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array:24 [ "pii" => "S2013251424001433" "issn" => "20132514" "doi" => "10.1016/j.nefroe.2024.01.021" "estado" => "S300" "fechaPublicacion" => "2024-07-01" "aid" => "1233" "copyright" => "Sociedad Española de Nefrología" "copyrightAnyo" => "2024" "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Nefrologia (English Version). 2024;44:486-95" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "Traduccion" => array:1 [ "en" => array:19 [ "pii" => "S021169952400002X" "issn" => "02116995" "doi" => "10.1016/j.nefro.2024.01.002" "estado" => "S300" "fechaPublicacion" => "2024-07-01" "aid" => "1233" "copyright" => "Sociedad Española de Nefrología" "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Nefrologia. 2024;44:486-95" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review</span>" "titulo" => "Hepatitis C virus infection is associated with proteinuria according to a systematic review with meta-analysis" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "486" "paginaFinal" => "495" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "La infección por el virus de la hepatitis C se asocia con proteinuria según una revisión sistemática de la literatura con metaanálisis" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Study 1 Szczech L, et al. 2002; study 2 Liangpunsakul S and Chalasani N, 2015; study 3 Tsui J, et al. 2006; study 4 Huang J, et al. 2006; study 5 Ishizaka N, et al. 2008; study 6 Yanik E, et al. 2010; study 7 Derbala M, et al. 2010; study 8 Lee J, et al. 2010; study 9 Yanagisawa N, et al. 2011; study 10 Aoufi Rabih S, et al. 2012; study 11 Reynes J, et al. 2013; study 12 Zeng Q, et al. 2014; study 13 Kurbanova N, et al. 2015; study 14 Antonello V, et al. 2015; study 15 Lucas G, et al. 2016; study 16 Zeder A, et al. 2016." "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1442 "Ancho" => 2508 "Tamanyo" => 90546 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">aOR and 95% confidence intervals for each study (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>16 cross-sectional studies; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>163,979 unique patients) (outcome: prevalence of proteinuria). aOR of proteinuria associated with exposure to HCV: 1.47 (95% CI, 1.3; 1.66) (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001) R<span class="elsevierStyleItalic"><span class="elsevierStyleInf">i</span></span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.61. <span class="elsevierStyleItalic">Q</span> value by <span class="elsevierStyleItalic">χ</span><span class="elsevierStyleSup">2</span> test 27.3 (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.026) (asymptotic tests).</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Fabrizio Fabrizi, Maria F. Donato, Luca Nardelli, Federica Tripodi, Francesca Zanoni, Giuseppe Castellano" "autores" => array:6 [ 0 => array:2 [ "nombre" => "Fabrizio" "apellidos" => "Fabrizi" ] 1 => array:2 [ "nombre" => "Maria F." "apellidos" => "Donato" ] 2 => array:2 [ "nombre" => "Luca" "apellidos" => "Nardelli" ] 3 => array:2 [ "nombre" => "Federica" "apellidos" => "Tripodi" ] 4 => array:2 [ "nombre" => "Francesca" "apellidos" => "Zanoni" ] 5 => array:2 [ "nombre" => "Giuseppe" "apellidos" => "Castellano" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "S2013251424001433" "doi" => "10.1016/j.nefroe.2024.01.021" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2013251424001433?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S021169952400002X?idApp=UINPBA000064" "url" => "/02116995/0000004400000004/v1_202407151348/S021169952400002X/v1_202407151348/en/main.assets" ] ] "itemSiguiente" => array:19 [ "pii" => "S2013251424001597" "issn" => "20132514" "doi" => "10.1016/j.nefroe.2024.07.007" "estado" => "S300" "fechaPublicacion" => "2024-07-01" "aid" => "1231" "copyright" => "Sociedad Española de Nefrología" "documento" => "article" "crossmark" => 1 "subdocumento" => "ssu" "cita" => "Nefrologia (English Version). 2024;44:496-502" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Brief review</span>" "titulo" => "Hyperaldosteronism and hyperparathyroidism. A disturbing friendship" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "496" "paginaFinal" => "502" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Hiperaldosteronismo e hiperparatiroidismo. Una amistad inquietante" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1378 "Ancho" => 2923 "Tamanyo" => 274730 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">PTH/HA relationship.</p> <p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">ANG II: angiotensin II; PL: phospholipase C; PQ: protein kinase C; PTH: parathyroid hormone; R/ANG/ALD: renin/angiotensin II/aldosterone system.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Juan A. Martín Navarro, Laura Medina Zahonero, Fabio L. Procaccini, Raquel Barba Teba, Veronica Rubio Menendez, Esther Valle Alvarez, Miryam Elena PoloCánovas, Mayra Ortega-Díaz, Marta Puerta Carretero, Rafael Lucena Valverde, Patricia Muñoz Ramos, Roberto Alcázar Arroyo, Patricia de Sequera Ortiz" "autores" => array:13 [ 0 => array:2 [ "nombre" => "Juan A." "apellidos" => "Martín Navarro" ] 1 => array:2 [ "nombre" => "Laura" "apellidos" => "Medina Zahonero" ] 2 => array:2 [ "nombre" => "Fabio L." "apellidos" => "Procaccini" ] 3 => array:2 [ "nombre" => "Raquel" "apellidos" => "Barba Teba" ] 4 => array:2 [ "nombre" => "Veronica" "apellidos" => "Rubio Menendez" ] 5 => array:2 [ "nombre" => "Esther" "apellidos" => "Valle Alvarez" ] 6 => array:2 [ "nombre" => "Miryam Elena" "apellidos" => "PoloCánovas" ] 7 => array:2 [ "nombre" => "Mayra" "apellidos" => "Ortega-Díaz" ] 8 => array:2 [ "nombre" => "Marta" "apellidos" => "Puerta Carretero" ] 9 => array:2 [ "nombre" => "Rafael" "apellidos" => "Lucena Valverde" ] 10 => array:2 [ "nombre" => "Patricia" "apellidos" => "Muñoz Ramos" ] 11 => array:2 [ "nombre" => "Roberto" "apellidos" => "Alcázar Arroyo" ] 12 => array:2 [ "nombre" => "Patricia" "apellidos" => "de Sequera Ortiz" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0211699523001935" "doi" => "10.1016/j.nefro.2023.12.005" "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/S0211699523001935?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2013251424001597?idApp=UINPBA000064" "url" => "/20132514/0000004400000004/v1_202408300447/S2013251424001597/v1_202408300447/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S201325142400155X" "issn" => "20132514" "doi" => "10.1016/j.nefroe.2024.07.005" "estado" => "S300" "fechaPublicacion" => "2024-07-01" "aid" => "1173" "copyright" => "Sociedad Española de Nefrología" "documento" => "article" "crossmark" => 1 "subdocumento" => "rev" "cita" => "Nefrologia (English Version). 2024;44:475-85" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review</span>" "titulo" => "Nomenclature in Palliative and Kidney Supportive Care: Not Just at the End-of-Life" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "475" "paginaFinal" => "485" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Nomenclatura en cuidados paliativos y de soporte renal: no solo al final de la vida" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1535 "Ancho" => 2500 "Tamanyo" => 273175 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Fig. " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Structure of palliative care in patients with advanced chronic kidney disease.