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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Idiopathic membranous nephropathy &#40;IMN&#41;&#44; a slowly progressive disease of the kidney&#44; is currently regarded as one of the most common causes of adult-onset nephrotic syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">1</span></a> The clinical course of IMN is multivariate and hard for clinical practice to predict&#46; Around one-third of IMN patients demonstrates spontaneous complete remission &#40;CR&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">2</span></a> while one-third of patients harboring long-term preservation of renal function are prone to persistent proteinuria&#46; However&#44; the remaining one-third of patients eventually develop and progress to end-stage kidney disease &#40;ESRD&#41; within five to fifteen years&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Debates exist regarding the treatment of IMN due to various potential types with the progression of IMN&#46; Steroids plus immunosuppressive therapy &#40;IST&#41; has been recommended according to Kidney Disease Improving Global outcomes &#40;KDIGO&#41; guidelines for patients who are at an increased risk for developing ESKD&#46; The combination of corticosteroids with ISTs&#44; including cyclophosphamide &#40;CTX&#41;&#44; chlorambucil&#44;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">4</span></a> cyclosporine &#40;CSA&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">5</span></a> tacrolimus &#40;TAC&#41;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">6</span></a> and rituximab&#44;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">7</span></a> has been thought to be the current available treatment protocols&#46; However&#44; the profound influence of different immunosuppressive agents remains equivocal according to previous randomized controlled trials for the ideal therapy options with higher response and lower adverse effects for IMN&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The activation of immune response has been generally proven to be associated with the inhibition of calcineurin inhibitors through the down-regulation of interleukin-2 transcription&#44; which is also a pivotal immunological process for T cell activation in IMN&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">8</span></a> TAC is one of the valid alternative therapy method toward treating IMN as a new type of calcineurin inhibitor &#40;CNI&#41; according to a placebo-controlled randomized trial in some reports&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">6</span></a> Despite the favorable effects on the IMN patients&#44; TAC has no association with remarkable increase of glucose intolerance as well as infections&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Current treatment protocols with the use of oral corticosteroids in combination with cyclophosphamide &#40;CYC&#41; have demonstrated beneficial efficacy in patients with nephrotic syndrome in several prospective trials&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">4&#44;9&#44;10</span></a> However&#44; the increased risk of adverse events should not be ignored due to its influence on the renal function&#44; which limits its clinical use&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Furthermore&#44; several studies were conducted to investigate the overall therapy effects as well as the safety of the combination of TAC-corticosteroid with cyclophosphamide &#40;CTX&#41;-steroid&#44;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">11&#8211;14</span></a> but showing conflicting results&#46; There has been much debate concerning the assessment of tacrolimus with cyclophosphamide&#44; both combined with corticosteroids for IMN treatment&#46; Here&#44; the present meta-analysis was conducted for the comparison of the overall efficacy and drug safety of tacrolimus and cyclophosphamide in IMN patients&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods and materials</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Search strategy</span><p id="par0030" class="elsevierStylePara elsevierViewall">Two investigators independently searched electronic databases&#58; PubMed&#44; Embase&#44; Cochrane library up to April 2018&#46; The process was established to find all articles with the keywords&#58; &#8220;Idiopathic membranous nephropathy&#8221; AND &#8220;cyclophosphamide&#8221;&#44; AND &#8220;tacrolimus&#8221;&#46; Medical Subject Heading &#40;MeSH&#41; terms that were associated with this meta-analysis were used&#46; The reference lists of all articles that dealt with the topic of interest were also hand-searched to check for additional relevant publications&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Eligibility criteria</span><p id="par0035" class="elsevierStylePara elsevierViewall">Studies that met the following criteria should be included in the meta-analysis&#58; &#40;1&#41; the studies were designed as randomized controlled trials&#59; &#40;2&#41; the studies were designed to compare TAC-corticosteroid with a CTX-steroid combination therapy&#59; &#40;3&#41; articles involving IMN patients&#59; &#40;4&#41; the end-point of interests were efficacy &#40;complete or partial remission&#41; and drug-related toxicity &#40;incidence of severe adverse effects &#40;SAEs&#41;&#41;&#44; and HRs with corresponding 95&#37; CIs were provided&#59; if duplicated or overlapped data were found in multiple studies&#44; the one with complete data were included&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Quality assessment</span><p id="par0040" class="elsevierStylePara elsevierViewall">The quality of the retrieved studies was assessed by two reviewers separately&#46; The risk of bias items &#40;ROBI&#41; that have been recommended by The Cochrane Handbook for Systematic Reviews of Interventions were utilized&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Data extraction</span><p id="par0045" class="elsevierStylePara elsevierViewall">Two authors independently extracted the relevant data from each trial&#46; Disagreement was settled by discussion&#46; The main categories based on the following parameters from the eligible studies&#58; family name of first author&#44; year of publication&#44; study period&#44; follow-up period&#44; main outcomes&#46; We extracted the corresponding hazard ratios &#40;HRs&#41; and risk ratios &#40;RRs&#41; to describe the outcomes of interest data&#44; respectively&#44; with its 95&#37; confidence intervals &#40;CIs&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Statistical analysis</span><p id="par0050" class="elsevierStylePara elsevierViewall">In the pooled analysis&#44; the endpoints of interest included remission rate and SAE data&#44; and lnHRs and the their lnLLs and lnULs were directly extracted as data points with reported HRs and corresponding 95&#37; CIs&#46; Based on heterogeneity of the current study&#44; we performed a sensitivity analysis to further assess the overall results&#46; The heterogeneity across studies was examined through the <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span> statistic&#44;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">15</span></a> describing as followed respectively&#58; low&#44; 25&#8211;50&#37;&#59; moderate&#44; 50&#8211;75&#37;&#59; or high&#44; &#62;75&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">16</span></a> We applied the fixed-effect models to calculate the total HRs when low heterogeneity showed in studies&#46; In other cases&#44; we used the random effects model&#46; All analysis was conducted through the use of Review Manager version 5&#46;3 software &#40;Revman&#59; The Cochrane collaboration Oxford&#44; United Kingdom&#41;&#46; Studies with a <span class="elsevierStyleItalic">p</span> value less than 0&#46;05 was thought to have statistical significance&#46; Forest plots showed the findings of our meta-analysis&#46; To assess the publication bias&#44; the Begg test and the Egger test were conducted&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Literature search process and study characteristics</span><p id="par0055" class="elsevierStylePara elsevierViewall">Totally&#44; 318 publications were identified originally for evaluation&#46; Based on the criteria described in the methods&#44; 11 publications were evaluated in more detail&#44; but some did not provide enough detail of outcomes of two approaches&#46; Therefore&#44; a final total of 6 RCTs<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">11&#8211;13&#44;17&#8211;19</span></a> met the criterion&#44; and the 2 papers of Ramachandran are the same study with different follow-up time at 12 and 24 months&#46; The search process is described in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">All included studies in this study were based on evidence with moderate to high quality&#46; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> describes the primary characteristics of the eligible studies in more detail&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Clinical and methodological heterogeneity</span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Pooled analysis of overall remission &#40;OR&#41; rates comparing tacrolimus and cyclophosphamide groups</span><p id="par0065" class="elsevierStylePara elsevierViewall">Pooled data of the OR from five studies showed that no significant differences were found in the IMN patients in terms of favoring tacrolimus compared with the cyclophosphamide group &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;15&#59; 95&#37; CI&#44; 0&#46;43&#8211;3&#46;07&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;78&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Pooled