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but the further characterization of disease progression in the latter two is still lacking&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">3&#44;4</span></a> What these genes have in common is that they are thought to lead to inefficient maturation and transportation of membrane or secreted proteins&#44; with a specific dose sensitivity for <span class="elsevierStyleItalic">PC1</span>&#44; leading to kidney or liver cysts&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">5</span></a> ADPKD is characterized by the continuous development and growth of cysts&#46; This results in progressive renal enlargement with hypertension&#44; abdominal fullness and pain&#44; episodes of cyst bleeding&#44; gross hematuria&#44; kidney calculi&#44; cyst infection&#44; and reduced quality of life &#40;QOL&#41;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">6&#44;7</span></a> while approximately 50&#37; of patients with ADPKD irreversibly progress to end-stage renal disease &#40;ESRD&#41; by the age of 60&#44; requiring dialysis and kidney transplantation&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">8</span></a> This not only seriously affects the quality of life of patients&#44; but also greatly wastes social resources&#46; Therefore&#44; exploring effective therapeutic measures for ADPKD has become a hot research topic in this field&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Tolvaptan is a selective vasopressin-2-receptor &#40;V2R&#41; antagonist&#44; which is mainly used for the treatment of high-volume and normal-volume hyponatremia&#44; including heart failure&#44; liver cirrhosis and syndrome of inappropriate antidiuretic hormone secretion&#46; In recent years&#44; several large-scale international clinical randomized controlled trials have shown that tolvaptan can effectively inhibit the growth of renal cysts in patients with ADPKD and delay the deterioration of renal function&#46; Many countries&#44; including the United States&#44; have approved the use of tolvaptan in the treatment of rapidly progressive adult ADPKD patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">9&#8211;14</span></a> However&#44; Gross et al&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">15</span></a> have revealed that tolvaptan is associated with the deterioration of GFR function in patients with ADPKD&#44; and tolvaptan can aggravate GFR by 3&#8211;5&#37;&#46; In addition&#44; some studies have suggested<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">16</span></a> that tolvaptan in the treatment of ADPKD can cause severe adverse events such as pulmonary embolism&#46; Therefore&#44; the safety of tolvaptan in the treatment of ADPKD is also questioned&#46; Therefore&#44; we intended to conduct a systematic evaluation of the efficacy and safety of tolvaptan in patients with ADPKD in order to provide evidence-based evidence for the treatment of ADPKD with tolvaptan&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Literature search</span><p id="par0015" class="elsevierStylePara elsevierViewall">We searched the online databases PubMed&#44; Web of Science&#44; Cochrane Library&#44; and Embase for related research until January 2022&#46; The following search terms were used&#58; &#8220;TKV&#44;&#8221; &#8220;eGFR&#44;&#8221; &#8220;ADPKD&#44;&#8221; &#8220;polycystic kidney disease and tolvaptan&#44;&#8221; &#8220;kidney disease&#44;&#8221; as well as &#8220;Vasopressin v<span class="elsevierStyleInf">2</span> receptor antagonist&#8221;&#46; The method of combining subject words and free words was adopted flexibly for retrieval&#44; and the corresponding settings were made according to the characteristics of different databases&#44; with &#8220;Polycystic Kidney Disease and Tolvaptan&#8221; limited as the key word&#46; Details of search strategy are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Inclusion and exclusion criteria</span><p id="par0020" class="elsevierStylePara elsevierViewall">The following criteria were used for study inclusion and selection&#58; &#40;i&#41; study design&#58; a randomized controlled trial&#59; &#40;ii&#41; type of participants&#58; adults &#40;age<span class="elsevierStyleHsp" style=""></span>&#8807;<span class="elsevierStyleHsp" style=""></span>18 years&#41; with ADPKD&#59; &#40;iii&#41; intervention&#58; tolvaptan&#59; &#40;iv&#41; controlled studies&#58; placebo or no treatment&#59; &#40;v&#41; outcome assessed&#58; the main outcome was the delay of eGFR and TKV&#59; secondary outcomes were the primary outcome measures&#58; renal pain&#44; hematuria&#44; proteinuria&#44; hypertension&#44; and incidence of nocturia events&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">The exclusion criteria were as follows&#58; &#40;i&#41; animal research and cell experimental research&#59; &#40;ii&#41; repeated literature by the same research group&#44; and select the latest report with the most complete data&#59; &#40;iii&#41; review literature&#44; case studies&#44; guidelines&#44; systematic analysis and other non-RCT literature&#59; &#40;iv&#41; the data provided by the research is incomplete or missing&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Study eligibility and selection</span><p id="par0030" class="elsevierStylePara elsevierViewall">Literature screening&#44; data extraction and quality evaluation were conducted independently by two researchers&#46; The final results were cross checked by the two researchers&#46; If there was no agreement&#44; a third-party expert would be consulted and the revised risk assessment tool for randomized trial bias developed by Cochrane Collaboration<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">17</span></a> would be used to assess all potential relevant deviations&#46; Each study outcome was assigned as &#8220;low risk of bias&#44;&#8221; &#8220;some concerns&#44;&#8221; or &#8220;high risk of bias&#46;&#8221; Extraction of literature data&#58; &#40;i&#41; basic information of the literature &#40;including publication&#44; first author&#44; year and region of publication&#41;&#59; &#40;ii&#41; study type is RCT&#59; &#40;iii&#41; the types of subjects included in the analysis&#44; the total number of cases and the frequency of polycystic kidney outcomes in each group&#59; &#40;iv&#41; the time&#44; dose and type of tolvaptan used&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Data