</p> <p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">CKD G5: grade 5 chronic kidney disease (refers to cases with a glomerular filtration rate that drops below 15 ml/min/1.73 m<span class="elsevierStyleSup">2</span>); KRT: kidney replacement therapy: comprehensive conservative care, synonymous with conservative kidney management (CKM).</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Lina Nitola-Mendoza, Miguel Sánchez-Cárdenas, Néstor Rodriguez-Chitiva, José María Mora Gutiérrez, Rosely Rodriguez-Pena, Gregorio Romero-González, Monserrat Bleda Pérez, Paula Cuenca Casbas, Agnès Calsina-Berna, Margarita Álvaro-Pardo, Virginia Granados Casas, Paula Garrido Ballart, Patricia Beroiz Groh, Jordi Bover, Ramón Miralles Basseda, Juan Pablo Leiva-Santos, Alberto Alonso-Babarro, Joaquim Julià-Torras" "autores" => array:18 [ 0 => array:2 [ "nombre" => "Lina" "apellidos" => "Nitola-Mendoza" ] 1 => array:2 [ "nombre" => "Miguel" "apellidos" => "Sánchez-Cárdenas" ] 2 => array:2 [ "nombre" => "Néstor" "apellidos" => "Rodriguez-Chitiva" ] 3 => array:2 [ "nombre" => "José María" "apellidos" => "Mora Gutiérrez" ] 4 => array:2 [ "nombre" => "Rosely" "apellidos" => "Rodriguez-Pena" ] 5 => array:2 [ "nombre" => "Gregorio" "apellidos" => "Romero-González" ] 6 => array:2 [ "nombre" => "Monserrat" "apellidos" => "Bleda Pérez" ] 7 => array:2 [ "nombre" => "Paula" "apellidos" => "Cuenca Casbas" ] 8 => array:2 [ "nombre" => "Agnès" "apellidos" => "Calsina-Berna" ] 9 => array:2 [ "nombre" => "Margarita" "apellidos" => "Álvaro-Pardo" ] 10 => array:2 [ "nombre" => "Virginia" "apellidos" => "Granados Casas" ] 11 => array:2 [ "nombre" => "Paula" "apellidos" => "Garrido Ballart" ] 12 => array:2 [ "nombre" => "Patricia" "apellidos" => "Beroiz Groh" ] 13 => array:2 [ "nombre" => "Jordi" "apellidos" => "Bover" ] 14 => array:2 [ "nombre" => "Ramón" "apellidos" => "Miralles Basseda" ] 15 => array:2 [ "nombre" => "Juan Pablo" "apellidos" => "Leiva-Santos" ] 16 => array:2 [ "nombre" => "Alberto" "apellidos" => "Alonso-Babarro" ] 17 => array:2 [ "nombre" => "Joaquim" "apellidos" => "Julià-Torras" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "S0211699523000759" "doi" => "10.1016/j.nefro.2023.05.006" "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/S0211699523000759?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S201325142400155X?idApp=UINPBA000064" "url" => "/20132514/0000004400000004/v1_202408300447/S201325142400155X/v1_202408300447/en/main.assets" ] "en" => array:17 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Review</span>" "titulo" => "Hepatitis C virus infection is associated with proteinuria according to a systematic review with meta-analysis" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "486" "paginaFinal" => "495" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Fabrizio Fabrizi, Maria F. Donato, Luca Nardelli, Federica Tripodi, Francesca Zanoni, Giuseppe Castellano" "autores" => array:6 [ 0 => array:4 [ "nombre" => "Fabrizio" "apellidos" => "Fabrizi" "email" => array:1 [ 0 => "fabrizio.fabrizi@policlinico.mi.it" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Maria F." "apellidos" => "Donato" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Luca" "apellidos" => "Nardelli" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "Federica" "apellidos" => "Tripodi" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "Francesca" "apellidos" => "Zanoni" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 5 => array:3 [ "nombre" => "Giuseppe" "apellidos" => "Castellano" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Division of Nephrology, Dialysis, and Kidney Transplant, Foundation IRCCS Cà Granda Ospedale Maggiore Policlinico, Milano, Italy" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Division of Gastroenterology and Hepatology, Foundation IRCCS Cà Granda Ospedale Maggiore Policlinico, Italy" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Department of Clinical Sciences and Community Health, University School of Medicine, Milano, Italy" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "<span class="elsevierStyleItalic">Corresponding author</span>." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "La infección por el virus de la hepatitis C se asocia con proteinuria según una revisión sistemática de la literatura con metaanálisis" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1211 "Ancho" => 2508 "Tamanyo" => 125030 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Funnel plot of precision by log odds ratio (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>16 cross-sectional studies; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>163,979 unique patients) (outcome: prevalence of proteinuria).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Hepatitis C virus infection is an important agent of liver disease worldwide. Recent information has been accumulated showing that chronic hepatitis C virus infection plays important activities in various tissues and organs other than the liver.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">1</span></a> It appears that the kidney is an important target of the extra-hepatic activity of HCV and a relationship between HCV and CKD has been recently mentioned. The relationship between CKD and HCV infection is bi-directional as HCV is both a cause and consequence of chronic kidney disease. HCV and CKD are major public health issues all over the world, the Global Burden of Disease (GBD) Chronic Kidney Disease Collaboration has reported that the global prevalence of CKD in 2017 was 9.1% (95% uncertainty interval [UI] 8.5–9.8), which is roughly 700 million cases. According to the 2023 report from the World Health Organization, an estimated 58 million people globally have chronic hepatitis C virus, with about 1.5 million new infections occurring per year. WHO in 2016 established the goal to eliminate HBV and HCV as a public health threat by 2030 and we are currently very far from this goal; in fact, only 21% of the 58 million with chronic HCV had been diagnosed in 2019, and 13% treated globally.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The current prevalence of chronic kidney disease cannot fully explained by conventional risk factors such as comorbidities (arterial hypertension, diabetes and ageing, among others) or life-style factors (smoke, overweight, etc.); additional agents have been mentioned such as positive family history of CKD<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">3</span></a> or viral hepatitis (mostly, HBV and HCV).<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">1</span></a> Our meta-analysis of clinical observational studies (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>40; 4,072,867 patients) had revealed a relationship between anti-HCV positive serologic status and increased incidence of chronic kidney disease; the summary estimate for adjusted HR with HCV across the surveys, 1.54 (95% CI, 1.26; 1.87) (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001).