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Hepatitis C and Its Metabolic Complications in Kidney Disease
Fabrizio Fabrizi
,
Corresponding author
fabrizi@policlinico.mi.it

Correspondence and reprint request:
, Francesca M. Donato**, Piergiorgio Messa*,***
* Division of Nephrology, Maggiore Hospital and IRCCS Foundation. Milano, Italy
** Division of Gastroenterology, Maggiore Hospital and IRCCS Foundation. Milano, Italy
*** Division of Nephrology, Maggiore Hospital and IRCCS Foundation, University School of Medicine. Milano, Italy
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="s0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0040">Introduction</span><p id="p0010" class="elsevierStylePara elsevierViewall">Hepatitis C virus infection is still frequent among patients undergoing long-term dialysis all over the world&#46; Hepatitis C virus was identified in 1989&#59; since then&#44; an enormous body of evidence has been accumulated showing a large frequency of anti-HCV positive patients on maintenance dialysis patients in developed countries&#46; The epidemiology of HCV infection in patients on long-term dialysis in developed countries has been studied by large multicenter surveys&#59; prevalence and incidence rates are decreasing due to the implementation of infection control procedures&#44; as recommended in several clinical guide-lines&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">1&#44;2</span></a></p><p id="p0015" class="elsevierStylePara elsevierViewall">According to the DOPPS &#40;the Dialysis Outcomes and Practice Patterns Study&#41;&#44; a large observational survey published more than 10 years ago&#44; the prevalence of anti-HCV antibody positive patients was 13&#46;5&#37; in a large cohort &#40;n &#61; 8&#44;615&#41; of patients on maintenance dialysis in 308 Dialysis Centers in developed world &#40;France&#44; Germany&#44; Italy&#44; Japan&#44; Spain&#44; United Kingdom&#44; and USA&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">3</span></a> An update of the DOPPS was recently made- the rate of anti-HCV positive patients undergoing maintenance dialysis &#40;n &#61; 49&#44;762&#41; in various developed countries &#40;n &#61; 12&#41; was 9&#46;5&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">4</span></a></p><p id="p0020" class="elsevierStylePara elsevierViewall">The epidemiology of HCV infection among patients undergoing maintenance dialysis in developing countries is less known&#44; the information is mostly based on small&#44; single-center surveys&#46; As listed in <a class="elsevierStyleCrossRef" href="#t0010">table 1</a>&#44; the evidence accumulated to date shows important heterogeneity and very high &#40;&#62; 50&#37;&#41; prevalence rates&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">5-17</span></a></p><elsevierMultimedia ident="t0010"></elsevierMultimedia><p id="p0025" class="elsevierStylePara elsevierViewall">The aim of this paper is to make a review of the medical literature regarding the increased risk of cardiovascular and kidney disease that has been observed in various groups of HCV-infected patients&#46; The link between such increased risk and the metabolic consequences of chronic HCV infection has been explored&#46;</p></span><span id="s0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0045">Material and Methods</span><span id="s0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0050">Data Sources and Searches</span><p id="p0030" class="elsevierStylePara elsevierViewall">We reviewed English-language citations from the National Library of Medicine&#39;s Medline database from 1989 through July 1&#44; 2016&#46; Data on HCV status were not available before 1989&#44; when the first &#8211;generation assay for anti-HCV antibody was manufactured&#46; Four Medline database engines &#40;Ovid&#44; PubMed&#44; Embase&#44; and Grateful Med&#41; were used&#46; Medline searches were limited to human studies&#46; An additional search was performed with electronic searches of the Current Contents Cochrane Library&#59; manual searches of selected specialty journals were performed to identify all pertinent literature&#46; Unpublished studies and abstracts were not considered for inclusion in this review&#46; The relationships between CKD&#44; HCV and anti-HCV therapy in the general population were explored with the following search terms&#58; &#8216;chronic kidney disease&#8217; OR &#8216;CKD&#8217; OR &#8216;kidney failure&#8217; OR &#8216;kidney injury&#8217; OR &#8216;renal disease&#8217; OR &#8216;renal failure&#8217; OR &#8216;renal insufficiency&#8217; AND &#8216;hepatitis C&#8217; OR &#8216;hepatitis C virus infection&#8217; OR &#8216;HCV&#8217; OR &#8216;chronic HCV&#8217; AND &#8216;anti-HCV therapy&#8217; OR &#8216;anti-HCV treatment&#8217; OR &#8216;interferon&#8217;&#46; The impact of HCV upon survival in the dialysis population was evaluated