synthesis and analysis</span><p id="par0035" class="elsevierStylePara elsevierViewall">The eGFR&#44; TKV&#44; treatment duration&#44; and different doses of the drug changes were expressed as the mean difference &#40;MD&#41; of the 95&#37; confidence intervals&#46; For adverse events&#44; risk ratios &#40;RR&#41; and 95&#37; confidence intervals were calculated using raw data&#44; followed by a meta-analysis using a random-effect model that was selected to explain the expected heterogeneity in study design&#44; study drug timing and dose&#44; and some outcome definitions&#44; all using software Review Manager version 5&#46;3&#46; Although all studies strictly followed the inclusion and exclusion criteria&#44; heterogeneity was inevitable&#46; Heterogeneity was assessed using <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span> statistics &#40;<span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#8807;<span class="elsevierStyleHsp" style=""></span>50&#37; or the corresponding <span class="elsevierStyleItalic">P</span> value<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;10 indicated statistically significant heterogeneity between studies&#41;&#44; and as fewer than 10 studies were identified&#44; publication bias could not be assessed visually in the funnel plot&#46; A <span class="elsevierStyleItalic">P</span> value<span class="elsevierStyleHsp" style=""></span>&#8806;<span class="elsevierStyleHsp" style=""></span>0&#46;05 was considered statistically significant&#46; All <span class="elsevierStyleItalic">P</span>-values were statistically significant set to 0&#46;05 with a confidence interval of 95&#37;&#46; This study is registered at the PROSPERO registry under reference number CRD42022328034&#46;</p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Results</span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Study selection</span><p id="par0040" class="elsevierStylePara elsevierViewall">According to the established retrieval strategy&#44; 1301 relevant studies were preliminarily retrieved&#46; 818 articles were excluded by removing duplicates&#46; Forty-five potentially eligible studies were identified by screening the remaining headings and abstracts&#44; and exclusion of the review animal studies categories&#44; and studies and trials that did not meet our inclusion criteria were excluded after further reading&#46; After screening&#44; 8 studies met our inclusion criteria &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> summarizes the characteristics of the included trials&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Study characteristics</span><p id="par0045" class="elsevierStylePara elsevierViewall">The characteristics of the included trials are summarized in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; 8 RCT studies were enrolled&#44; totaling 2135 patients&#44; including 1366 cases in the experimental group and 769 cases in the control group&#46; In the 8 studies&#44; the experimental group was tolvaptan and the control group was placebo&#46; Doses of tolvaptan ranged from 15<span class="elsevierStyleHsp" style=""></span>mg to 90<span class="elsevierStyleHsp" style=""></span>mg per day and were gradually increased weekly if tolerated&#46; The follow-up period ranged from 8 weeks to 3 years&#44; in all including studies&#44; to evaluate changes in eGFR&#44; TKV&#44; and some adverse events or complications &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; Among them&#44; regarding the change of therapeutic effect of TKV&#44; as mentioned by the Eiji Higashihara et al&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">18</span></a>&#44; 51 subjects &#40;81&#37;&#41; completed 3 years of treatment with tolvaptan&#59; initial baseline TKV &#40;1422<span class="elsevierStyleHsp" style=""></span>ml for placebo and 1635<span class="elsevierStyleHsp" style=""></span>ml for tolvaptan&#41;&#46; During the overall three-year period&#44; total renal volume increased by 5&#46;8&#37;&#47;year in the placebo group and 1&#46;7&#37;&#47;year in the tolvaptan group&#46; The work of Casteleijn et al&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">19</span></a> mentioned that the TKV volume had a baseline of 1668<span class="elsevierStyleHsp" style=""></span>ml in the placebo group and 1705<span class="elsevierStyleHsp" style=""></span>ml in the tolvaptan group&#44; and that tolvaptan&#44; a vasopressin V2 receptor antagonist&#44; increased the total renal volume by 2&#46;8&#37; &#91;95&#37; CI &#40;2&#46;5&#8211;3&#46;1&#41;&#93; per year in the tolvaptan group and 5&#46;5&#37; &#91;95&#37; CI &#40;5&#46;1&#8211;6&#46;0&#41;&#93; per year in the placebo group over the 3-year period&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Risk of bias and quality assessment</span><p id="par0050" class="elsevierStylePara elsevierViewall">The overall research quality is medium to high&#44; and there are some potential deviations&#46; The deviation risk is evaluated based on several fields&#44; including allocation deviation&#44; loss deviation&#44; and detection deviation and reporting deviation&#46; The evaluation results are given in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> by using the Cochrane deviation risk tool&#46; Most studies have not disclosed enough hidden details about sequence generation or allocation&#46; The use of other treatment methods&#44; I&#46;E&#46; the control of blood pressure and low back pain&#44; has not been explicitly reported in some studies&#44; thus indicating that there are &#8220;high risks&#8221; and &#8220;some concerns&#8221; in the field of deviation &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Primary outcomes</span><p id="par0055" class="elsevierStylePara elsevierViewall">As shown in <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#44; four studies<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">18&#8211;21</span></a> in patients with ADPKD reported rates of change in eGFR and two studies<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">18&#44;19</span></a> reported annual rates of change in TKV&#46; Analysis of pooled data revealed heterogeneity between eGFR and TKV as compared to controls&#44; a randomized-effect model for meta-analysis&#44; and glomerular filtration rate &#91;MD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;89&#44; 95&#37; CI &#40;0&#46;74&#44; 