analysis of complete remission &#40;CR&#41; rates comparing tacrolimus and cyclophosphamide groups</span><p id="par0070" class="elsevierStylePara elsevierViewall">We applied the random effects model to pool the ischemic stroke recurrent data&#44; since the heterogeneity across the five studies was significant&#46; The pooling CR data did not show advantage in the tacrolimus or cyclophosphamide groups &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;34&#44; 95&#37; CI<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;38&#8211;4&#46;66&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;65&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Pooled analysis of partial remission &#40;PR&#41; rates comparing tacrolimus and cyclophosphamide groups</span><p id="par0075" class="elsevierStylePara elsevierViewall">For the partial remission rate&#44; no significant differences compared tacrolimus and cyclophosphamide groups were observed &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;84&#44; 95&#37; CI<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;38&#8211;1&#46;89&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;68&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Pooled analysis of AEs comparing tacrolimus and cyclophosphamide groups</span><p id="par0080" class="elsevierStylePara elsevierViewall">Systematic evaluations of AEs data analysis are shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46; The most common treatment-related adverse events are diarrhea &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;84&#44; 95&#37; CI<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;25&#8211;2&#46;85&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;79&#41;&#44; glucose intolerance &#40;or diabetes mellitus&#41; &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;91&#44; 95&#37; CI<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;55&#8211;6&#46;64&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;31&#41;&#44; gastrointestinal syndrome &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;73&#44; 95&#37; CI<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;31&#8211;1&#46;73&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;48&#41;&#44; and hypertension &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;35&#44; 95&#37; CI<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;75&#8211;7&#46;36&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;14&#41;&#44; and there was no statistical significant difference between the two groups&#46; The adverse events differed in sensitivity analysis in developing urinary tract infection &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;35&#59; 95&#37; CI&#44; 0&#46;15&#8211;0&#46;77&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;010&#41; and tremor &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#46;65&#59; 95&#37; CI&#44; 1&#46;95&#8211;58&#46;25&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;006&#41; with patients treated with tacrolimus&#46; Increased risk of leukopenia was identified among cyclophosphamide group with significance as compared with the tacrolimus group &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;14&#59; 95&#37; CI&#44; 0&#46;03&#8211;0&#46;83&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;03&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Discussion</span><p id="par0085" class="elsevierStylePara elsevierViewall">IMN&#44; a slowly progressive disease of the kidney&#44; is currently regarded as one of the most common causes of nephrotic syndrome &#40;NS&#41; in adult patients&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">20</span></a> Through the complement-mediated injury of the podocyte and its slit pore membrane&#44; the glomerular capillary permeability could be altered by in situ formation of subepithelial immune deposits&#44;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">21</span></a> and the occurrence as well as the progression of IMN is highly associated with abnormal activation of the immune system&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Immunosuppressive agents have been expected to be a valid alternative treatment for IMN patients&#44; including calcineurin inhibitors &#40;such as tacrolimus&#41; and alkylating agents &#40;cyclophosphamide or chlorambucil&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">22</span></a> The following factors&#44; such as the severity of renal dysfunction&#44; the level of persistent proteinuria&#44; as well as the development in renal function over time are crucial for clinical practice to choose ideal initial therapy toward treating IMN&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">23</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Researchers have evaluated the therapeutic role of immunosuppressive agents for patients with IMN in an effort to optimize the balance between efficacy and adverse event profiles&#46; Corticosteroids in combination with CTX or TAC were the two drugs that are widely accepted as initial therapies for patients with nephrotic IMN recommend by KDIGO&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">24</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">TAC has demonstrated more beneficial effects of immunosuppression with acceptable adverse effects for patients with IMN&#44;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">6</span></a> whereas according to other investigators&#44; the CTX-steroid combination appeared to be safer and more effective&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">25</span></a> There is no consistent or supportive data on the comparison of tacrolimus and cyclophosphamide&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The current concise meta-analysis details the remission&#44; tolerability and side effects of the two drugs&#44; which are important factors for IMN treatment&#46; Our results showed similar remission rates using TAC as the experimental group and CTX as the control group based regimens toward the treatment of IMN but with a different side-effect profile&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">There were several reasons that may contribute to the present results&#46; Firstly&#44; the short-term follow-up of the included trials would generate more doubtful outcomes&#46; As suggested by Xu&#8217; study&#44;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">11</span></a> the combination of tacrolimus and corticosteroids was a valid alternative option with tolerable side effects after 18 months&#8217; observation for patients with persistent nephrotic proteinuria&#46; In Ramachandran&#8217; study&#44;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">18</span></a> taking the final clinical response into account&#44; the TAC based regimen needs long-term follow-up&#44; since more than half of the patients relapse after stopping calcineurin inhibitors&#46; In addition&#44; no superior effects could be found in tacrolimus as compared with CTX after 6 months&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">13</span></a> With respect to the clinical response&#44; beneficial effect could be observed for long-term prognosis in CR&#44;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">26</span></a> and the risk of renal failure could be reduced through achieving PR independently&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">27</span></a> Therefore&#44; more detailed trails with longer follow-ups are warranted to further confirm the above results&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Secondly&#44; the side effects and drug toxicity might be affected by different dosing parameters of drugs&#44; such as longer duration but low dose of TAC to maintain remission from nephrotic syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">28</span></a> The nephrotoxicity of TAC has received much attention from investigators&#46; In Peng&#8217; study&#44;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">19</span></a> the dosage of TAC was 0&#46;05<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d&#44; and the trough concentration of TAC was 4&#8211;8<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#44; which was lower than that reported in kidney transplant recipients and patients with primary nephrotic syndrome&#46; While&#44; there are limited data about the treatment effects of low-dose TAC for nephrotic syndrome&#44; and the optimal dosage regimen of TAC remains unclear&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">12</span></a> Furthermore&#44; the treatment effects of the two drugs could be partially explained by its influence of immunosuppression for IMN&#46; Both autoantibodies have been proposed as biomarkers of MN autoimmune activity&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">29&#8211;31</span></a> High anti-PLA2R1 antibody levels have recently been reported as a reliable prognostic factor&#44;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">32&#8211;35</span></a> which is likely to modify clinical response for treatment of IMN in the future&#46; In addition&#44; risk&#8211;benefit assessment for individual patients should be carried out in the management of IMN in order to gain best therapy effects&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">36</span></a> Different immunosuppressive therapy plays pivotal role toward treating high risk individuals&#44; therefore ideal therapy options are always needed in order to increase the remission rate for patients&#46; Lots of expectations have been laid upon the new immune-suppressive therapies that might be associated with improved outcomes in reducing the probable toxicity while maintaining their efficacy&#46; The further exploration and research