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The efficacy of fluconazole for anti-fungal prophylaxis in peritoneal dialysis patients: A systematic review and meta-analysis
Eficacia de fluconazol para profilaxis antifúngica en los pacientes de diálisis peritoneal: revisión sistemática y metaanálisis
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Indirect effects on kidney and heart.<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">74,75</span></a> (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Heart failure, diabetes mellitus and chronic kidney disease favor inflammation, which increases hepcidin levels. This favors functional iron deficiency, decreasing iron availability in the bone marrow and at the myocardial level. Likewise, inflammation reduces erythropoiesis by inhibiting erythropoietin synthesis and its effects on erythropoiesis.</p> <p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">SGLT2i reduce inflammation, functional iron deficiency and increase erythropoietin levels, improving erythropoiesis. 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Blue arrows: positive effects.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Aleix Cases, Secundino Cigarrán, José Luis Górriz, Julio Nuñez" "autores" => array:4 [ 0 => array:2 [ "nombre" => "Aleix" "apellidos" => "Cases" ] 1 => array:2 [ "nombre" => "Secundino" "apellidos" => "Cigarrán" ] 2 => array:2 [ "nombre" => "José" "apellidos" => "Luis Górriz" ] 3 => array:2 [ "nombre" => "Julio" "apellidos" => "Nuñez" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0211699523001728" "doi" => "10.1016/j.nefro.2023.11.001" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0211699523001728?idApp=UINPBA000064" ] ] "EPUB" => 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"<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Fernanda" "apellidos" => "Pinheiro Martin Tapioca" "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 2 => array:3 [ "nombre" => "Felipe" "apellidos" => "Costa Neves" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "Sheila" "apellidos" => "Nunes Freitas Teixeira" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "Luiz Carlos" "apellidos" => "Santana Passos" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Division of Nephrology, Ana Nery Hospital, Salvador, Bahia, Brazil" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Bahiana School of Medicine, Salvador, Bahia, Brazil" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Medicine and Health Program, Federal University of Bahia, Salvador, Bahia, Brazil" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Division of Cardiology, Ana Nery Hospital, Salvador, Bahia, Brazil" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author</span>." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Eficacia de fluconazol para profilaxis antifúngica en los pacientes de diálisis peritoneal: revisión sistemática y metaanálisis" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 650 "Ancho" => 3175 "Tamanyo" => 176853 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">In a subgroup analysis of observational studies, the incidence of fungal peritonitis was a significantly lower in the fluconazole group.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Fungal peritonitis (FP) is a catastrophic complication that can occur in patients on peritoneal dialysis (PD). It is associated with a high rate of treatment failure and mortality, and current guidelines recommend immediate catheter removal upon identification of fungi.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a> Most cases of FP are preceded by antibiotic exposure,<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">2</span></a> which is frequently used in patients on PD for empirical treatment of PD-related episodes of peritonitis, posing a significant risk factor for FP.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Nowadays, PD-related peritonitis remains one of the most serious complications for PD. Indeed, it is the leading cause of PD technique failure and carries a significant risk of death in this patient population.<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">4</span></a> FP represents only about 1–12% of overall cases of peritonitis in patients on dialysis.<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">5–7</span></a> However, it is associated with devastating impacts in clinical practice, including catheter removal, migration to hemodialysis, and high mortality rates, ranging from 10 to 36% in the literature,<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">8,9</span></a> nearly ten-fold higher as compared with bacterial peritonitis.<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">10</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Antifungal prophylaxis for FP has been studied previously using various antimycotic agents, including fluconazole, ketoconazole, and nystatin.<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">11</span></a> However, there are conflicting findings in the literature about the efficacy of these therapies in the prevention of FP.<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">12–17</span></a> Fluconazole, a member of the triazole class of antifungal medications, inhibits the synthesis of ergosterol, a crucial component of fungal cell membranes.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">18</span></a> It has a broad-spectrum activity against various fungal species, including Candida albicans, the most common cause of FP in PD patients.<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">3</span></a> It is well tolerated, with a favorable safety profile, making it a suitable option for prophylaxis in patients on PD.