<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">4</span></a> However, between-study heterogeneity was found (<span class="elsevierStyleItalic">Q</span> value by Chi-squared [<span class="elsevierStyleItalic">χ</span><span class="elsevierStyleSup">2</span>] test 500.3, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.0001).</p><p id="par0015" class="elsevierStylePara elsevierViewall">The frequency of proteinuria according to anti-HCV positive serologic status was also assessed (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>10 studies). There was a consistent link between positive anti-HCV serologic status and increased frequency of proteinuria, adjusted risk of proteinuria associated with HCV across the surveys, 1.633 (95% CI, 1.29; 2.05) (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001). These results were not conclusive for at least two reasons – large heterogeneity (<span class="elsevierStyleItalic">Q</span> value by Chi-square test [<span class="elsevierStyleItalic">χ</span><span class="elsevierStyleSup">2</span>]<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>37.47 (<span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>75.9%) (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.0001), and limited number (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>10) of clinical studies.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">4</span></a> Several mechanisms have been advocated to explain the increased risk of proteinuria in HCV-infected individuals. Although chronic HCV infection is associated with tubulo-interstitial injury, the most common type of HCV-associated kidney damage is glomerular disease and an association between HCV infection and glomerular disease has been observed in native kidneys and after solid organ transplant.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">1</span></a> A variety of glomerular diseases, such as membrano-proliferative glomerulonephritis, membranous nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, interstitial nephritis, renal thrombotic microangiopathy, and proliferative glomerulonephritis have been identified in patients with exposure to HCV. The most frequent HCV-related glomerular disease is immune complex-mediated membrano-proliferative glomerulonephritis, usually reflecting the presence of type II cryoglobulinemia. Cases of HCV-associated MPGN without cryoglobulinemia have not infrequently been reported.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">1</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The recent publication of large and additional studies has led us to summarize again the scientific information concerning the relationship between proteinuria and exposure to HCV infection. We have performed a systematic review of the medical literature with a meta-analysis of clinical observational studies.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Material and methods</span><p id="par0025" class="elsevierStylePara elsevierViewall">This work is in agreement with the Preferred Reporting Items for Systematic reviews and Meta-analyses statement.<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">5</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Search strategy and data extraction</span><p id="par0030" class="elsevierStylePara elsevierViewall">Citations in English language from the national Library of Medicine's Medline database from 1989 to June 20, 2023 were evaluated by two authors (F.F., and C.M.A.). Initial testing for HCV was made in 1989 and data on HCV status are therefore not available for the time before 1989. The current research was performed by four Medline databases engines (Embase, Grateful Med, Ovid, and PubMed), and was limited to human studies.</p><p id="par0035" class="elsevierStylePara elsevierViewall">The following algorithm in medical subject heading and in free text words was applied: (‘HCV’ or ‘HCV antibody positive serologic status’ or ‘HCV viremia’ or ‘Hepatitis C’ or ‘Hepatitis C Virus Infection’ or ‘HCV RNA’) AND (‘Albuminuria’ or ‘Macroalbuminuria’ or ‘Microalbuminuria’ or ‘Proteinuria’ or ‘Albumin/creatinine ratio’), AND (‘Incidence’ or ‘Prevalence’).</p><p id="par0040" class="elsevierStylePara elsevierViewall">We performed an additional search with electronic searches of the Cochrane Library; manual searches of selected specialty journals were made to identify all pertinent literature. We also searched reference lists from qualitative topic reviews and published clinical studies. It was previously demonstrated that a Medline search alone might not be sensitive enough.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">6</span></a> Data on study design, study period, patient characteristics, HCV prevalence, antiviral therapy towards HCV, and kidney disease outcomes were abstracted. Authors of selected papers were contacted to obtain missing data and only information from patients with known HCV status were included in the meta-analysis. We achieved consensus for all data. We deleted duplicate reports for the same patients, which included contact with authors when necessary. We pre-specified eligibility and exclusion criteria. Our search was limited to human studies that were published in the English literature.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Inclusion criteria</span><p id="par0045" class="elsevierStylePara elsevierViewall">We retrieved studies if they met numerous inclusion criteria as follows:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">•</span><p id="par0050" class="elsevierStylePara elsevierViewall">They presented original data from cohort and longitudinal studies;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">•</span><p id="par0055" class="elsevierStylePara elsevierViewall">The outcome of interest was clearly defined as frequency of detectable proteinuria in the adult general population according to HCV status;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">•</span><p id="par0060" class="elsevierStylePara elsevierViewall">The studies provided adjusted risk estimates and their confidence intervals. Both case–control and cohort studies were considered as eligible for inclusion in the analysis.</p></li></ul></p><p id="par0065" class="elsevierStylePara elsevierViewall">If data on the same population were duplicated in more than one report, we enrolled the most recent study in the analysis. Information on HCV status was identified at the time of enrolment. We included reports where the diagnosis of HCV infection was conducted by testing for anti-HCV antibody in serum and/or detection of HCV RNA by nucleic acid testing. Surveys based on administrative codes (ICD-9) were also addressed.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Ineligible studies</span><p id="par0070" class="elsevierStylePara elsevierViewall">We have excluded studies if they reported inadequate information or data on the link between proteinuria and HCV positive status. We have excluded unpublished studies and reports that were published in abstract form only. Letters and reviews (narrative or systematic reviews, meta-analyses) were not considered.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Quality assessment</span><p id="par0075" class="elsevierStylePara elsevierViewall">The quality of the 23 studies was evaluated using a scale from the ‘Newcastle–Ottawa Scale (NOS)’.