of the potential role of PLA2 receptor antibodies might gain insight into better targeted therapies&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">37</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Admittedly&#44; there were a few limitations in the current study that should not be ignored&#46; First&#44; the imbalance existed between the two groups due to different quality and the different definition of CR and PR of the included studies&#44; and findings of the current study might be affected by the clinical heterogeneity among trials&#46; Second&#44; the current study on long-term remission rate for the efficacy of the drugs provided insufficient data&#46; Thirdly&#44; rate of relapses is another important evidence to help to inform decision-making when choosing the standard treatment option for IMN patients&#46; The therapeutic attempts are justifiable if the lower rate of relapses can be achieved&#46; While&#44; the current study on the rate of relapses provided insufficient data&#46; Thus&#44; there was no strong statistical evidence to analyzed&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Conclusion</span><p id="par0125" class="elsevierStylePara elsevierViewall">In conclusion&#44; aggregated results indicated that tacrolimus and cyclophosphamide had comparable effects on remission rate as well as tolerable adverse events in the treatment of IMN patients&#46; However&#44; more detailed and high-quality RCTs with longer follow-ups are warranted in order to provide direct and strong evidence for the comparison of TAC and CTX&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Conflict of interests</span><p id="par0130" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interests&#46;</p></span></span>"
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          "titulo" => "Resumen"
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              "titulo" => "Antecedentes y objetivos"
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              "titulo" => "M&#233;todos"
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          "titulo" => "Introduction"
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              "titulo" => "Search strategy"
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              "titulo" => "Eligibility criteria"
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              "titulo" => "Quality assessment"
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              "titulo" => "Data extraction"
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              "titulo" => "Statistical analysis"
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            0 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Literature search process and study characteristics"
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            1 => array:3 [
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              "titulo" => "Clinical and methodological heterogeneity"
              "secciones" => array:4 [
                0 => array:2 [
                  "identificador" => "sec0055"
                  "titulo" => "Pooled analysis of overall remission &#40;OR&#41; rates comparing tacrolimus and cyclophosphamide groups"
                ]
                1 => array:2 [
                  "identificador" => "sec0060"
                  "titulo" => "Pooled analysis of complete remission &#40;CR&#41; rates comparing tacrolimus and cyclophosphamide groups"
                ]
                2 => array:2 [
                  "identificador" => "sec0065"
                  "titulo" => "Pooled analysis of partial remission &#40;PR&#41; rates comparing tacrolimus and cyclophosphamide groups"
                ]
                3 => array:2 [
                  "identificador" => "sec0070"
                  "titulo" => "Pooled analysis of AEs comparing tacrolimus and cyclophosphamide groups"
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          "titulo" => "Discussion"
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    "pdfFichero" => "main.pdf"
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    "fechaRecibido" => "2018-05-26"
    "fechaAceptado" => "2018-10-07"
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1128236"
          "palabras" => array:4 [
            0 => "Tacrolimus"
            1 => "Cyclophosphamide"
            2 => "Idiopathic membranous nephropathy"
            3 => "Meta-analysis"
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        ]
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          "titulo" => "Palabras clave"
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          "palabras" => array:4 [
            0 => "Tacrolimus"
            1 => "Ciclofosfamida"
            2 => "Nefropat&#237;a membranosa idiop&#225;tica"
            3 => "Metaan&#225;lisis"
          ]
        ]
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    "resumen" => array:2 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background and aims</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Idiopathic membranous nephropathy &#40;IMN&#41;&#44; which is considered one of the most common causes of nephrotic syndrome in adult patients&#44; is frequently managed with immunosuppressive agents&#46; Both tacrolimus &#40;TAC&#41; and cyclophosphamide &#40;CTX&#41; are recommended as immunosuppressive agents in the management of IMN&#46; However&#44; profound effects and moderate evidence on the two drugs remains poorly defined at this period&#46; The meta-analysis aims to summarize current best evidence on the efficacy as well as safety of TAC and CTX among IMN patients&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">We searched the publications on comparison of the safety and efficacy of TAC versus CTX for IMN up to April 2018&#46; After rigorous reviewing on the quality&#44; the data was extracted from eligible trials&#46; All trials analyzed the summary hazard ratios &#40;HRs&#41; of the endpoints of interest&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Moderate-strong evidence indicated that tacrolimus and cyclophosphamide had comparable effects on remission rate &#40;either CR or PR&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; No significant differences were found in the following parameters&#58; the rates of diarrhea&#44; glucose intolerance &#40;or diabetes mellitus&#41;&#44; gastrointestinal syndrome&#44; as well as hypertension because of adverse effects &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; However&#44; patients with TAC therapy had a higher chance to develop urinary tract infection &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;010&#41; and tremor &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;006&#41;&#46; Additionally&#44; remarkably higher risk existed in leukopenia among the CTX group as compared with the TAC group &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;03&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">This meta-analysis presents a comprehensive assessment of current available evidence for the therapy of IMN&#44; indicating a comparable remission rate with both TAC and CTX&#44; while the long-term effects are needed for further verification&#46; Nevertheless&#44; different adverse effect profiles of two groups need careful consideration&#46; Remarkably higher rates of urinary tract infection and tremor were observed among TAC group&#44; while higher risk of leukopenia was found among CTX group&#46; Further research into the treatment efficacy of both drugs is warranted to confirm the present conclusions&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Antecedentes y objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La nefropat&#237;a membranosa idiop&#225;tica &#40;NMI&#41;&#44; que se considera una de las causas m&#225;s comunes del s&#237;ndrome nefr&#243;tico en pacientes adultos&#44; se trata con frecuencia con inmunodepresores&#46; Tanto el tacrolimus &#40;TAC&#41; como la ciclofosfamida &#40;CTX&#41; se recomiendan como inmunosupresores en el tratamiento de la NMI&#46; Sin embargo&#44; los efectos profundos y la evidencia moderada de los 2 f&#225;rmacos contin&#250;an estando mal definidas en este per&#237;odo&#46; El metaan&#225;lisis pretende resumir la mejor evidencia actual sobre la eficacia y la seguridad del TAC y la CTX entre los pacientes con NMI&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se realizaron b&#250;squedas de publicaciones sobre comparaci&#243;n de seguridad y eficacia del TAC frente a la CTX para la NMI hasta abril de 2018&#46; Despu&#233;s de una revisi&#243;n rigurosa de la calidad&#44; los datos se extrajeron de los ensayos id&#243;neos&#46; Todos los ensayos analizaron los cocientes de riesgo instant&#225;neos resumidos de los criterios de valoraci&#243;n de inter&#233;s&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">La evidencia moderada-s&#243;lida indic&#243; que el TAC y la CTX tuvieron efectos comparables en la tasa de remisi&#243;n &#40;remisi&#243;n completa o remisi&#243;n parcial&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#41;&#46; No se encontraron diferencias importantes en los siguientes par&#225;metros&#58; tasas de diarrea&#44; intolerancia a la glucosa &#40;o diabetes mellitus&#41;&#44; s&#237;ndrome gastrointestinal&#44; as&#237; como hipertensi&#243;n por efectos adversos &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#41;&#46; Sin embargo&#44; los pacientes con TAC como tratamiento tuvieron mayor probabilidad de desarrollar infecci&#243;n urinaria &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;010&#41; y temblor &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;006&#41;&#46; Adem&#225;s&#44; exist&#237;a un riesgo notablemente mayor de leucopenia entre el grupo que tomaba CTX que en el grupo que tomaba TAC &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;03&#41;&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Este metaan&#225;lisis presenta una evaluaci&#243;n exhaustiva de la evidencia disponible actualmente sobre el tratamiento de la NMI&#44; que indica una tasa de remisi&#243;n comparable con TAC y CTX&#44; mientras que los efectos a largo plazo son necesarios para una comprobaci&#243;n adicional&#46; Sin embargo&#44; el perfil de diferentes efectos adversos de 2 grupos debe considerarse cuidadosamente&#46; Se observaron tasas notablemente m&#225;s altas de infecci&#243;n urinaria y temblor entre el grupo que tomaba TAC&#44; mientras que se encontr&#243; mayor riesgo de leucopenia entre el grupo que tomaba CTX&#46; Es necesaria investigaci&#243;n adicional sobre la eficacia del tratamiento de ambos f&#225;rmacos para confirmar las conclusiones actuales&#46;</p></span>"