</p><p id="par0020" class="elsevierStylePara elsevierViewall">The 2022 updates from the International Society for Peritoneal Dialysis (ISPD) and the Sociedad Española de Nefrología guideline recommend the use of antifungal prophylaxis to prevent peritonitis in patients on PD who have been exposed to antibiotics. This recommendation is supported by a 1B level of evidence (LOE).<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">1,19</span></a> This is based on data from a previous Cochrane meta-analysis that included various strategies for peritonitis prevention. However, the prior meta-analysis included a limited number of studies and pooled different antifungal agents under the same comparison.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">2</span></a> Therefore, we performed a meta-analysis evaluating the efficacy of fluconazole compared with no antifungal prophylaxis during episodes of peritonitis for the reduction of FP.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Materials and methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Eligibility criteria</span><p id="par0025" class="elsevierStylePara elsevierViewall">Only studies meeting the following eligibility criteria were included in this meta-analysis: (1) randomized controlled trials (RCTs) or nonrandomized studies; (2) comparing fluconazole (intervention group) with no antifungal prophylaxis (control group); (3) in patients on PD; (4) with an episode of peritonitis; and (5) reporting the incidence of FP. We excluded studies with (1) no control group; (2) with antibiotic therapy for non-peritonitis bacterial infections; or (3) with a report on the efficacy of other strategies for prophylaxis of FP, but without a report on fluconazole data.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Search strategy and data extraction</span><p id="par0030" class="elsevierStylePara elsevierViewall">We systematically searched PubMed, EMBASE, and Cochrane Central Register of Controlled Trials in January 20, 2023 with the following search terms: ‘peritoneal dialysis’, ‘fluconazole’ and ‘peritonitis’. A complete electronic search strategy is reported in the <a class="elsevierStyleCrossRef" href="#sec0070">Supplementary Appendix</a>. We manually searched the references from all included studies for any additional studies. Two authors (M.G. and F.T.) independently extracted the data following predefined search criteria and quality assessment. This study was registered with the International Prospective Register of Systematic Reviews (PROSPERO) under the number CRD42023394932.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Endpoints and subanalyses</span><p id="par0035" class="elsevierStylePara elsevierViewall">The main outcome of interest was the incidence of fungal peritonitis as defined by the ISPD criteria for FP. Prespecified subanalyses included data restricted to (1) non-RCTs; and (2) studies with daily doses of fluconazole. In addition, a leave-one-out sensitivity analysis was performed to examine the robustness of the results. This was accomplished by systematically removing each study from the analysis and recalculating the results.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Quality assessment</span><p id="par0040" class="elsevierStylePara elsevierViewall">Non-randomized studies were appraised with the Newcastle–Ottawa Scale (NOS).<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">20</span></a> The NOS scores studies on a 0–9 scale based on the quality of patient selection, comparability of groups, and adjudication of outcomes. Quality assessment of the RCT included was performed using the Cochrane Collaboration's tool RoB-2 for assessing risk of bias in randomized trials for quality assessment of individual randomized studies.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">21</span></a> Publication bias was assessed using funnel-plot analysis of point estimates according to study weights.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Statistical analysis</span><p id="par0045" class="elsevierStylePara elsevierViewall">This systematic review and meta-analysis were conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement guidelines.<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">22</span></a> Odds-ratios (OR) with 95% confidence intervals were used to compare treatment effects for categorical endpoints. Cochran <span class="elsevierStyleItalic">Q</span> test and <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span> statistics were used to assess for heterogeneity; <span class="elsevierStyleItalic">p</span> values below 0.10 and <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span> over 25% were considered significant for heterogeneity. We used a fixed-effect model for outcomes with low heterogeneity (<span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>25%). Otherwise, a DerSimonian and Laird random-effects model was used. We also performed a sensitivity analysis with the generic inverse variance method using adjusted risk estimates from observational studies, when available. Review Manager 5.4 (Cochrane Centre, The Cochrane Collaboration, Denmark) was used for statistical analysis.</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Results</span><p id="par0050" class="elsevierStylePara elsevierViewall">The initial search yielded 593 results, as shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>. After removing duplicate records and ineligible studies, we thoroughly reviewed 24 studies. Six studies were ultimately included, comprising 4515 episodes of peritonitis from one RCT<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">23</span></a> and five cohort studies.