3&#46;04&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>59&#37;&#93; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>a&#41; and total kidney volume &#91;MD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;3&#46;32&#44; 95&#37; CI &#40;&#8722;4&#46;57&#44; &#8722;2&#46;07&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>70&#37;&#93; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>b&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Secondary outcomes</span><p id="par0060" class="elsevierStylePara elsevierViewall">As shown in <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#44; five studies<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">9&#44;19&#44;22&#8211;24</span></a> have reported the treatment duration of tolvaptan in the treatment of ADPKD patients&#46; Due to large heterogeneity&#44; a random effect model was used for meta-analysis&#46; We divided the treatment duration of tolvaptan into three time periods&#44; and analyzed the time periods in monthly subgroups&#46; Compared with the control group&#44; the overall treatment duration &#91;MD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;69&#46;99&#44; 95&#37; CI &#40;&#8722;91&#46;05&#44; &#8722;48&#46;94&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#93; was statistically significant&#44; with a one-month treatment effect &#91;MD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;35&#46;68&#44; 95&#37; CI &#40;&#8722;70&#46;08&#44; &#8722;1&#46;29&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;04&#44; <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#93;&#59; two-month treatment effect &#91;MD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;72&#46;69&#44; 95&#37; CI &#40;&#8722;139&#46;24&#44; &#8722;6&#46;10&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;03&#44; <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#93;&#59; march treatment effect &#91;MD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;107&#46;49&#44; 95&#37; CI &#40;&#8722;211&#46;18&#44; &#8722;3&#46;81&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;04&#44; <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#93;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">As shown in <a class="elsevierStyleCrossRefs" href="#fig0020">Figs&#46; 4 and 5</a>&#44; five studies<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">9&#44;19&#44;22&#8211;24</span></a> reported the adverse reactions of patients taking tolvaptan in the experimental group and placebo in the control group&#46; The adverse events in 1876 subjects included renal pain&#44; hematuria&#44; thirst&#44; nocturia&#44; hypertension&#44; etc&#46; The statistical analysis of adverse event data is as follows&#58; the incidence of renal pain &#91;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;66&#44; 95&#37; CI &#40;0&#46;54&#44; 0&#46;81&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#93; &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>a&#41; and hematuria &#91;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;55&#44; 95&#37; CI &#40;0&#46;41&#44; 0&#46;74&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#93; &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>b&#41; in the treatment group were lower than that in the control group&#44; while in thirst &#91;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;75&#44; 95&#37; CI &#40;2&#46;34&#44; 3&#46;24&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#44; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#93; &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>c&#41; and nocturia &#91;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;01&#44; 95&#37; CI &#40;1&#46;27&#44; 7&#46;11&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#44; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>60&#37;&#93; &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>d&#41; were higher than those of the control group&#46; There was no heterogeneity in the incidence of hypertension in the composite data analysis&#44; and the treatment group &#91;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;92&#44; 95&#37; CI &#40;0&#46;82&#44; 1&#46;03&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;13&#44; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#37;&#93; &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>a&#41; compared with the control group indicated that there is no statistical significance in the adverse events of hypertension in the treatment group&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">As shown in <a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>b&#44; two studies<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">18&#44;22</span></a> have reported to compare the different doses of the drug to reduce the risk of renal pain in patients with ADPKD&#46; Meta-analysis was conducted for comprehensive data and there was no heterogeneity&#46; There was no statistical significance in the high-dose group when compared with the low-dose group &#91;MD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;26&#44; 95&#37; CI &#40;0&#46;65&#44; 2&#46;44&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;50&#44; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#93; &#40;<a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 5</a>b&#41;&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Discussion</span><p id="par0075" class="elsevierStylePara elsevierViewall">Evidence-based medicine needs to understand the heterogeneity of results by considering the integrity of evidence&#44; and guide clinical practice with reliable evidence&#46; In this study&#44; we systematically analyzed the effects of tolvaptan on patients with ADPKD&#46; The results of this study showed that&#58; &#40;i&#41; the use of tolvaptan effectively slowed the decline of eGFR and TKV&#46; Efficacy analyses for ADPKD patients in the different months remained consistent across subgroups&#44; delaying the progression of TKV in the different months&#44; and not worsening efficacy over time&#46; Rather&#44; efficacy might have been better&#46; However&#44; due to the scarcity of available data and some heterogeneity&#44; this finding should be considered exploratory rather than definitive&#46; &#40;ii&#41; After the meta-analysis of the efficacy of tolvaptan in different doses&#44; there was no statistically significant difference between the doses&#46; However&#44; due to the small