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">7</span></a> The Newcastle–Ottawa Scale is a scoring system that assesses all aspects of an observational epidemiologic survey from a methodological point of view. When a study included relevant information that could be associated with the NOS, one point was added. Seven items in cross-sectional studies and eight items in cohort and case–control studies that could be related to the NOS were retrieved. Therefore, cross-sectional studies assigned 8–10, 6–7, 4–5, or 0–3 points (stars) were assessed as very good, good, satisfactory or unsatisfactory studies, respectively. Similarly, cohort and case–control studies with 7–9, 5–6, 4 and 0–3 points (stars) were retrieved as very good, good, satisfactory or unsatisfactory studies, respectively. We carried out subgroup analyses based on those reports provided with very good quality. Data extraction and quality scoring were performed independently by two reviewers (F.F., and F.M.D.) and the results were merged by consensus. The complete protocol for quality scoring is available on-line.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Outcomes measures</span><p id="par0080" class="elsevierStylePara elsevierViewall">We made separate meta-analyses according to the outcome. The current meta-analysis included cross-sectional studies and longitudinal studies addressing the prevalence and incidence of proteinuria, respectively. The primary end-point was to provide adjusted estimates of the risk (and 95% CIs) of incidence (or prevalence) of proteinuria according to HCV infection. Multivariate analysis was conducted in each study to evaluate the independent impact of HCV positive status on the frequency of proteinuria after adjustment for potential confounders (covariates) (e.g., age, gender, diabetes mellitus, and others). Cox proportional hazard regression analysis and logistic regression analysis were carried out in longitudinal and cross-sectional studies, respectively.</p><p id="par0085" class="elsevierStylePara elsevierViewall">An additional outcome was the occurrence of albuminuria according to HCV infection in studies without adjustment for covariates (univariate analysis only).</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Data synthesis and analysis</span><p id="par0090" class="elsevierStylePara elsevierViewall">We weighted study-specific log hazard ratios (relative risks or odds ratios for cohort studies) by the inverse of their variances to obtain a pooled effect estimate and its 95% confidence intervals. We used the assumption that odds ratios provide a reasonable approximation of the RR in case control studies and in cohort studies in which the outcome occurs unfrequently (around 10%) in the unexposed population. In addition, we assumed that hazards can be thought as incidence rates (dichotomous, non-time-varying exposures) and thus the HRs can be roughly interpreted as incidence rate ratios. We combined cohort studies and case–control studies in the absence of statistical heterogeneity. For each study, we adopted the estimate of the effect measure that was adjusted for the largest number of confounders. When results from the fixed and random effects models were different, we presented the second as it represents a more conservative approach. We adopted the random-effects model, as reported by DerSimonian and Laird,<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">8</span></a> and the heterogeneity was evaluated by R<span class="elsevierStyleInf"><span class="elsevierStyleItalic">i</span></span> (i.e., the proportion of total variance due to between-study variance). Heterogeneity was considered consistent if R<span class="elsevierStyleInf"><span class="elsevierStyleItalic">i</span></span> was ≥0.75. The origin of the heterogeneity was addressed adopting stratified analysis: we identified subgroups of studies defined by study characteristics such as country of origin, reference year, or size. Sensitivity analysis adopting a fixed-effect model was also conducted to evaluate the consistency of results. We assessed publication bias graphically by using a funnel plot as well as quantitatively with Egger's regression. Multivariate meta-regression analysis was performed with the aim to observe the impact of continuous covariates on the outcome (prevalence or incidence of proteinuria among HCV-infected patients). Statistical analysis was performed with the software HEpiMA (version 2.1.3)<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">9</span></a> and Comprehensive Meta-analysis (Biostat Inc., USA, 2005). A 5% significance was adopted for the alpha risk. Every estimate was given with its 95% CI.</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Results</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Literature review</span><p id="par0095" class="elsevierStylePara elsevierViewall">As listed in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>, we identified 452 articles and 68 were evaluated for eligibility. The list of the 68 full-text papers is reported available on request. Twenty-three studies met our inclusion criteria and were published in 22 papers<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">10–31</span></a> and carried out in 3 continents (Europe, Asia and America); a total of 198,675 unique patients were retrieved. Thus, one study contributed data on more than one kidney disease outcome; however, the cohort was considered once in our meta-analysis. There was a 100% concordance between reviewers with regard to final inclusion and exclusion of studies reviewed based on the predefined inclusion and exclusion criteria.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">Information on HCV status was collected at the time of study inclusion. We pooled studies where the diagnosis of HCV infection and chronic kidney disease were done by administrative codes (ICD-9-CM codes).</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Patient characteristics</span><p id="par0105" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRefs" href="#tbl0005">Tables 1 and 2</a> report some salient demographic and clinical characteristics of subjects enrolled in the included studies. The mean age of subject cohorts ranged from 38.5 to 60.8 years. The gender distribution ranged from 0 to 100% male. The average follow-up was between 15 and 132 months (longitudinal studies) and the pooled prevalence of HCV positive individuals was 0.19 (95% CI, 0.17; 0.21). Nine studies were from the USA, seven from Asia, five from Europe, and one from southern America. The quality of study scores ranged between 5 and 7 (longitudinal studies) and 6 and 9 (cross-sectional studies) (data not shown). The great majority of studies made diagnosis of HCV infection by detecting anti-HCV antibody in serum; one study assessed the presence of HCV antigen<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">14</span></a> or HCV RNA<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">24</span></a> in serum. Information on diagnosis of HCV was missed in one survey.<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">23</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Summary estimate of outcome (prevalence of proteinuria)</span><p id="par0110" class="elsevierStylePara elsevierViewall">Sixteen studies (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>163,797 unique patients; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>9854 HCV-positive and <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>153,943 HCV-negative patients) evaluated the prevalence of proteinuria among HCV-infected patients.