<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">24–28</span></a> Among these episodes, 1124 (24.8%) were administered fluconazole prophylaxis, while 3390 (75.1%) did not receive any antifungal prophylaxis. Study characteristics are detailed in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>. One study also had an arm with nystatin prophylaxis; however, episodes of peritonitis treated with nystatin were not included in this meta-analysis, as per inclusion/exclusion criteria.<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">26</span></a> There was some variability in the duration of prophylaxis, doses, and duration of follow-up, as reported in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">Patients receiving fluconazole had a significantly lower incidence of FP (1.0%) as compared with those who did not receive prophylaxis (3.0%) during an episode of peritonitis with antibiotic exposure (OR 0.22; 95% CI 0.12–0.41; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0%; <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). In a subgroup analysis of studies using daily dose of fluconazole, there was also a significant reduction in the incidence of FP in those who received fluconazole (OR 0.31; 95% CI 0.14–0.69; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.004; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0%; <a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). In a subanalysis restricted to observational studies, the incidence of FP was also significantly lower in fluconazole-treated individuals (OR 0.23; 95% CI 0.12–0.46; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.01; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0%; <a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>). Leave-one-out sensitivity analyses confirmed the consistency of results after removing each study sequentially and recalculating results. The OR remained statistically significant, ranging from 0.15 to 0.25, when each study was systematically withdrawn from the analysis.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">The RCT was appraised using the Cochrane Collaboration's tool RoB-2, and it was considered to have a low risk of bias in all the domains accessed (<a class="elsevierStyleCrossRef" href="#sec0070">Table S1</a>). In this study, patients and investigators were unblinded. All five nonrandomized publications achieved ≥7 points in the NOS. A funnel plot analysis of the primary outcome showed a symmetric distribution of studies with similar weights and point estimates that converged toward the pooled treatment effect as weight increased, indicating no evidence of publication bias (<a class="elsevierStyleCrossRef" href="#fig0025">Fig. 5</a>).</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Discussion</span><p id="par0065" class="elsevierStylePara elsevierViewall">This systematic review and meta-analysis including 6 studies and 4515 episodes of peritonitis compared the efficacy of fluconazole prophylaxis with no prophylaxis in patients on PD upon antibiotic exposure for treatment of peritonitis. The main findings from the pooled analyses showed that fluconazole significantly reduced the risk of FP to one-third of that in the no prophylaxis group (1% vs. 3%, respectively). Moreover, this finding was robust and remained significant in leave-one-out sensitivity analyses and exploration of subgroups, including data restricted to daily fluconazole dosing and observational studies.</p><p id="par0070" class="elsevierStylePara elsevierViewall">Most FP events are preceded by antibiotic exposure, either for PD-related infections, such as peritonitis, exit-site infection, or tunnel infection, or for other common clinical bacterial infections.<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">29</span></a> A previous metanalysis of RCTs showed a significantly lower risk of fungal peritonitis when compared with placebo/no prophylaxis (RR 0.28; 95% CI 0.12–0.63).<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">2</span></a> However, that prior meta-analysis included only two RCTs, with different antifungal regimens, specifically nystatin<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">13</span></a> or fluconazole.<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">23</span></a> Our meta-analysis builds on prior results by showing evidence of benefit from fluconazole specifically in this patient population.</p><p id="par0075" class="elsevierStylePara elsevierViewall">Interestingly, observational studies were not included in the prior meta-analysis.<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">24–28</span></a> This is notable because these studies had mixed and conflicting results for this intervention, creating uncertainty in the literature as to the benefit of fluconazole prophylaxis in the prevention of FP in patients with peritonitis. However, our results found a significant reduction in FP with fluconazole therapy even among the subgroup restricted to observational studies. The low heterogeneity (<span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0%) of this analysis indicates that the observational studies were consistent with each other, but likely underpowered to show a statistically significant benefit, which becomes evident in the pooled analysis of these studies (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>).</p><p id="par0080" class="elsevierStylePara elsevierViewall">The ISPD 2022 expert consensus statement on peritonitis recommends anti-fungal prophylaxis whenever PD patients receive an antibiotic course, regardless of the indication for that antibiotic course (level 1B of evidence).<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">1</span></a> This recommendation has no preference for either nystatin or fluconazole, with the latter being recommended at a dose of 200<span class="elsevierStyleHsp" style=""></span>mg every 48<span class="elsevierStyleHsp" style=""></span>h. The 2022 guideline from the Sociedad Española de Nefrología supports the use of fluconazole for prophylactic purposes in this scenario, but it does not provide information on the dosage for its use.