amount of literature currently studied&#44; statistical evidence does not show that there is no difference between low dose and high dose of tolvaptan&#46; In the future&#44; more high-quality articles and expanded sample size can be considered&#44; and the difference between the two groups can be counted again&#46; Perhaps the comparison between two groups of measures has a statistical difference&#46; &#40;iii&#41; Statistical analysis was performed on adverse reaction events in the tolvaptan experimental group&#46; The adverse reaction events of renal pain and hematuria in the experimental group were less than those in the control group&#44; but the number of adverse events such as thirst and nocturia was greater than that in the control group&#46; In terms of improving the progression of ADPKD&#44; the adverse reactions of thirst and nocturia can be completely tolerated&#44; at the same time&#44; it is also because the medicinal mechanism of tolvaptan determines that&#58; Tolvaptan was a selective arginine vasopressin &#40;AVP&#41; V<span class="elsevierStyleInf">2</span> receptor antagonist&#46; Vasopressin binds to V<span class="elsevierStyleInf">2</span>-type receptors in the distal tubules and collecting ducts&#44; promotes urine concentration&#44; inhibits bulbar feedback&#44; and promotes sodium salt reabsorption&#46; The mechanism of tolvaptan is to antagonize the binding of vasopressin to V<span class="elsevierStyleInf">2</span> receptor&#44; so it can inhibit urine concentration&#44; stimulate tubuloglomerular feedback&#44; and inhibit sodium salt reabsorption&#46;<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">25&#8211;27</span></a> Therefore&#44; it can also be demonstrated that the adverse reactions of tolvaptan are part of the drug mechanism&#44; but its adverse reactions are acceptable after the larger efficacy in alleviating the progression of ADPKD&#46; Among all the adverse events&#44; pulmonary embolism is undoubtedly the most serious&#46; In general&#44; when vasopressin binds to vasopressin V<span class="elsevierStyleInf">2</span> receptor&#44; cAMP is activated and vascular endothelial cells release von Willebrand factor&#44; both of which may lead to an increase in the clotting cascade&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">28</span></a> Tovaptan inhibits the release of von Willebrand factor by vascular endothelial cells through its antagonism against vasopressin V<span class="elsevierStyleInf">2</span> receptor&#44; and may reduce the hemostatic ability&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">29</span></a> Therefore&#44; administration of Tovaptan to patients with ADPKD accompanied by dehydration may be at risk of pulmonary embolism&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">16</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">So how does tolvaptan alleviate the progression of ADPKD&#63; The epidemiological survey of ADPKD affects 12&#46;5 million people of all ethnic groups worldwide&#44; accounts for up to 10&#37; of patients with end stage renal disease &#40;ESRD&#41;&#44; and constitutes a major public health burden&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">30</span></a> Most ADPKD of patients begin to suffer from a series of clinical symptoms after middle age&#44; which can affect multiple systems of the whole body&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">31&#44;32</span></a> Tolvaptan was a selective arginine vasopressin &#40;AVP&#41; V<span class="elsevierStyleInf">2</span> receptor antagonist and it can inhibit the production of cyclic AMP &#40;cAMP&#41; induced by AVP&#44; reduce protein kinase R-like ER kinase&#47;extracellular regulated protein kinases &#40;pERK&#47;ERK&#41; activity&#44; and inhibit the proliferation of cyst cells in patients with ADPKD&#46; Inhibiting AVP induced creatinine secretion limits the expansion of existing cysts and allows net fluid absorption to reduce cyst size and TKV&#44; thereby slowing cyst growth in ADPKD&#46;<a class="elsevierStyleCrossRefs" href="#bib0340"><span class="elsevierStyleSup">33&#8211;35</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">The advantages of this study lie in&#58; &#40;i&#41; compared with other studies&#44; the literature has been updated&#44; the sample size is larger&#44; and the test efficiency is improved&#59; &#40;ii&#41; there was a significant benefit of taking tolvaptan from the first year &#91;MD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;35&#46;68&#44; 95&#37; CI &#40;&#8722;70&#46;08&#44; &#8722;1&#46;29&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;04&#44; <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#93; and continuing to the third year &#91;MD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;107&#46;49&#44; 95&#37; CI &#40;&#8722;211&#46;18&#44; &#8722;3&#46;81&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;04&#44; <a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#93;&#44; which can further provide clues for clinical treatment according to literature published by Torres&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">9</span></a> The therapeutic effect of ADPKD does not appear until at least one year after administration&#44; and it can alleviate the increase in total renal volume and the decrease in renal function after three years of administration&#46; The above results are consistent with the results of this study&#44; suggesting that long-term high-dose treatment is more conducive to the treatment of ADPKD&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">This study has the following deficiencies&#58; &#40;i&#41; there are certain limitations in this study&#46; First&#44; the literature on the treatment of ADPKD with tolvaptan is limited&#44; except for some studies with low quality and incomplete data&#46; The number of studies finally included in this study is only 8&#46; In the future&#44; we can consider including more high quality studies to expand the sample size to make the results more convincing&#46; &#40;ii&#41; The heterogeneity of adverse reactions in the results is high&#44; which may be due to the inconsistent experimental design of included studies&#44; the differences in the dosage and method of tolvaptan administration&#44; the follow-up questions&#44; and the differences in the selection of the control group&#46; In addition&#44; the research subjects