | 111 | 62 | 173 |
| 2021 March | 45 | 38 | 83 |
| 2021 February | 29 | 18 | 47 |
| 2021 January | 38 | 21 | 59 |
| 2020 December | 31 | 23 | 54 |
| 2020 November | 42 | 13 | 55 |
| 2020 October | 42 | 29 | 71 |
| 2020 September | 49 | 20 | 69 |
| 2020 August | 57 | 20 | 77 |
| 2020 July | 40 | 12 | 52 |
| 2020 June | 47 | 15 | 62 |
| 2020 May | 38 | 6 | 44 |
| 2020 April | 30 | 20 | 50 |
| 2020 March | 41 | 17 | 58 |
| 2020 February | 37 | 25 | 62 |
| 2020 January | 34 | 14 | 48 |
| 2019 December | 49 | 22 | 71 |
| 2019 November | 33 | 23 | 56 |
| 2019 October | 24 | 14 | 38 |
| 2019 September | 30 | 17 | 47 |
| 2019 August | 19 | 18 | 37 |
| 2019 July | 29 | 21 | 50 |
| 2019 June | 29 | 19 | 48 |
| 2019 May | 20 | 18 | 38 |
| 2019 April | 70 | 31 | 101 |
| 2019 March | 47 | 19 | 66 |
| 2019 February | 29 | 19 | 48 |
| 2019 January | 36 | 22 | 58 |
| 2018 December | 95 | 46 | 141 |
| 2018 November | 107 | 17 | 124 |
| 2018 October | 110 | 20 | 130 |
| 2018 September | 87 | 15 | 102 |
| 2018 August | 48 | 20 | 68 |
| 2018 July | 41 | 13 | 54 |
| 2018 June | 32 | 15 | 47 |
| 2018 May | 50 | 15 | 65 |
| 2018 April | 55 | 8 | 63 |
| 2018 March | 41 | 7 | 48 |
| 2018 February | 43 | 11 | 54 |
| 2018 January | 45 | 5 | 50 |
| 2017 December | 56 | 10 | 66 |
| 2017 November | 55 | 14 | 69 |
| 2017 October | 40 | 10 | 50 |
| 2017 September | 47 | 17 | 64 |
| 2017 August | 41 | 31 | 72 |
| 2017 July | 47 | 27 | 74 |
| 2017 June | 42 | 25 | 67 |
| 2017 May | 48 | 22 | 70 |
| 2017 April | 50 | 20 | 70 |
| 2017 March | 32 | 33 | 65 |
| 2017 February | 32 | 10 | 42 |
| 2017 January | 53 | 12 | 65 |
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