<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">19</span></a> The PDOPPS cohort conducted a prior study which revealed a noteworthy variance in antifungal prophylaxis utilization across various countries. Routine use of antifungal prophylaxis was observed in Australia and New Zealand, while Japan, Thailand, and the United Kingdom exhibited minimal usage.<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">30</span></a> Although the doses and posology of fluconazole varied among the studies included in this meta-analysis, a subgroup of studies that used daily fluconazole also found a significant reduction in the incidence of FP in those who received prophylaxis with fluconazole.<a class="elsevierStyleCrossRefs" href="#bib0270"><span class="elsevierStyleSup">24,25,27</span></a> After conducting our study, we strongly suggest following the current guidelines and administering antifungal prophylaxis with fluconazole when a patient on peritoneal dialysis is being treated with antibiotics, with the dose of 200<span class="elsevierStyleHsp" style=""></span>mg on alternate days being a well-established scheme for this purpose.</p><p id="par0085" class="elsevierStylePara elsevierViewall">Our study has some limitations. First, most of the included studies were not randomized, which adds risk of bias related to confounding factors. However, the results of observational studies and the RCT were consistent with each other, with a low heterogeneity between studies (<span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0%). Also, sensitivity analyses confirmed consistency of study results after removing each individual study. Second, there was a variation in the dose of fluconazole prescribed by different studies. Third, the absence of patient-level data precluded evaluating additional outcomes, such as need to transition to hemodialysis, hospitalizations, and mortality. Whether fluconazole prophylaxis reduces these endpoints in PD-related peritonitis remains a gap in the literature. Finally, four studies used historical controls for the control group (no prophylaxis). Whether other concomitant interventions were distributed unevenly between patients treated with vs. without fluconazole prophylaxis is unclear.</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conclusion</span><p id="par0090" class="elsevierStylePara elsevierViewall">In this meta-analysis including 4515 episodes of peritonitis in patients on PD, prophylaxis with fluconazole was associated with a significant reduction in the incidence of FP as compared with no antifungal prophylaxis. Given the potential implications of FP, the low cost of fluconazole, and its safety profile, this agent should be considered as standard-of-care in patients with PD-related peritonitis. Future research should evaluate the role of fluconazole prophylaxis in patients on PD who are treated with antibiotic therapy for other, non-peritonitis, bacterial infections.</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Funding sources</span><p id="par0095" class="elsevierStylePara elsevierViewall">The authors report no funding sources for this manuscript.</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conflict of interest</span><p id="par0100" class="elsevierStylePara elsevierViewall">All authors report no relationships that could be construed as a conflict of interest. All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres2284148" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Materials and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1900322" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xpalclavsec1900321" "titulo" => "Abbreviations" ] 3 => array:3 [ "identificador" => "xres2284149" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción y objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Materiales y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 4 => array:2 [ "identificador" => "xpalclavsec1900320" "titulo" => "Palabras clave" ] 5 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 6 => array:3 [ "identificador" => "sec0010" "titulo" => "Materials and methods" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Eligibility criteria" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Search strategy and data extraction" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Endpoints and subanalyses" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Quality assessment" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Statistical analysis" ] ] ] 7 => array:2 [ "identificador" => "sec0040" "titulo" => "Results" ] 8 => array:2 [ "identificador" => "sec0045" "titulo" => "Discussion" ] 9 => array:2 [ "identificador" => "sec0050" "titulo" => "Conclusion" ] 10 => array:2 [ "identificador" => "sec0055" "titulo" => "Funding sources" ] 11 => array:2 [ "identificador" => "sec0060" "titulo" => "Conflict of interest" ] 12 => array:2 [ "identificador" => "xack784745" "titulo" => "Acknowledgments" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-04-26" "fechaAceptado" => "2023-07-24" "PalabrasClave" => array:2 [ "en" => array:2 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1900322" "palabras" => array:4 [ 0 => "Peritoneal dialysis" 1 => "Fungal peritonitis" 2 => "Fluconazole" 3 => "Antifungal prophylaxis" ] ] 1 => array:4 [ "clase" => "abr" "titulo" => "Abbreviations" "identificador" => "xpalclavsec1900321" "palabras" => array:9 [ 0 => "CKD" 1 => "FP" 2 => "ISPD" 3 => "LOE" 4 => "NOS" 5 => "OR" 6 => "PD" 7 => "PRISMA" 8 => "RCT" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1900320" "palabras" => array:4 [ 0 => "Diálisis peritoneal" 1 => "Peritonitis fúngica" 2 => "Fluconazol" 3 => "Profilaxis antifúngica" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction and objectives</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The efficacy of fluconazole as a prophylactic strategy in patients with chronic kidney disease (CKD) on peritoneal dialysis (PD) with prior antibiotic exposure is controversial in the current literature. This study aimed to compare a strategy of fluconazole prophylaxis versus no-prophylaxis for patients in PD on antibiotics for previous episodes of peritonitis.