received related interventions in the hospital&#44; and their environment might also have a certain impact on the intervention effect&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Conclusions</span><p id="par0095" class="elsevierStylePara elsevierViewall">Compared with the control group&#44; tolvaptan can delay the progression of eGFR and TKV&#44; suggesting that it may have a protective effect on the kidneys of patients with CKD&#46; In addition&#44; the fact that tolvaptan lasts from the first year to the third year may suggest that a longer period of tolvaptan may be more beneficial for the treatment of ADPKD&#44; and tolvaptan is now an important option for the treatment of patients with ADPKD&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Funding</span><p id="par0105" class="elsevierStylePara elsevierViewall">This study was supported by Scientific Research Project of Education Department of Hubei Province &#40;grant no&#46; B2017024&#41; and the Natural Science Foundation of Yichang City &#40;grant no&#46; A20-2-002&#41;&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Conflict of interests</span><p id="par0100" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest&#46;</p></span></span>"
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            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Inclusion and exclusion criteria"
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            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Study eligibility and selection"
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              "identificador" => "sec0030"
              "titulo" => "Data synthesis and analysis"
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          "titulo" => "Results"
          "secciones" => array:5 [
            0 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Study selection"
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              "titulo" => "Study characteristics"
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              "titulo" => "Risk of bias and quality assessment"
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            3 => array:2 [
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          "titulo" => "Funding"
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          "titulo" => "Conflict of interests"
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          "titulo" => "References"
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    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2022-05-08"
    "fechaAceptado" => "2022-10-06"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1765825"
          "palabras" => array:4 [
            0 => "TKV &#40;total kidney volume&#41;"
            1 => "eGFR &#40;estimated glomerular filtration rate&#41;"
            2 => "Tolvaptan"
            3 => "ADPKD &#40;autosomal dominant polycystic kidney disease&#41;"
          ]
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          "identificador" => "xpalclavsec1765826"
          "palabras" => array:4 [
            0 => "VRT &#40;volumen renal total&#41;"
            1 => "eGFR &#40;tasa de filtraci&#243;n glomerular estimada&#41;"
            2 => "Tolvaptan"
            3 => "ERPAD &#40;enfermedad renal poliqu&#237;stica autos&#243;mica dominante&#41;"
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      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The irreversible progression of autosomal dominant polycystic kidney disease &#40;ADPKD&#41; to end-stage renal disease &#40;ESRD&#41; is delayed by tolvaptan&#46; Therefore&#44; we aim to systematically estimate and evaluate the efficacy and safety of tolvaptan in the treatment of ADPKD&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Two reviewers independently searched all published randomized controlled trials studies in PubMed&#44; EMBASE&#44; Web of Science and Cochrane databases&#44; extracted data&#44; assessed bias risk and rated the quality of evidence&#46; Data were analyzed by the RevMan software&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">We identified 8 trials including 2135 patients&#46; Both of the decline of estimated glomerular filtration rate &#40;eGFR&#41; &#91;MD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;89&#44; 95&#37; CI &#40;0&#46;74&#44; 3&#46;04&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#93; and total kidney volume &#40;TKV&#41; &#91;MD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;3&#46;32&#44; 95&#37; CI &#40;&#8722;4&#46;57&#44; &#8722;2&#46;07&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#93; were delayed in tolvaptan group compared with placebo group in ADPKD patients&#46; The use of tolvaptan delayed TKV progression in the different-month subgroups &#91;MD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;69&#46;99&#44; 95&#37; CI &#40;&#8722;91&#46;05&#44; &#8722;48&#46;94&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#93;&#46; Tolvaptan reduced renal pain &#91;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;66&#44; 95&#37; CI &#40;0&#46;54&#44; 0&#46;81&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#93; and hematuria events &#91;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;55&#44; 95&#37; CI &#40;0&#46;41&#44; 0&#46;74&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#93; in ADPKD patients&#46; However&#44; the prevalence of thirst &#91;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;75&#44; 95&#37; CI &#40;2&#46;34&#44; 3&#46;24&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;001&#93; and nocturia events &#91;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#46;01&#44; 95&#37; CI &#40;1&#46;27&#44; 7&#46;11&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;01&#93; were increased in tolvaptan group&#46; There is no significant difference of hypertension events &#91;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;92&#44; 95&#37; CI &#40;0&#46;82&#44; 1&#46;03&#41;&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;13&#93; in tolvaptan group compared placebo group&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">This meta-analysis suggests that tolvaptan may improve clinical progression in patients with ADPKD without significantly increasing the risk of adverse reactions&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Background"
          ]
          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Methods"