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        "etiqueta" => "Fig&#46; 2"
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        "identificador" => "fig0015"
        "etiqueta" => "Fig&#46; 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
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          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">TAC&#58; tacrolimus&#59; CTX&#58; cyclophosphamide&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Study&#44; year&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">Study period&nbsp;\t\t\t\t\t\t\n
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                  \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">Follow-up period&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  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Total patients</th></tr><tr title="table-row"><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">TAC&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">CTX&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">Ramachandran&#44; 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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2011&#46;9&#46;21&#8211;2013&#46;12&#46;2&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">24 months&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">35&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">35&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">Ramachandran&#44; 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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2011&#46;9&#8211;2013&#46;12&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">12 months&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">35&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">35&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">Peng&#44; 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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2009&#46;1&#8211;2013&#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">9 months&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">30&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">30&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">He&#44; 2013&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">2008&#46;1&#8211;2010&#46;2&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">12 months&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">28&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">28&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">Xu&#44; 2013&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">2007&#46;6&#8211;2012&#46;10&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">18 months&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">48&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">52&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">Chen&#44; 2010&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">2004&#46;7&#8211;2008&#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">12 months&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">39&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">34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">TAC&#58; tacrolimus&#59; CTX&#58; cyclophosphamide&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Study&#44; year&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="4" align="center" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Diarrhea</th><th class="td" title="\n
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                  \t\t\t\t  " colspan="4" align="center" valign="\n
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                  \t\t\t\t  " colspan="4" align="center" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Gastrointestinal syndrome</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="4" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Hypertension</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="4" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Urinary tract infection</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="4" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Tremor</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="4" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Leukopenia</th></tr><tr title="table-row"><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">&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  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">TAC</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CTX</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">TAC</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CTX</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">TAC</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CTX</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">TAC</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CTX</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">TAC</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CTX</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">TAC</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CTX</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">TAC</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CTX</th></tr><tr title="table-row"><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">Events&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">Total&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">Events&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">Total&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">Events&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">Total&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">Events&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">Total&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">Events&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">Total&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">Events&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">Total&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">Events&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">Total&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">Events&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">Total&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">Events&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">Total&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">Events&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">Total&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">Events&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">Total&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">Events&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">Total&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">Events&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">Total&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">Events&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">Total&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">Ramachandran&#44; 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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">Ramachandran&#44; 2016&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Peng&#44; 2016&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2069430.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Systematic evaluations of AEs&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:37 [
            0 => array:3 [
              "identificador" => "bib0190"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Membranous nephropathy&#58; quo vadis&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "D&#46;C&#46; Cattran"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1046/j.1523-1755.2002.00125.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Kidney Int"
                        "fecha" => "2002"
                        "volumen" => "61"
                        "paginaInicial" => "349"
                        "paginaFinal" => "350"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11786118"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0195"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prognosis of patients with idiopathic membranous nephropathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Schieppati"
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Original article
A comparison of cyclophosphamide versus tacrolimus in terms of treatment effect for idiopathic membranous nephropathy: A meta-analysis
Comparación de ciclofosfamida con tacrolimus por lo que respecta al efecto del tratamiento en la nefropatía membranosa idiopática: un metaanálisis
Yan-Chun Li, Jing Huang, Xin Li, Su-Mei Zhao
Corresponding author
zhaosumei1998@126.com

Corresponding author.