<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">10–25</span></a> The pooled prevalence of proteinuria was 0.11 (95% CI, 0.09–0.14) (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>). We found a significant relationship between positive HCV status and increased prevalence of proteinuria, aOR 1.47 (95% CI, 1.3; 1.66) (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001). The funnel plot concerning the publication bias is reported in <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>; the Egger test reported significant publication bias (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.003). Tests for homogeneity of the aOR across the studies gave a <span class="elsevierStyleItalic">Q</span> value (by <span class="elsevierStyleItalic">χ</span><span class="elsevierStyleSup">2</span> test) of 27.3 (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.026). <a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a> reports the aOR and 95% confidence intervals for each cross-sectional study.</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Summary estimate of outcome (incidence of proteinuria)</span><p id="par0115" class="elsevierStylePara elsevierViewall">Seven longitudinal studies (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>35,170 unique patients; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>5556 anti-HCV positive and <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>29,614 anti-HCV negative) gave information on the incidence of proteinuria. The pooled incidence of proteinuria was 0.14 (95% CI, 0.04; 0.23). The summary estimate of adjusted HR with HCV across the surveys, 1.79 (95%CI, 1.17; 2.74) (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001).<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">24,26–31</span></a> Significant publication bias occurred (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.04), according to the Egger test. Tests for homogeneity of the aHR across the studies (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>7) gave a <span class="elsevierStyleItalic">Q</span> value of 27.82 by <span class="elsevierStyleItalic">χ</span><span class="elsevierStyleSup">2</span> test (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.0001).</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Stratified analysis (and meta-regression)</span><p id="par0120" class="elsevierStylePara elsevierViewall">Stratified analyses were carried out and did not show consistent differences in pooled aOR across various subgroups (<a class="elsevierStyleCrossRefs" href="#tbl0020">Tables 4 and 5</a>) but the homogeneity assumption was rejected in numerous subsets (<a class="elsevierStyleCrossRefs" href="#tbl0020">Tables 4 and 5</a>). As listed in <a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a>, we carried out multivariate meta-regression analysis and found a significant link between percentage of HCV-infected males and adjusted OR (cross-sectional studies). The limited number of studies with longitudinal design (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>7) and the incomplete information on many covariates precluded the conduction of meta-regression in this setting. We collected incomplete information on many clinical or biochemical parameters and this hampered the completion of many comparisons.</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><elsevierMultimedia ident="tbl0030"></elsevierMultimedia></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Univariate analysis</span><p id="par0125" class="elsevierStylePara elsevierViewall">We recorded studies (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>6; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>72,551 unique patients) addressing the occurrence of proteinuria according to HCV status (no adjustment for covariates made).<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">32–37</span></a> There was an increased frequency of proteinuria among HCV-exposed individuals and this reached statistical significance, pooled OR 1.54 (95% CI, 1.08; 2.19). The homogeneity assumption was not rejected, R<span class="elsevierStyleInf"><span class="elsevierStyleItalic">i</span></span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.88, <span class="elsevierStyleItalic">Q</span> value of 36.1 by <span class="elsevierStyleItalic">χ</span><span class="elsevierStyleSup">2</span> test (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.001).</p></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Discussion</span><p id="par0130" class="elsevierStylePara elsevierViewall">The occurrence of CKD in the world is rising and gives additional burden on both the healthcare and economy in the years to come. Previous studies have reported that patients with CKD are at a higher risk of progression to end-stage kidney disease (ESRD) which needs expensive renal replacement programmes. Progression to kidney failure and other adverse outcomes can be prevented or at least delayed by early detection and treatment – proteinuria and glycosuria are early biochemical markers for kidney disease which can be used as a proxy measure to give clue to clinicians to make diagnosis on the occurrence of kidney disease at an early stage. Among the various predictors of progression of CKD to ESRD, proteinuria appears to be an important one.</p><p id="par0135" class="elsevierStylePara elsevierViewall">The findings of the current meta-analysis reinforce the hypothesis that HCV infection is an important risk factor for the development of proteinuria in the adult general population. This meta-analysis (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>22 studies; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>198,967 unique patients) includes a number of studies greater than that reported in the previous one (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>10) and confirms the higher risk of proteinuria among HCV-infected individuals, overall estimate for adjusted OR with HCV across the cross-sectional surveys, 1.47 (95%CI, 1.3; 1.66) (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001). Of note, we noted in the current meta-analysis small between-study heterogeneity, particularly among cross-sectional studies (<span class="elsevierStyleItalic">Q</span> value by Chi-squared [<span class="elsevierStyleItalic">χ</span><span class="elsevierStyleSup">2</span>] test 27.3, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.02) and stratified analysis reported no heterogeneity in several comparisons (<a class="elsevierStyleCrossRefs" href="#tbl0020">Tables 4 and 5</a>). The results obtained with univariate analyses were in keeping with those obtained with multivariate regressions.