with the following search terms&#58; &#8216;hepatitis C&#8217; OR &#8216;hepatitis C virus infection&#8217; OR &#8216;HCV&#8217; OR &#8216;chronic HCV&#8217; AND &#8216;death risk&#8217; OR &#8216;mortality&#8217; OR &#8216;survival&#8217; AND &#8216;chronic kidney disease&#8217; OR &#8216;dialysis&#8217; OR &#8216;end-stage renal disease&#8217; OR &#8216;haemodialysis&#8217; OR &#8216;peritoneal dialysis&#8217;&#46;</p></span></span><span id="s0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0055">Results</span><span id="s0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0060">HCV and survival among patients on dialysis</span><p id="p0035" class="elsevierStylePara elsevierViewall">It is well known that cardiovascular diseases are the major causes of morbidity and mortality in patients with CKD Stage 5 including those on regular haemodialysis&#46; In addition&#44; the frequency of cardiovascular diseases among patients with chronic kidney disease is greater than that observed among patients with intact kidney function&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">18</span></a>It has been observed a great prevalence of traditional factors &#40;age&#44; male gender&#44; arterial hypertension&#44; diabetes mellitus&#44; dyslipidemia&#44; and physical inactivity&#41; for cardiovascular disease among patients with CKD stage 5&#46; In addition&#44; patients with CKD Stage 5 have disease-related risk factors for cardiovascular disease that include anaemia&#44; hyper-ho-mocysteinemia&#44; hyperparathyroidism&#44; oxidative stress&#44; hy-poalbuminemia&#44; and chronic inflammation&#44; among others&#46;</p><p id="p0040" class="elsevierStylePara elsevierViewall">Recently&#44; hepatitis C virus has been included in the group of non-traditional &#40;and modifiable&#41; risk factors for death in patients undergoing maintenance dialysis&#46; In fact&#44; numerous observational &#40;population-based and hospital-based&#41; studies have been published during the last twenty years suggesting a detrimental role of HCV upon survival among patients on regular dialysis&#46; We have performed a systematic review and meta-analysis of clinical studies&#44; and 145&#44;608 unique patients on long term dialysis &#40;n &#61; 14 observational studies&#41; were retrieved&#59; pooling of study results demonstrated that anti-HCV sero-positive status was an independent and significant risk factor for death in patients on maintenance dialysis&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">19</span></a> The summary estimate for adjusted relative risk &#40;all-cause mortality&#41; was 1&#46;35 with a 95&#37; confidence interval &#40;CI&#41; of 1&#46;25&#59; 1&#46;47 &#40;P &#60; 0&#46;01&#41; in anti-HCV positive patients&#46; It remains unclear if the elevated mortality risk due to HCV infection is attributable only to an increase in liver disease-related deaths&#46; A stratified analysis showed that the adjusted RR for liver disease-related death was 3&#46;82 &#40;95&#37; CI&#44; 1&#46;92&#59; 7&#46;61&#41;&#59; heterogeneity statistics&#44; R&#40;i&#41; &#61; 0&#46;58 &#40;P-value by Q-test &#61; 0&#46;087&#41;&#46; We updated our stratified analysis regarding the impact of anti-HCV seropositive status on CV risk in the dialysis population&#46; This information was given in four reports &#40;n &#61; 91&#44;916 patients&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">20-23</span></a> The adjusted HR for cardiovascular mortality that is associated with anti-HCV seropositive status was 1&#46;21 &#40;95&#37;CI&#44; 1&#46;06&#59; 1&#46;39&#41; &#40;<a class="elsevierStyleCrossRef" href="#f0010">Figure 1</a>&#41;&#59; according to asymptotic and bootstrap heterogeneity tests&#44; the homogeneity assumption was not rejected&#46;</p><elsevierMultimedia ident="f0010"></elsevierMultimedia><p id="p0045" class="elsevierStylePara elsevierViewall">These data confirm the extra-hepatic activity of chronic hepatitis C virus infection among patients with intact or impaired kidney function&#46; The increased cardiovascular risk in anti-HCV positive patients undergoing maintenance dialysis may stem from insulin resistance and fatty liver disease&#44; contributing to endothelial dysfunction and increase in systemic inflammatory markers&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">24-28</span></a> Insulin resistance and hepatic steatosis may contribute to the occurrence of other components of the metabolic syndrome such as arterial hypertension and dyslipidemia&#46;</p></span><span id="s0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0065">HCV and survival among patients with intact kidney function</span><p id="p0050" class="elsevierStylePara elsevierViewall">Historically&#44; HCV infection has been considered to affect only the liver&#44; via the development of cirrhosis and its complications&#46; HCV infection has also