Department of Nephrology, Beijing Chao-Yang Hospital, Beijing, China
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Idiopathic membranous nephropathy &#40;IMN&#41;&#44; a slowly progressive disease of the kidney&#44; is currently regarded as one of the most common causes of adult-onset nephrotic syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">1</span></a> The clinical course of IMN is multivariate and hard for clinical practice to predict&#46; Around one-third of IMN patients demonstrates spontaneous complete remission &#40;CR&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">2</span></a> while one-third of patients harboring long-term preservation of renal function are prone to persistent proteinuria&#46; However&#44; the remaining one-third of patients eventually develop and progress to end-stage kidney disease &#40;ESRD&#41; within five to fifteen years&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Debates exist regarding the treatment of IMN due to various potential types with the progression of IMN&#46; Steroids plus immunosuppressive therapy &#40;IST&#41; has been recommended according to Kidney Disease Improving Global outcomes &#40;KDIGO&#41; guidelines for patients who are at an increased risk for developing ESKD&#46; The combination of corticosteroids with ISTs&#44; including cyclophosphamide &#40;CTX&#41;&#44; chlorambucil&#44;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">4</span></a> cyclosporine &#40;CSA&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">5</span></a> tacrolimus &#40;TAC&#41;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">6</span></a> and rituximab&#44;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">7</span></a> has been thought to be the current available treatment protocols&#46; However&#44; the profound influence of different immunosuppressive agents remains equivocal according to previous randomized controlled trials for the ideal therapy options with higher response and lower adverse effects for IMN&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The activation of immune response has been generally proven to be associated with the inhibition of calcineurin inhibitors through the down-regulation of interleukin-2 transcription&#44; which is also a pivotal immunological process for T cell activation in IMN&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">8</span></a> TAC is one of the valid alternative therapy method toward treating IMN as a new type of calcineurin inhibitor &#40;CNI&#41; according to a placebo-controlled randomized trial in some reports&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">6</span></a> Despite the favorable effects on the IMN patients&#44; TAC has no association with remarkable increase of glucose intolerance as well as infections&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Current treatment protocols with the use of oral corticosteroids in combination with cyclophosphamide &#40;CYC&#41; have demonstrated beneficial efficacy in patients with nephrotic syndrome in several prospective trials&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">4&#44;9&#44;10</span></a> However&#44; the increased risk of adverse events should not be ignored due to its influence on the renal function&#44; which limits its clinical use&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Furthermore&#44; several studies were conducted to investigate the overall therapy effects as well as the safety of the combination of TAC-corticosteroid with cyclophosphamide &#40;CTX&#41;-steroid&#44;<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">11&#8211;14</span></a> but showing conflicting results&#46; There has been much debate concerning the assessment of tacrolimus with cyclophosphamide&#44; both combined with corticosteroids for IMN treatment&#46; Here&#44; the present meta-analysis was conducted for the comparison of the overall efficacy and drug safety of tacrolimus and cyclophosphamide in IMN patients&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods and materials</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Search strategy</span><p id="par0030" class="elsevierStylePara elsevierViewall">Two investigators independently searched electronic databases&#58; PubMed&#44; Embase&#44; Cochrane library up to April 2018&#46; The process was established to find all articles with the keywords&#58; &#8220;Idiopathic membranous nephropathy&#8221; AND &#8220;cyclophosphamide&#8221;&#44; AND &#8220;tacrolimus&#8221;&#46; Medical Subject Heading &#40;MeSH&#41; terms that were associated with this meta-analysis were used&#46; The reference lists of all articles that dealt with the topic of interest were also hand-searched to check for additional relevant publications&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Eligibility criteria</span><p id="par0035" class="elsevierStylePara elsevierViewall">Studies that met the following criteria should be included in the meta-analysis&#58; &#40;1&#41; the studies were designed as randomized controlled trials&#59; &#40;2&#41; the studies were designed to compare TAC-corticosteroid with a CTX-steroid combination therapy&#59; &#40;3&#41; articles involving IMN patients&#59; &#40;4&#41; the end-point of interests were efficacy &#40;complete or partial remission&#41; and drug-related toxicity &#40;incidence of severe adverse effects &#40;SAEs&#41;&#41;&#44; and HRs with corresponding 95&#37; CIs were provided&#59; if duplicated or overlapped data were found in multiple studies&#44; the one with complete data were included&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Quality assessment</span><p id="par0040" class="elsevierStylePara elsevierViewall">The quality of the retrieved studies was assessed by two reviewers separately&#46; The risk of bias items &#40;ROBI&#41; that have been recommended by The Cochrane Handbook for Systematic Reviews of Interventions were utilized&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Data extraction</span><p id="par0045" class="elsevierStylePara elsevierViewall">Two authors independently extracted the relevant data from each trial&#46; Disagreement was settled by discussion&#46; The main categories based on the following parameters from the eligible studies&#58; family name of first author&#44; year of publication&#44; study period&#44; follow-up period&#44; main outcomes&#46; We extracted the corresponding hazard ratios &#40;HRs&#41; and risk ratios &#40;RRs&#41; to describe the outcomes of interest data&#44; respectively&#44; with its 95&#37; confidence intervals &#40;CIs&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Statistical analysis</span><p id="par0050" class="elsevierStylePara elsevierViewall">In the pooled analysis&#44; the endpoints of interest included remission rate and SAE data&#44; and lnHRs and the their lnLLs and lnULs were directly extracted as data points with reported HRs and corresponding 95&#37; CIs&#46; Based on heterogeneity of the current study&#44; we performed a sensitivity analysis to further assess the overall results&#46; The heterogeneity across studies was examined through the <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span> statistic&#44;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">15</span></a> describing as followed respectively&#58; low&#44; 25&#8211;50&#37;&#59; moderate&#44; 50&#8211;75&#37;&#59; or high&#44; &#62;75&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">16</span></a> We applied the fixed-effect models to calculate the total HRs when low heterogeneity showed in studies&#46; In other cases&#44; we used the random effects model&#46; All analysis was conducted through the use of Review Manager version 5&#46;3 software &#40;Revman&#59; The Cochrane collaboration Oxford&#44; United Kingdom&#41;&#46; Studies with a <span class="elsevierStyleItalic">p</span> value less than 0&#46;05 was thought to have statistical significance&#46; Forest plots showed the findings of our meta-analysis&#46; To assess the publication bias&#44; the Begg test and the Egger test were conducted&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Results</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Literature search process and study characteristics</span><p id="par0055" class="elsevierStylePara elsevierViewall">Totally&#44; 318 publications were identified originally for evaluation&#46; Based on the criteria described in the methods&#44; 11 publications were evaluated in more detail&#44; but some did not provide enough detail of outcomes of two approaches&#46; Therefore&#44; a final total of 6 RCTs<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">11&#8211;13&#44;17&#8211;19</span></a> met the criterion&#44; and the 2 papers of Ramachandran are the same study with different follow-up time at 12 and 24 months&#46; The search process is described in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">All included studies in this study were based on evidence with moderate to high quality&#46; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> describes the primary characteristics of the eligible studies in more detail&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Clinical and methodological heterogeneity</span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Pooled analysis of overall remission &#40;OR&#41; rates comparing tacrolimus and cyclophosphamide groups</span><p id="par0065" class="elsevierStylePara elsevierViewall">Pooled data of the OR from five studies showed that no significant differences were found in the IMN patients in terms of favoring tacrolimus compared with the cyclophosphamide group &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;15&#59; 95&#37; CI&#44; 0&#46;43&#8211;3&#46;07&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;78&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Pooled