</p><p id="par0140" class="elsevierStylePara elsevierViewall">HCV has been implicated in derangements of multiple organ systems including cardiovascular, muscular, nervous, ocular, respiratory, skeletal, cutaneous, and urinary systems. Lymphoproliferative disorders such as lymphoma and mixed cryoglobulinemia are associated with HCV infection. Moreover, HCV has a deleterious impact on psychosocial status. Kidney involvement in HCV-infected patients was first observed more than 2 decades ago<a class="elsevierStyleCrossRef" href="#bib0395"><span class="elsevierStyleSup">38</span></a>; but the relationship between HCV and CKD (reduced GFR or detectable proteinuria) in the adult general population had remained controversial until a few years ago. The KDIGO HCV Work Study Group<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">1</span></a> recommended the screening for proteinuria in HCV-infected individuals and the findings obtained in this study reinforce such a recommendation.</p><p id="par0145" class="elsevierStylePara elsevierViewall">The relationship between detectable proteinuria and HCV infection has been explained with various underlying mechanisms; HCV can give proteinuria by immunological and non-immunological pathways (i.e., oxidative stress, pro-inflammatory cytokines, and others). The pathogenesis of glomerular disease associated with HCV infection involves immune-mediated damage (including the activity from cryoglobulins); HCV-associated membranous nephropathy is thought to be related to the deposition of immune complexes containing HCV proteins in the glomerular basement membrane.<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">1</span></a> Direct effects of virus on renal tissue have been cited; as an example, it has been mentioned the binding of HCV to CD81 and SR-B1 receptors in order to penetrate into the renal parenchymal cells.<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">39</span></a> HCV RNA has been recorded in mesangial cells, tubular epithelial cells, and endothelial cells (glomerular and tubular capillaries).<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">40</span></a> Viral HCV antigens have been demonstrated by immunohistochemistry, in situ hybridization, immuno-gold labelling, and laser capture microdissection.<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">40,41</span></a> On the other hand, HCV-infected patients are at risk for kidney damage due to hereditariness, cirrhosis, illicit drug use, and co-infection (HBV and/or HIV). It has been recently mentioned that an accelerated atherosclerosis also contributes to the increased risk of proteinuria among patents with HCV.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">4</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">The findings from the current meta-analysis show several limitations. First, the majority of reports have retrospective and cohort design and it is well known that studies with this design cannot give excellent evidence. Secondly, the current availability of safe and effective drugs for the treatment of HCV clearly hampers the conduction of longitudinal studies on the incidence of proteinuria among HCV-infected patients. Thirdly, each study retrieved in the current meta-analysis was performed with multivariate analysis in order to evaluate the independent and significant impact of clinical or demographic parameters (confounders) on the occurrence of proteinuria; residual confounding cannot be excluded as complete information on various confounders was missing. Finally, the link between HCV infection and proteinuria was less evident in longitudinal studies; the discrepancy between cross-sectional and longitudinal studies could be explained by the need of longer follow-ups.</p><p id="par0155" class="elsevierStylePara elsevierViewall">The results of the current meta-analysis support the notion that a strong link between detectable proteinuria and HCV positive status exists. The current availability of effective and safe drugs (DAAs) for the early treatment of HCV gives us the opportunity to improve the management of CKD in the adult general population. We suggest screening all patients for proteinuria at the time of HCV infection diagnosis.</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Institutional review board statement</span><p id="par0160" class="elsevierStylePara elsevierViewall">Not applicable.</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Informed consent statement</span><p id="par0165" class="elsevierStylePara elsevierViewall">Not applicable.</p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Data availability statement</span><p id="par0170" class="elsevierStylePara elsevierViewall">Not applicable.</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Funding</span><p id="par0175" class="elsevierStylePara elsevierViewall">No sources of funding were used for the preparation of this manuscript.</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Conflict of interest</span><p id="par0180" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:15 [ 0 => array:3 [ "identificador" => "xres2230891" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and aim" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1868116" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xpalclavsec1868118" "titulo" => "Abbreviations" ] 3 => array:3 [ "identificador" => "xres2230890" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción y objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 4 => array:2 [ "identificador" => "xpalclavsec1868117" "titulo" => "Palabras clave" ] 5 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 6 => array:3 [ "identificador" => "sec0010" "titulo" => "Material and methods" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Search strategy and data extraction" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Inclusion criteria" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Ineligible studies" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Quality assessment" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Outcomes measures" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Data synthesis and analysis" ] ] ] 7 => array:3 [ "identificador" => "sec0045" "titulo" => "Results" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "Literature review" ] 1 => array:2 [ "identificador" => "sec0055" "titulo" => "Patient characteristics" ] 2 => array:2 [ "identificador" => "sec0060" "titulo" => "Summary estimate of outcome (prevalence of proteinuria)" ] 3 => array:2 [ "identificador" => "sec0065" "titulo" => "Summary estimate of outcome (incidence of proteinuria)" ] 4 => array:2 [ "identificador" => "sec0070" "titulo" => "Stratified analysis (and meta-regression)" ] 5 => array:2 [ "identificador" => "sec0075" "titulo" => "Univariate analysis" ] ] ] 8 => array:2 [ "identificador" => "sec0080" "titulo" => "Discussion" ] 9 => array:2 [ "identificador" => "sec0085" "titulo" => "Institutional review board statement" ] 10 => array:2 [ "identificador" => "sec0090" "titulo" => "Informed consent statement" ] 11 => array:2 [ "identificador" => "sec0095" "titulo" => "Data availability statement" ] 12 => array:2 [ "identificador" => "sec0100" "titulo" => "Funding" ] 13 => array:2 [ "identificador" => "sec0105" "titulo" => "Conflict of interest" ] 14 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "en" => array:2 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1868116" "palabras" => array:4 [ 0 => "Chronic kidney disease" 1 => "Hepatitis C virus" 2 => "Meta-analysis" 3 => "Proteinuria" ] ] 1 => array:4 [ "clase" => "abr" "titulo" => "Abbreviations" "identificador" => "xpalclavsec1868118" "palabras" => array:27 [ 0 => "AH" 1 => "ALT" 2 => "AST" 3 => "CI" 4 => "CKD" 5 => "CC" 6 => "CS" 7 => "CVD" 8 => "DAAs" 9 => "DM" 10 => "eGFR" 11 => "ESRD" 12 => "HBsAg" 13 => "HBV" 14 => "HBV DNA" 15 => "HCV" 16 => "HD" 17 => "HIV" 18 => "HR" 19 => "KDIGO" 20 => "KT" 21 => "NR" 22 => "OR" 23 => "RR" 24 => "RRT" 25 => "RT" 26 => "UACR" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1868117" "palabras" => array:4 [ 0 => "Enfermedad renal crónica" 1 => "Virus de la hepatitis C" 2 => "Metaanálisis" 3 => "Proteinuria" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Introduction and aim</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Hepatitis C virus infection and chronic kidney disease are major public health issues all over the world. It has been suggested a role of HCV as a risk factor for the development and progression of chronic kidney disease (defined by reduced glomerular filtration rate and/or detectable proteinuria) in the general population but conflicting findings have been given.