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Materials and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">We performed a systematic review and meta-analysis of observational studies and randomized controlled trials (RCTs) comparing fluconazole prophylaxis with no prophylaxis for PD-related peritonitis. The search was conducted on PubMed, EMBASE, and Cochrane Central in January 23, 2023. The outcome of interest was the occurrence of fungal peritonitis (FP).</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">We included six studies (1 RCT, 5 observational) with 4515 occurrences of peritonitis, of which 1098 (24.8%) received fluconazole prophylaxis in variable doses, whereas 3417 (75.6%) did not receive prophylaxis during peritonitis episodes. Overall, fluconazole prophylaxis was associated with a lower incidence of FP (OR 0.22; 95% CI 0.12–0.41; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0%). Subgroup analysis of studies that administered daily doses of fluconazole also demonstrated a reduced incidence of FP in patients who received antifungal prophylaxis (OR 0.31; CI 0.14–0.69; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.004; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0%).</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">In this meta-analysis of 4515 episodes of PD-related peritonitis, prophylaxis with fluconazole significantly reduced episodes of FP as compared with no antifungal prophylaxis.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and objectives" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Materials and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Introducción y objetivos</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">La eficacia de fluconazol como estrategia profiláctica en los pacientes con enfermedad renal crónica (ERC) sometidos a diálisis peritoneal (DP) con exposición antibiótica previa es controvertida en la literatura actual. El objetivo de este estudio fue comparar la estrategia de profilaxis con fluconazol frente a no profilaxis para los pacientes de DP con régimen antibiótico por episodios previos de peritonitis.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Materiales y métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Realizamos una revisión sistemática y metaanálisis de estudios observacionales y ensayos controlados aleatorizados (ECA), comparando la profilaxis con fluconazol y la no profilaxis para la peritonitis relacionada con DP. Dicha búsqueda se realizó en PubMed, EMBASE y Cochrane Central el 23 de enero de 2023. El resultado de interés fue la aparición de peritonitis fúngica (PF).</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Incluimos seis estudios (1 ECA, 5 observacionales) con 4.515 episodios de peritonitis, de los cuales 1.098 (24,8%) recibieron profilaxis de fluconazol en dosis variables, mientras que 3.417 (75,6%) no recibieron profilaxis durante los episodios de peritonitis. En general, la profilaxis de fluconazol estuvo asociada a una menor incidencia de PF (OR: 0,22; IC 95%: 0,12-0,41; p<span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0,001; I<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0%). El análisis de subgrupo de los estudios que administraron dosis diarias de fluconazol también demostró una incidencia reducida de PF en los pacientes que recibieron profilaxis antifúngica (OR: 0,31; IC 95%: 0,14-0,69; p<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0,004, I<span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0%).</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">En este metaanálisis de 4.515 episodios de peritonitis relacionada con DP, la profilaxis con fluconazol redujo significativamente los episodios de PF, en comparación con la no profilaxis antifúngica.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción y objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Materiales y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "<p id="par0115" class="elsevierStylePara elsevierViewall">The following are the supplementary data to this article:<elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>" "etiqueta" => "Appendix A" "titulo" => "Supplementary data" "identificador" => "sec0070" ] ] ] ] "multimedia" => array:7 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1990 "Ancho" => 1667 "Tamanyo" => 179055 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">PRISMA flow diagram of study screening and selection.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 707 "Ancho" => 3175 "Tamanyo" => 195140 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">The incidence of fungal peritonitis was a significantly lower in patients who received fluconazole prophylaxis.</p>" ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 549 "Ancho" => 3175 "Tamanyo" => 153070 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">In a subgroup analysis of studies with daily dosing of fluconazole, the incidence of fungal peritonitis was significantly lower in the fluconazole group.</p>" ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 650 "Ancho" => 3175 "Tamanyo" => 176853 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">In a subgroup analysis of observational studies, the incidence of fungal peritonitis was a significantly lower in the fluconazole group.