analysis of complete remission &#40;CR&#41; rates comparing tacrolimus and cyclophosphamide groups</span><p id="par0070" class="elsevierStylePara elsevierViewall">We applied the random effects model to pool the ischemic stroke recurrent data&#44; since the heterogeneity across the five studies was significant&#46; The pooling CR data did not show advantage in the tacrolimus or cyclophosphamide groups &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;34&#44; 95&#37; CI<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;38&#8211;4&#46;66&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;65&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Pooled analysis of partial remission &#40;PR&#41; rates comparing tacrolimus and cyclophosphamide groups</span><p id="par0075" class="elsevierStylePara elsevierViewall">For the partial remission rate&#44; no significant differences compared tacrolimus and cyclophosphamide groups were observed &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;84&#44; 95&#37; CI<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;38&#8211;1&#46;89&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;68&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Pooled analysis of AEs comparing tacrolimus and cyclophosphamide groups</span><p id="par0080" class="elsevierStylePara elsevierViewall">Systematic evaluations of AEs data analysis are shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46; The most common treatment-related adverse events are diarrhea &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;84&#44; 95&#37; CI<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;25&#8211;2&#46;85&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;79&#41;&#44; glucose intolerance &#40;or diabetes mellitus&#41; &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;91&#44; 95&#37; CI<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;55&#8211;6&#46;64&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;31&#41;&#44; gastrointestinal syndrome &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;73&#44; 95&#37; CI<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;31&#8211;1&#46;73&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;48&#41;&#44; and hypertension &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;35&#44; 95&#37; CI<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;75&#8211;7&#46;36&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;14&#41;&#44; and there was no statistical significant difference between the two groups&#46; The adverse events differed in sensitivity analysis in developing urinary tract infection &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;35&#59; 95&#37; CI&#44; 0&#46;15&#8211;0&#46;77&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;010&#41; and tremor &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10&#46;65&#59; 95&#37; CI&#44; 1&#46;95&#8211;58&#46;25&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;006&#41; with patients treated with tacrolimus&#46; Increased risk of leukopenia was identified among cyclophosphamide group with significance as compared with the tacrolimus group &#40;OR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;14&#59; 95&#37; CI&#44; 0&#46;03&#8211;0&#46;83&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;03&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span></span></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Discussion</span><p id="par0085" class="elsevierStylePara elsevierViewall">IMN&#44; a slowly progressive disease of the kidney&#44; is currently regarded as one of the most common causes of nephrotic syndrome &#40;NS&#41; in adult patients&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">20</span></a> Through the complement-mediated injury of the podocyte and its slit pore membrane&#44; the glomerular capillary permeability could be altered by in situ formation of subepithelial immune deposits&#44;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">21</span></a> and the occurrence as well as the progression of IMN is highly associated with abnormal activation of the immune system&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">Immunosuppressive agents have been expected to be a valid alternative treatment for IMN patients&#44; including calcineurin inhibitors &#40;such as tacrolimus&#41; and alkylating agents &#40;cyclophosphamide or chlorambucil&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">22</span></a> The following factors&#44; such as the severity of renal dysfunction&#44; the level of persistent proteinuria&#44; as well as the development in renal function over time are crucial for clinical practice to choose ideal initial therapy toward treating IMN&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">23</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Researchers have evaluated the therapeutic role of immunosuppressive agents for patients with IMN in an effort to optimize the balance between efficacy and adverse event profiles&#46; Corticosteroids in combination with CTX or TAC were the two drugs that are widely accepted as initial therapies for patients with nephrotic IMN recommend by KDIGO&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">24</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">TAC has demonstrated more beneficial effects of immunosuppression with acceptable adverse effects for patients with IMN&#44;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">6</span></a> whereas according to other investigators&#44; the CTX-steroid combination appeared to be safer and more effective&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">25</span></a> There is no consistent or supportive data on the comparison of tacrolimus and cyclophosphamide&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">The current concise meta-analysis details the remission&#44; tolerability and side effects of the two drugs&#44; which are important factors for IMN treatment&#46; Our results showed similar remission rates using TAC as the experimental group and CTX as the control group based regimens toward the treatment of IMN but with a different side-effect profile&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">There were several reasons that may contribute to the present results&#46; Firstly&#44; the short-term follow-up of the included trials would generate more doubtful outcomes&#46; As suggested by Xu&#8217; study&#44;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">11</span></a> the combination of tacrolimus and corticosteroids was a valid alternative option with tolerable side effects after 18 months&#8217; observation for patients with persistent nephrotic proteinuria&#46; In Ramachandran&#8217; study&#44;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">18</span></a> taking the final clinical response into account&#44; the TAC based regimen needs long-term follow-up&#44; since more than half of the patients relapse after stopping calcineurin inhibitors&#46; In addition&#44; no superior effects could be found in tacrolimus as compared with CTX after 6 months&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">13</span></a> With respect to the clinical response&#44; beneficial effect could be observed for long-term prognosis in CR&#44;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">26</span></a> and the risk of renal failure could be reduced through achieving PR independently&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">27</span></a> Therefore&#44; more detailed trails with longer follow-ups are warranted to further confirm the above results&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Secondly&#44; the side effects and drug toxicity might be affected by different dosing parameters of drugs&#44; such as longer duration but low dose of TAC to maintain remission from nephrotic syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">28</span></a> The nephrotoxicity of TAC has received much attention from investigators&#46; In Peng&#8217; study&#44;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">19</span></a> the dosage of TAC was 0&#46;05<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;d&#44; and the trough concentration of TAC was 4&#8211;8<span class="elsevierStyleHsp" style=""></span>ng&#47;mL&#44; which was lower than that reported in kidney transplant recipients and patients with primary nephrotic syndrome&#46; While&#44; there are limited data about the treatment effects of low-dose TAC for nephrotic syndrome&#44; and the optimal dosage regimen of TAC remains unclear&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">12</span></a> Furthermore&#44; the treatment effects of the two drugs could be partially explained by its influence of immunosuppression for IMN&#46; Both autoantibodies have been proposed as biomarkers of MN autoimmune activity&#46;<a class="elsevierStyleCrossRefs" href="#bib0330"><span class="elsevierStyleSup">29&#8211;31</span></a> High anti-PLA2R1 antibody levels have recently been reported as a reliable prognostic factor&#44;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">32&#8211;35</span></a> which is likely to modify clinical response for treatment of IMN in the future&#46; In addition&#44; risk&#8211;benefit assessment for individual patients should be carried out in the management of IMN in order to gain best therapy effects&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">36</span></a> Different immunosuppressive therapy plays pivotal role toward treating high risk individuals&#44; therefore ideal therapy options are always needed in order to increase the remission rate for patients&#46; Lots of expectations have been laid upon the new immune-suppressive therapies that might be associated with improved outcomes in reducing the probable toxicity