been shown to increase the risk of overall mortality and the occurrence of extra-hepatic complications&#44; such as lympho-proliferative disorders and metabolic alterations &#40;insulin resistance and diabetes mellitus&#41;&#46; HCV-driven B cell lympho-prolifera-tive disorders likely comprise a spectrum of disease&#44; varying from asymptomatic clonal B cell expansions to pathogenic cryoglobulinemia and lymphoma&#46;</p><p id="p0055" class="elsevierStylePara elsevierViewall">Since 2001&#44; numerous observational studies have investigated the relationship between HCV infection and cardiovascular risk in the adult general population&#46; A novel meta-analysis of observational studies &#40;n &#61; 22&#59; n &#61; 730&#44;645 unique patients&#41; found a negative impact of HCV infection upon cardiovascular mortality&#44; aOR&#44; 1&#46;65 &#40;95&#37; CI&#44; 1&#46;07&#59; 2&#46;56&#44; P &#61; 0&#46;02&#41;&#44; and development of carotid plaques aOR&#44; 2&#46;27 &#40;95&#37; CI&#44; 1&#46;76&#59; 2&#46;94&#44; P &#60; 0&#46;01&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">29</span></a> In addition&#44; a detrimental role of HCV on cerebro-cardiovascular events&#44; aOR&#44; 1&#46;30 &#40;95&#37; 1&#46;10&#59; 1&#46;55&#44; P &#61; 0&#46;002&#41; was observed&#46; The authors also observed significant heterogeneity in the first and third subset of studies &#40;I<span class="elsevierStyleSup">2</span> &#61; 76&#44; P &#61; 0&#46;02 and I<span class="elsevierStyleSup">2</span> &#61; 91&#37;&#44; P &#60; 0&#46;001&#44; respectively&#41;&#44; and this precluded definitive conclusions&#46; In other words&#44; aggregate data from 22 studies showed that compared to uninfected controls&#44; HCV-infected individuals have increased risks of cardiovascular mortality and subclinical atherosclerosis in the adult general population&#46;</p><p id="p0060" class="elsevierStylePara elsevierViewall">The meta-analyses reported above have limitations&#44; which are intrinsic to the nature of included studies and provide the basis for future research&#46; These are based on observational studies and&#44; consequently&#44; could be biased by residual confounding &#40;confounding remaining after adjustment&#41;&#46; As an example&#44; information on some covariates &#40;such as injection drug use or exposure to nephrotoxic drugs&#41; was not given in all the included studies&#46; It was believed that meta-analyses should be conducted only on RCTs in order to reduce the risk of misleading conclusions&#46; However&#44; many diseases can only be studied obser-vationally&#46; If these studies have good quality&#44; it is appropriate to include them in a meta-analysis&#46; Our conclusion is that awaiting further studies&#44; patients with HCV infection&#44; either undergoing dialysis or having intact kidney function&#44; should be regarded as being at increased risk of cardiovascular risk&#44; regardless of the presence of conventional risk factors for kidney disease&#46;</p></span><span id="s0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0070">Impact of HCV upon CKD&#58; data from the general population</span><p id="p0065" class="elsevierStylePara elsevierViewall">Knowledge has been recently gathered regarding a link between hepatitis C virus and chronic kidney disease&#46; Hepatitis C virus and chronic kidney disease are prevalent in the general population and associated in various ways-patients with end-stage renal disease are at increased risk of acquiring HCV and some types of renal disease are precipitated by HCV infection&#46; Conventional risk factors for chronic kidney disease such as ageing&#44; diabetes&#44; hypertension and metabolic syndrome do not fully explain the current frequency of chronic kidney disease in the adult general population of developed countries&#46; In addition to these conventional risk factors&#44; various pieces of evidence in the last decade have implicated hepatitis C virus infection as a cause of kidney disease&#46; Numerous surveys have been performed in the last decade to address this point&#46; A meta-analysis of observational studies with cross-sectional design &#40;n &#61; 8 studies&#44; n &#61; 788&#44;027 unique patients&#41; did not find an increased prevalence of CKD among patients with HCV&#44; adjusted OR with HCV across the studies&#44; 1&#46;16 &#40;95&#37; CI&#44; 0&#46;98&#59; 1&#46;33&#44; P &#61; NS&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">30</span></a> Pooling results from longitudinal studies &#40;n &#61; 9&#59; n &#61; 1&#44;947&#44;034 unique patients&#41; demonstrated a relationship between anti-HCV positive serologic status and an increased incidence of chronic kidney disease in the adult general population- the summary estimate for adjusted hazard ratio with HCV was 1&#46;43 &#40;95&#37; CI&#44; 1&#46;23&#59; 1&#46;63&#44; P &#61; 0&#46;0001&#41;&#44; according