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          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
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            "titulo" => "Conclusions"
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      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Antecedentes</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La progresi&#243;n irreversible de la enfermedad renal poliqu&#237;stica autos&#243;mica dominante &#40;ERPAD&#41; a enfermedad renal en etapa final &#40;ESRD&#41; es demorada por tolvaptan&#46; Por tanto&#44; nuestro objetivo fue estimar y calcular sistem&#225;ticamente la eficacia y seguridad de tolvaptan en el tratamiento de ERPAD&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Dos revisores buscaron de manera independiente todos los estudios publicados sobre ensayos controlados aleatorizados en las bases de datos de PubMed&#44; Embase&#44; Web of Science y Cochrane&#44; extrayendo datos&#44; evaluando el riesgo de sesgo y calificando la calidad de la evidencia&#46; Los datos fueron analizados utilizando el <span class="elsevierStyleItalic">software</span> RevMan&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Identificamos ocho ensayos&#44; que incluyeron 2&#46;135 pacientes&#46; Tanto la reducci&#243;n de la tasa de filtraci&#243;n glomerular estimada &#40;eGFR&#41; &#91;MD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#44;89&#44; IC 95&#37; &#40;0&#44;74&#44; 3&#44;04&#41;&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#93; como el volumen renal total &#40;VRT&#41; &#91;MD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;3&#44;32&#44; IC 95&#37; &#40;&#8722;4&#44;57&#44; &#8722;2&#44;07&#41;&#44; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#93; se demoraron en el grupo tolvaptan&#44; en comparaci&#243;n con el grupo placebo en los pacientes con ERPAD&#46; El uso de tolvaptan demor&#243; la progresi&#243;n del VRT en los subgrupos de diferentes meses &#91;MD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;69&#44;99&#44; IC 95&#37; &#40;&#8722;91&#44;05&#44; &#8722;48&#44;94&#41;&#44; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#93;&#46; Tolvaptan redujo el dolor renal &#91;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;66&#44; IC 95&#37; &#40;0&#44;54&#44; 0&#44;81&#41;&#44; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#93; y los episodios de hematuria &#91;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;55&#44; IC 95&#37; &#40;0&#44;41&#44; 0&#44;74&#41;&#44; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#93; en los pacientes con ERPAD&#46; Sin embargo&#44; la prevalencia de episodios de sed &#91;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#44;75&#44; IC 95&#37; &#40;2&#44;34&#44; 3&#44;24&#41;&#44; p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#93; y nocturia &#91;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>3&#44;01&#44; IC 95&#37; &#40;1&#44;27&#44; 7&#44;11&#41;&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;01&#93; se increment&#243; en el grupo tolvaptan&#46; No existe diferencia significativa en cuanto a episodios de hipertensi&#243;n &#91;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;92&#44; IC 95&#37; &#40;0&#44;82&#44; 1&#44;03&#41;&#44; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;13&#93; en el grupo tolvaptan&#44; en comparaci&#243;n con el grupo placebo&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Este metaan&#225;lisis sugiere que tolvaptan puede mejorar la progresi&#243;n cl&#237;nica en los pacientes con ERPAD&#44; sin incrementar significativamente el riesgo de reacciones adversas&#46;</p></span>"
        "secciones" => array:4 [
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            "titulo" => "Antecedentes"
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        "etiqueta" => "Fig&#46; 1"
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          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Flow chart of the literature search&#46; Preferred reporting items for systematic reviews and meta-analyses flow chart of the study search and review process&#46;</p>"
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        "identificador" => "fig0010"
        "etiqueta" => "Fig&#46; 2"
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Forest plots of the included randomized controlled trials&#46; Included patients had ADPKD&#58; &#40;a&#41; showing a difference in estimated glomerular filtration rates between tolvaptan and placebo&#59; &#40;b&#41; showing a difference in annual rate of change of renal volume rates between tolvaptan and placebo&#46; 95&#37; CI&#58; 95 confidence interval&#59; df&#58; degrees of freedom&#59; IV&#58; inverse variance&#46;</p>"
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          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Forest plots of the included randomized controlled trials&#46; Included patients had ADPKD&#58; this figure shows the overall efficacy of tolvaptan versus placebo treatment duration&#44; with subgroups defining efficacy by month of treatment&#46; 95&#37; CI&#58; 95 confidence interval&#59; df&#58; degrees of freedom&#59; IV&#58; inverse variance&#46;</p>"
        ]
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          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Forest plots of the included randomized controlled trials&#46; Included patients had ADPKD&#58; &#40;a&#41; shows the difference between tolvaptan and placebo in estimating the change in the rate of renal pain&#59; &#40;b&#41; shows the difference between tolvaptan and placebo in estimating the change in the rate of hematuria&#59; &#40;c&#41; shows the difference between tolvaptan and placebo in estimating the change in the rate of thirst&#59; &#40;d&#41; shows the difference between tolvaptan and placebo in estimating the change in the rate of nocturia&#46; 95&#37; CI&#58; 95 confidence interval&#59; df&#58; degrees of freedom&#59; M-H&#58; Mantel-Haenszel&#46;</p>"
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          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Forest plots of the included randomized controlled trials&#46; Included patients had ADPKD&#58; &#40;a&#41; shows the difference between tolvaptan and placebo in estimating change in the rate of the hypertension&#59; &#40;b&#41; shows the difference between tolvaptan and placebo in estimating changes in treatment with different doses of the drug&#46; 95&#37; CI&#58; 95 confidence interval&#59; df&#58; degrees of freedom&#59; M-H&#58; Mantel-Haenszel&#46;</p>"