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A systematic review of the published medical literature was conducted to assess whether positive HCV serologic status is associated with greater rate of proteinuria in the adult general population. We used a random-effect model to generate a summary estimate of the relative risk of proteinuria with HCV across the published studies.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">We identified 23 studies (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>198,967 unique patients) and performed separate meta-analyses according to the study design. Overall effect estimate was significant in cross-sectional (OR, 1.47, 95%CI, 1.3; 1.66) (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001) and obvious between-study heterogeneity was observed (<span class="elsevierStyleItalic">Q</span> value by Chi-squared [<span class="elsevierStyleItalic">χ</span><span class="elsevierStyleSup">2</span>] test 27.3, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.02). The risk of proteinuria after exposure to HCV was also consistent among longitudinal studies (HR, 1.79, 95% CI, 1.17; 2.74) (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001) and between-study heterogeneity occurred (<span class="elsevierStyleItalic">Q</span> value, 27.82 by <span class="elsevierStyleItalic">X</span><span class="elsevierStyleSup">2</span> test, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.0001). Stratified analysis did not report heterogeneity in several comparisons-pooling studies based on urine protein/creatinine ratio (UACR) showed that the adjusted OR with HCV was 1.64 (95% CI, 1.41; 1.91, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001) without heterogeneity (<span class="elsevierStyleItalic">Q</span> value by Chi-squared [<span class="elsevierStyleItalic">χ</span><span class="elsevierStyleSup">2</span>] test 9.98, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>NS). Meta-regression recorded a link between greater prevalence of proteinuria in males with HCV exposure (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.03). Studies based on univariate analysis (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>6, <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>72, 551 unique patients) gave similar results, pooled OR 1.54 (95% CI, 1.08; 2.19) (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.0001).</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">An important relationship between HCV infection and higher risk of proteinuria in the general population exists. Research aimed to understand the biological mechanisms underlying such association is under way. We encourage to screen all patients with HCV exposure for proteinuria.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Introduction and aim" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material 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 objetivo</span><p id="spar0205" class="elsevierStyleSimplePara elsevierViewall">La infección por virus de hepatitis C y la enfermedad renal crónica son cuestiones de salud pública mayores a nivel mundial. Se ha sugerido el rol del VHC como factor de riesgo para el desarrollo y progresión de la enfermedad renal crónica (definida como reducción de la tasa de filtración glomerular y/o proteinuria detectable) en la población general, aunque se han aportado hallazgos contrapuestos.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y métodos</span><p id="spar0210" class="elsevierStyleSimplePara elsevierViewall">Se realizó una revisión sistemática de la literatura médica publicada, para evaluar si el estatus serológico positivo de VHC está asociado a una mayor tasa de proteinuria en la población general adulta. Utilizamos un modelo de efecto aleatorio para generar una estimación resumida del riesgo relativo de proteinuria con VHC en los estudios publicados.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0215" class="elsevierStyleSimplePara elsevierViewall">Identificamos 23 estudios (n = 198.967 pacientes únicos) y realizamos un metaanálisis separado, de acuerdo con el diseño del estudio. En general, la estimación del efecto fue significativa en los estudios transversales (OR, 1,47, 95% IC, 1,3; 1,66) (p < 0,001), observándose heterogeneidad obvia entre estudios (valor Q mediante la prueba χ<span class="elsevierStyleSup">2</span> 27,3, p = 0,02). El riesgo de proteinuria tras la exposición a VHC fue también consistente entre los estudios longitudinales (HR, 1,79, 95% IC, 1,17; 2,74) (p < 0,001) produciéndose heterogeneidad entre estudios (valor Q, 27,82 mediante la prueba χ<span class="elsevierStyleSup">2</span>, p = 0,0001). El análisis estratificado no reportó heterogeneidad en diversos estudios comparativos-agrupados basados en el ratio proteína/creatinina en orina (UACR), reflejando que el valor de OR ajustado con VHC fue de 1,64 (95% IC, 1,41; 1,91, p < 0,001) sin heterogeneidad (valor Q mediante la prueba χ<span class="elsevierStyleSup">2</span> 9,98, p = NS). La metarregresión registró un vínculo entre la mayor prevalencia de proteinuria en varones con exposición a VHC (p = 0,03). Los estudios basados en análisis univariantes (n = 6, n = 72.551 pacientes únicos) arrojaron resultados similares, OR agrupado de 1,54 (95% IC, 1,08; 2,19) (p = 0,0001).</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0220" class="elsevierStyleSimplePara elsevierViewall">Existe una relación importante entre la infección por VHC y el mayor riesgo de proteinuria en la población general. La investigación dirigida a comprender los mecanismos biológicos subyacentes a dicha asociación está en curso. Animamos a cribar la proteinuria en todos los pacientes con exposición al VHC.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Introducción y objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "multimedia" => array:9 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1598 "Ancho" => 2508 "Tamanyo" => 218662 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Flow diagram of study 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" => 1211 "Ancho" => 2508 "Tamanyo" => 125030 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Funnel plot of precision by log odds ratio (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>16 cross-sectional studies; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>163,979 unique patients) (outcome: prevalence of proteinuria).