while maintaining their efficacy&#46; The further exploration and research of the potential role of PLA2 receptor antibodies might gain insight into better targeted therapies&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">37</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">Admittedly&#44; there were a few limitations in the current study that should not be ignored&#46; First&#44; the imbalance existed between the two groups due to different quality and the different definition of CR and PR of the included studies&#44; and findings of the current study might be affected by the clinical heterogeneity among trials&#46; Second&#44; the current study on long-term remission rate for the efficacy of the drugs provided insufficient data&#46; Thirdly&#44; rate of relapses is another important evidence to help to inform decision-making when choosing the standard treatment option for IMN patients&#46; The therapeutic attempts are justifiable if the lower rate of relapses can be achieved&#46; While&#44; the current study on the rate of relapses provided insufficient data&#46; Thus&#44; there was no strong statistical evidence to analyzed&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Conclusion</span><p id="par0125" class="elsevierStylePara elsevierViewall">In conclusion&#44; aggregated results indicated that tacrolimus and cyclophosphamide had comparable effects on remission rate as well as tolerable adverse events in the treatment of IMN patients&#46; However&#44; more detailed and high-quality RCTs with longer follow-ups are warranted in order to provide direct and strong evidence for the comparison of TAC and CTX&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Conflict of interests</span><p id="par0130" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interests&#46;</p></span></span>"
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          "titulo" => "Resumen"
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              "titulo" => "Antecedentes y objetivos"
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              "titulo" => "M&#233;todos"
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              "titulo" => "Resultados"
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          "titulo" => "Introduction"
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            0 => array:2 [
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              "titulo" => "Search strategy"
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              "titulo" => "Eligibility criteria"
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              "titulo" => "Quality assessment"
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              "titulo" => "Data extraction"
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          "titulo" => "Results"
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            0 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Literature search process and study characteristics"
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              "titulo" => "Clinical and methodological heterogeneity"
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                0 => array:2 [
                  "identificador" => "sec0055"
                  "titulo" => "Pooled analysis of overall remission &#40;OR&#41; rates comparing tacrolimus and cyclophosphamide groups"
                ]
                1 => array:2 [
                  "identificador" => "sec0060"
                  "titulo" => "Pooled analysis of complete remission &#40;CR&#41; rates comparing tacrolimus and cyclophosphamide groups"
                ]
                2 => array:2 [
                  "identificador" => "sec0065"
                  "titulo" => "Pooled analysis of partial remission &#40;PR&#41; rates comparing tacrolimus and cyclophosphamide groups"
                ]
                3 => array:2 [
                  "identificador" => "sec0070"
                  "titulo" => "Pooled analysis of AEs comparing tacrolimus and cyclophosphamide groups"
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          "titulo" => "Discussion"
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    "pdfFichero" => "main.pdf"
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    "fechaRecibido" => "2018-05-26"
    "fechaAceptado" => "2018-10-07"
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1128236"
          "palabras" => array:4 [
            0 => "Tacrolimus"
            1 => "Cyclophosphamide"
            2 => "Idiopathic membranous nephropathy"
            3 => "Meta-analysis"
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          "palabras" => array:4 [
            0 => "Tacrolimus"
            1 => "Ciclofosfamida"
            2 => "Nefropat&#237;a membranosa idiop&#225;tica"
            3 => "Metaan&#225;lisis"
          ]
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    "resumen" => array:2 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background and aims</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Idiopathic membranous nephropathy &#40;IMN&#41;&#44; which is considered one of the most common causes of nephrotic syndrome in adult patients&#44; is frequently managed with immunosuppressive agents&#46; Both tacrolimus &#40;TAC&#41; and cyclophosphamide &#40;CTX&#41; are recommended as immunosuppressive agents in the management of IMN&#46; However&#44; profound effects and moderate evidence on the two drugs remains poorly defined at this period&#46; The meta-analysis aims to summarize current best evidence on the efficacy as well as safety of TAC and CTX among IMN patients&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">We searched the publications on comparison of the safety and efficacy of TAC versus CTX for IMN up to April 2018&#46; After rigorous reviewing on the quality&#44; the data was extracted from eligible trials&#46; All trials analyzed the summary hazard ratios &#40;HRs&#41; of the endpoints of interest&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Moderate-strong evidence indicated that tacrolimus and cyclophosphamide had comparable effects on remission rate &#40;either CR or PR&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; No significant differences were found in the following parameters&#58; the rates of diarrhea&#44; glucose intolerance &#40;or diabetes mellitus&#41;&#44; gastrointestinal syndrome&#44; as well as hypertension because of adverse effects &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#41;&#46; However&#44; patients with TAC therapy had a higher chance to develop urinary tract infection &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;010&#41; and tremor &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;006&#41;&#46; Additionally&#44; remarkably higher risk existed in leukopenia among the CTX group as compared with the TAC group &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;03&#41;&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusion</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">This meta-analysis presents a comprehensive assessment of current available evidence for the therapy of IMN&#44; indicating a comparable remission rate with both TAC and CTX&#44; while the long-term effects are needed for further verification&#46; Nevertheless&#44; different adverse effect profiles of two groups need careful consideration&#46; Remarkably higher rates of urinary tract infection and tremor were observed among TAC group&#44; while higher risk of leukopenia was found among CTX group&#46; Further research into the treatment efficacy of both drugs is warranted to confirm the present conclusions&#46;</p></span>"
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        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Antecedentes y objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La nefropat&#237;a membranosa idiop&#225;tica &#40;NMI&#41;&#44; que se considera una de las causas m&#225;s comunes del s&#237;ndrome nefr&#243;tico en pacientes adultos&#44; se trata con frecuencia con inmunodepresores&#46; Tanto el tacrolimus &#40;TAC&#41; como la ciclofosfamida &#40;CTX&#41; se recomiendan como inmunosupresores en el tratamiento de la NMI&#46; Sin embargo&#44; los efectos profundos y la evidencia moderada de los 2 f&#225;rmacos contin&#250;an estando mal definidas en este per&#237;odo&#46; El metaan&#225;lisis pretende resumir la mejor evidencia actual sobre la eficacia y la seguridad del TAC y la CTX entre los pacientes con NMI&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Se realizaron b&#250;squedas de publicaciones sobre comparaci&#243;n de seguridad y eficacia del TAC frente a la CTX para la NMI hasta abril de 2018&#46; Despu&#233;s de una revisi&#243;n rigurosa de la calidad&#44; los datos se extrajeron de los ensayos id&#243;neos&#46; Todos los ensayos analizaron los cocientes de riesgo instant&#225;neos resumidos de los criterios de valoraci&#243;n de inter&#233;s&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">La evidencia moderada-s&#243;lida indic&#243; que el TAC y la CTX tuvieron efectos comparables en la tasa de remisi&#243;n &#40;remisi&#243;n completa o remisi&#243;n parcial&#41; &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#41;&#46; No se encontraron diferencias importantes en los siguientes par&#225;metros&#58; tasas de diarrea&#44; intolerancia a la glucosa &#40;o diabetes mellitus&#41;&#44; s&#237;ndrome gastrointestinal&#44; as&#237; como hipertensi&#243;n por efectos adversos &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#44;05&#41;&#46; Sin embargo&#44; los pacientes con TAC como tratamiento tuvieron mayor probabilidad de desarrollar infecci&#243;n urinaria &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;010&#41; y temblor &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;006&#41;&#46; Adem&#225;s&#44; exist&#237;a un riesgo notablemente mayor de leucopenia entre el grupo que tomaba CTX que en el grupo que tomaba TAC &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;03&#41;&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusi&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Este metaan&#225;lisis presenta una evaluaci&#243;n exhaustiva de la evidencia disponible actualmente sobre el tratamiento de la NMI&#44; que indica una tasa de remisi&#243;n comparable con TAC y CTX&#44; mientras que los efectos a largo plazo son necesarios para una comprobaci&#243;n adicional&#46; Sin embargo&#44; el perfil de diferentes efectos adversos de 2 grupos debe considerarse cuidadosamente&#46; Se observaron tasas notablemente m&#225;s altas de infecci&#243;n urinaria y temblor entre el grupo que tomaba TAC&#44; mientras que se encontr&#243; mayor riesgo de leucopenia entre el grupo que tomaba CTX&#46; Es necesaria investigaci&#243;n adicional sobre la eficacia del tratamiento de ambos f&#225;rmacos para confirmar las conclusiones actuales&#46;</p></span>"