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          "leyenda" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Note&#58; T&#58; tolvaptan&#59; P&#58; placebo&#59; SD&#58; mean <elsevierMultimedia ident="202401080422440259"></elsevierMultimedia>&#58; estimated glomerular filtration rate &#40;eGFR&#41;&#59; <elsevierMultimedia ident="2024010804224402510"></elsevierMultimedia>&#58; total volume of kidney &#40;TKV&#41;&#59; <elsevierMultimedia ident="2024010804224402511"></elsevierMultimedia>&#58; renal pain&#59; <elsevierMultimedia ident="2024010804224402512"></elsevierMultimedia>&#58; hematuria&#59; <elsevierMultimedia ident="2024010804224402513"></elsevierMultimedia>&#58; nocturia&#59; <elsevierMultimedia ident="2024010804224402514"></elsevierMultimedia>&#58; thirst&#59; <elsevierMultimedia ident="2024010804224402515"></elsevierMultimedia>&#58; hypertension&#46;</p>"
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                  \t\t\t\t" scope="col">Number of cases &#40;T&#47;P&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">P&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Higashihara<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">18</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2011&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">America&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">51&#47;102&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>17&#47;34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">P<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>34&#47;68&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>42<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#46;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">P<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>42<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tolvaptan 15&#47;15&#44; 45&#47;15&#44; 90&#47;30<span class="elsevierStyleHsp" style=""></span>mg once daily&#44; with gradual weekly increases of 45&#47;15&#44; 90&#47;30<span class="elsevierStyleHsp" style=""></span>mg if tolerated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3yr&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><elsevierMultimedia ident="202401080422440251"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Torres<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">9</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2012&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">America&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">961&#47;484&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>495&#47;466&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">P<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>251&#47;233&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>39<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">P<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>39<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tolvaptan 45&#47;15&#44; 60&#47;30&#44; 90&#47;30<span class="elsevierStyleHsp" style=""></span>mg once daily as tolerated with a gradual increase of 60&#47;30<span class="elsevierStyleHsp" style=""></span>mg&#44; 90&#47;30<span class="elsevierStyleHsp" style=""></span>mg per week&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3yr&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><elsevierMultimedia ident="202401080422440252"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Satoru Muto<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">23</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Japan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">118&#47;59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>59&#47;59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">P<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>35&#47;24&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>38&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">P<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>40&#46;4<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tovaptan 60&#47;120<span class="elsevierStyleHsp" style=""></span>mg&#44; once daily&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1yr&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><elsevierMultimedia ident="202401080422440253"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Casteleijn<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">19</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2017&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Netherlands&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">961&#47;484&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>495&#47;466&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">P<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>251&#47;233&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>39<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">P<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>39<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tolvaptan 45&#47;15&#44; 60&#47;30&#44; 90&#47;30<span class="elsevierStyleHsp" style=""></span>mg once daily&#44; with gradual weekly increases of 60&#47;30<span class="elsevierStyleHsp" style=""></span>mg&#44; 90&#47;30<span class="elsevierStyleHsp" style=""></span>mg if tolerated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3yr&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><elsevierMultimedia ident="202401080422440254"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Torres<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">24</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">America&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">958&#47;481&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>494&#47;464&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">P<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>249&#47;232&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>38&#46;6<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">P<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>39&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>6&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tolvaptan 45&#47;15&#44; 