</p>" ] ] 2 => array:8 [ "identificador" => "fig0015" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Study 1 Szczech L, et al. 2002; study 2 Liangpunsakul S and Chalasani N, 2015; study 3 Tsui J, et al. 2006; study 4 Huang J, et al. 2006; study 5 Ishizaka N, et al. 2008; study 6 Yanik E, et al. 2010; study 7 Derbala M, et al. 2010; study 8 Lee J, et al. 2010; study 9 Yanagisawa N, et al. 2011; study 10 Aoufi Rabih S, et al. 2012; study 11 Reynes J, et al. 2013; study 12 Zeng Q, et al. 2014; study 13 Kurbanova N, et al. 2015; study 14 Antonello V, et al. 2015; study 15 Lucas G, et al. 2016; study 16 Zeder A, et al. 2016." "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1442 "Ancho" => 2508 "Tamanyo" => 90546 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">aOR and 95% confidence intervals for each study (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>16 cross-sectional studies; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>163,979 unique patients) (outcome: prevalence of proteinuria). aOR of proteinuria associated with exposure to HCV: 1.47 (95% CI, 1.3; 1.66) (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>0.001) R<span class="elsevierStyleItalic"><span class="elsevierStyleInf">i</span></span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.61. <span class="elsevierStyleItalic">Q</span> value by <span class="elsevierStyleItalic">χ</span><span class="elsevierStyleSup">2</span> test 27.3 (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.026) (asymptotic tests).</p>" ] ] 3 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Author (ref. number) [ref. year] \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">Country \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">Proteinuria, <span class="elsevierStyleItalic">n</span> \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, yrs \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">Study size \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">Anti-HCV pos. pts, <span class="elsevierStyleItalic">n</span> \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">Szczech L, et al.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">10</span></a> [2002] \t\t\t\t\t\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">USA \t\t\t\t\t\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">671/2057 (32%) \t\t\t\t\t\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">38.5<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>7.7 \t\t\t\t\t\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">2059 \t\t\t\t\t\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">854 (41.5%) \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">Liangpunsakul S and Chalasani N<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">11</span></a> [2005] \t\t\t\t\t\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">USA \t\t\t\t\t\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">108/1357 (7.9%) \t\t\t\t\t\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">47.6<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>19 \t\t\t\t\t\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">15,336 \t\t\t\t\t\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">368 (2.4%) \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">Tsui J, et al.<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">12</span></a> [2006] \t\t\t\t\t\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">USA \t\t\t\t\t\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">NS \t\t\t\t\t\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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">15,029 \t\t\t\t\t\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">366 (2.4%) \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">Huang J, et al.<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">13</span></a> [2006] \t\t\t\t\t\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">Taiwan \t\t\t\t\t\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">707/9934 (7.1%) \t\t\t\t\t\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">55.2<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>6 \t\t\t\t\t\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">9934 \t\t\t\t\t\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">642 (6.4%) \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">Ishizaka N, et al.<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">14</span></a> [2008] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Japan \t\t\t\t\t\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">1179/12,535 (9.4%) \t\t\t\t\t\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<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>10.6 \t\t\t\t\t\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">12,535 \t\t\t\t\t\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">72 (0.6%) \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">Yanik E, et al.<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">15</span></a> [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">USA \t\t\t\t\t\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">76/902 (8.4%) \t\t\t\t\t\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">49.5 (21; 80) \t\t\t\t\t\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">902 \t\t\t\t\t\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">772 (85.7%) \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">Derbala M, et al.<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">16</span></a> [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">Qatar \t\t\t\t\t\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">45/300 (15%) \t\t\t\t\t\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">46 (41; 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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">300 \t\t\t\t\t\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">233 (77.6%) \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">Lee J, et al.<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">17</span></a> [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">Taiwan \t\t\t\t\t\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">2140/54,966 (3.9%) \t\t\t\t\t\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">60.8<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>11.5 \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="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">54,966 \t\t\t\t\t\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">5189 (9.4%) \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">Yanagisawa N, et al.<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">18</span></a> [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">Japan \t\t\t\t\t\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">36/725 (4.9%) \t\t\t\t\t\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">46.6<span class="elsevierStyleHsp" style=""></span>±<span class="elsevierStyleHsp" style=""></span>11.7 \t\t\t\t\t\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">732 \t\t\t\t\t\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">24 (3.3%) \t\t\t\t\t\t