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        "etiqueta" => "Fig&#46; 2"
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        "identificador" => "fig0015"
        "etiqueta" => "Fig&#46; 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
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          "leyenda" => "<p id="spar0070" class="elsevierStyleSimplePara elsevierViewall">TAC&#58; tacrolimus&#59; CTX&#58; cyclophosphamide&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Study&#44; year&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">Study period&nbsp;\t\t\t\t\t\t\n
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                  \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">Follow-up period&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  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Total patients</th></tr><tr title="table-row"><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">TAC&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">CTX&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">Ramachandran&#44; 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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2011&#46;9&#46;21&#8211;2013&#46;12&#46;2&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">24 months&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">35&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">35&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">Ramachandran&#44; 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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2011&#46;9&#8211;2013&#46;12&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">12 months&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">35&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">35&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">Peng&#44; 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="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2009&#46;1&#8211;2013&#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">9 months&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">30&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">30&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">He&#44; 2013&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">2008&#46;1&#8211;2010&#46;2&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">12 months&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">28&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">28&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">Xu&#44; 2013&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">2007&#46;6&#8211;2012&#46;10&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">18 months&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">48&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">52&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">Chen&#44; 2010&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">2004&#46;7&#8211;2008&#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">12 months&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">39&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">34&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">TAC&#58; tacrolimus&#59; CTX&#58; cyclophosphamide&#46;</p>"
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Study&#44; year&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="4" align="center" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Diarrhea</th><th class="td" title="\n
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                  \t\t\t\t  " colspan="4" align="center" valign="\n
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                  \t\t\t\t  " colspan="4" align="center" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Gastrointestinal syndrome</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="4" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Hypertension</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="4" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Urinary tract infection</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="4" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Tremor</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="4" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Leukopenia</th></tr><tr title="table-row"><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">&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  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">TAC</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CTX</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">TAC</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CTX</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">TAC</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CTX</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">TAC</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CTX</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">TAC</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CTX</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">TAC</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CTX</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">TAC</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">CTX</th></tr><tr title="table-row"><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">Events&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">Total&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">Events&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">Total&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">Events&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">Total&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">Events&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">Total&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">Events&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">Total&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">Events&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">Total&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">Events&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">Total&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">Events&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">Total&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">Events&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">Total&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">Events&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">Total&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">Events&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">Total&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">Events&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">Total&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">Events&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">Total&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">Events&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">Total&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">Ramachandran&#44; 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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&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="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">Ramachandran&#44; 2016&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Peng&#44; 2016&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab2069430.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Systematic evaluations of AEs&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:37 [
            0 => array:3 [
              "identificador" => "bib0190"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Membranous nephropathy&#58; quo vadis&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "D&#46;C&#46; Cattran"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1046/j.1523-1755.2002.00125.x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Kidney Int"
                        "fecha" => "2002"
                        "volumen" => "61"
                        "paginaInicial" => "349"
                        "paginaFinal" => "350"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11786118"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0195"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prognosis of patients with idiopathic membranous nephropathy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Schieppati"
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Article information
ISSN: 20132514
Original language: English
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Idiomas
Nefrología (English Edition)