</p>" ] ] 4 => array:7 [ "identificador" => "fig0025" "etiqueta" => "Fig. 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 1435 "Ancho" => 2175 "Tamanyo" => 94859 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Funnel plot analysis for the outcome of fungal peritonitis showed no evidence of publication bias.</p>" ] ] 5 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study \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">Design \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">Fluconazole dose \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">Number of patients \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">Male, <span class="elsevierStyleItalic">n</span>FG/NP \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">Age<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>, yFG/NP \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">Peritonitis episodes, FG/NP \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">Patient-months evaluated, FG/NP \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">Davenport 2011 \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">Non-RCT \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">50<span class="elsevierStyleHsp" style=""></span>mg, daily \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">4095 \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">NA \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">NA \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">546/2776 \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">NA \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">Kumar 2014 \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">Non-RCT<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \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">200<span class="elsevierStyleHsp" style=""></span>mg, daily \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">224 \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">72/65 \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">50/53 \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">40/102 \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">NA \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">Moreiras-Plaza 2007 \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">Non-RCT<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \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">100<span class="elsevierStyleHsp" style=""></span>mg<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> \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">166 \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">50/44 \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">50/46 \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">131/121 \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">2269/1450 \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">Morey 2001 \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">Non-RCT<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \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">50<span class="elsevierStyleHsp" style=""></span>mg, daily \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">123 \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">53/25 \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">54.5/53.5 \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">103/76 \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">1690/595 \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">Restrepo 2010 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RCT \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">200<span class="elsevierStyleHsp" style=""></span>mg, EOD \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">226 \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">NA \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">NA \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">210/210 \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">NA \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">Wadhwa 1996 \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">Non-RCT<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \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">100<span class="elsevierStyleHsp" style=""></span>mg, EOD<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a> \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">234 \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">71/77 \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">53.8/48.8 \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">95/105 \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">1832/1705 \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3704366.png" ] ] ] "notaPie" => array:4 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Groups defined by different time periods.</p>" ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" 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We would also reckon the aid of Dr. Rhanderson Cardoso for this manuscript, been a constant inspiration and educator on medical research.</p>" "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/20132514/0000004400000002/v2_202410292119/S2013251424000853/v2_202410292119/en/main.assets" "Apartado" => array:4 [ "identificador" => "42660" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Original articles" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/20132514/0000004400000002/v2_202410292119/S2013251424000853/v2_202410292119/en/main.pdf?idApp=UINPBA000064&text.app=https://revistanefrologia.com/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2013251424000853?idApp=UINPBA000064" ]
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