60&#47;30&#44; 90&#47;30<span class="elsevierStyleHsp" style=""></span>mg once daily&#44; with gradual weekly increases of 60&#47;30<span class="elsevierStyleHsp" style=""></span>mg&#44; 90&#47;30<span class="elsevierStyleHsp" style=""></span>mg if tolerated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3yr&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><elsevierMultimedia ident="202401080422440255"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Perrone<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">22</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2020&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">America&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">134&#47;43&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>73&#47;61&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">P<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20&#47;23&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>34<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#46;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">P<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>33&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tolvaptan 50<span class="elsevierStyleHsp" style=""></span>mg&#47;once daily&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8wk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><elsevierMultimedia ident="202401080422440256"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Silvia Lai<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">21</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2020&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Italy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#47;26&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>7&#47;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">P<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>15&#47;11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>36&#46;7<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9&#46;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">P<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>42&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>7&#46;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tolvaptan 45&#47;15&#44; 60&#47;30&#44; 90&#47;30<span class="elsevierStyleHsp" style=""></span>mg once daily&#44; with gradual weekly increases of 60&#47;30<span class="elsevierStyleHsp" style=""></span>mg&#44; 90&#47;30<span class="elsevierStyleHsp" style=""></span>mg if tolerated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1yr&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><elsevierMultimedia ident="202401080422440257"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Shigeo Horie<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">20</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2021&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Japan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">92&#47;55&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>48&#47;44&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">P<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>33&#47;22&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">T<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>38&#46;9<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>11&#46;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">P<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>40&#46;5<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>5&#46;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tolvaptan 60&#47;30<span class="elsevierStyleHsp" style=""></span>mg&#44; 90&#47;60<span class="elsevierStyleHsp" style=""></span>mg once daily&#44; with a gradual increase of 90&#47;30<span class="elsevierStyleHsp" style=""></span>mg weekly if tolerated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Placebo&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3yr&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><elsevierMultimedia ident="202401080422440258"></elsevierMultimedia>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Author&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Allocation bias&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Performance bias&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Attrition bias&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Detection bias&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Reporting bias&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Higashihara et al&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">18</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Some concern&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Torres et al&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">9</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Satoru Muto et al&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">23</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Some concern&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Casteleijn et al&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">19</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Some concern&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Some concern&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Torres et al&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">24</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Perrone et al&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">22</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Some concern&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Silvia Lai et al&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">21</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Some concern&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Some concern&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Shigeo Horie et al&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">20</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Some concern&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                      "titulo" => "Polycystic kidney disease"
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                        0 => array:2 [
                          "etal" => false
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                            0 => "P&#46;D&#46; Wilson"
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