to a random-effect model&#46; Significant heterogeneity &#40;test for homogeneity of the aHR across the nine studies &#61; Q-value &#91;by &#967;<span class="elsevierStyleSup">2</span> test&#93; of 123&#46;6&#44; P &#61; 0&#46;001&#41; was noted and this precluded more definitive conclusions&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">30</span></a> According to an updated systematic review with meta-analysis of cross-sectional studies &#40;n &#61; 7&#41;&#44; HCV positive serology was an independent risk factor for proteinuria in the adult general population&#59; adjusted odds ratio with HCV&#44; 1&#46;50 &#40;95&#37; confidence intervals&#44; 1&#46;23&#59; 1&#46;82&#44; P &#61; 0&#46;0001&#41; &#40;n &#61; 7 studies&#44; n &#61; 141&#44;085 unique pa-tients&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">31-37</span></a></p><p id="p0070" class="elsevierStylePara elsevierViewall">Epidemiologic data regarding the prevalence of chronic kidney disease in HCV-infected patients were until recently limited and used variable criteria for the definition of CKD&#59; also&#44; the demographic&#47;clinical characteristics of the representative patient population were variable&#46; Three studies performed in the US a few years ago<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">38-40</span></a> reported that the unadjusted prevalence of low GFR &#40;GFR &#60; 60 mL&#47;min&#47;1&#46;73 m<span class="elsevierStyleSup">2</span>&#41; ranged at baseline between 5&#46;1&#37; and 8&#46;0&#37; among anti-HCV seropositive individuals&#46; The unadjusted prevalence of renal insufficiency &#40;serum creatinine&#62; 1&#46;5 mg&#47;dL&#41; in a large study of anti-HCV seropositive veterans from the US was 4&#46;8&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">41</span></a> In a large cohort of HCV positive&#47;HIV positive patients from North America&#44; the unadjusted frequency of low GFR &#40;GFR &#60; 60 mL&#47;min&#47;1&#46;73 m<span class="elsevierStyleSup">2</span>&#41; at baseline ranged between 3&#46;7&#37; and 4&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">42</span></a> Based on modified K&#47;DOQI guidelines&#44; serial measurements of eGFR and proteinuria were obtained in a large cohort of metropolitan residents in the US- the prevalence of CKD was greater among anti-HCV positive&#47;HCV RNA positive patients compared to &#40;age-&#44; race-&#44; and gender-matched&#41; anti-HCV negative controls&#44; 9&#46;1&#37; <span class="elsevierStyleItalic">vs&#46;</span> 5&#46;1&#37;&#44; P &#60; 0&#46;04&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">43</span></a></p><p id="p0075" class="elsevierStylePara elsevierViewall">There is emerging information concerning the role of HCV in extra-hepatic manifestations&#44; including metabolic derangements and&#44; more recently&#44; accelerated atherosclerosis&#46; An accelerated atherosclerosis at kidney level induced by HCV has been mentioned&#46; Atherosclerosis&#44; either sublinical or manifest&#44; is a chronic inflammatory disease&#59; in addition to the &#8216;traditional&#8217; factors of atherosclerosis other &#8216;novel&#8217; factors &#40;such as chronic HCV infection&#41; have been advocated&#46; The possible role of an infectious agent in the development of experimental atherosclerosis in rodents was reported more than a century ago<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">44</span></a> and this hypothesis had gained renewed interest recently&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">45</span></a>It is likely that HCV promotes atherogenesis through several direct and indirect biological mechanisms&#46; HCV RNA sequences have been isolated from carotid plaques&#58;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">46</span></a> HCV could play a direct atherogenic role by inducing arterial inflammation&#46; Chronic HCV causes hepatic&#44; systemic inflammation and hepatic steatosis which is currently considered an early mediator of atherosclerosis&#46; Steatosis promotes the development of atherosclerosis through multiple factors including insulin resistance&#44; hypo-adiponectinemia&#44; metabolic syndrome&#44; oxidative stress&#44; hyper-homocysteinaemia&#44; and increased synthesis of tumor necrosis factor-alpha&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">24-28</span></a> These activities occur independently of traditional known risk factors such as smoking&#44; hypercholesterolemia&#44; and hypertension&#46; In addition to local hepatic inflammation&#44; a concomitant low-grade systemic inflammation has been mentioned in several reports&#44; as suggested by activation of blood mono-cytes&#44; higher levels of systemic markers of inflammation&#44; particularly fibrinogen&#44; C reactive protein&#44; erythrocyte sedimentation rate&#44; and N-terminal pro-brain natriuretic peptide&#46;</p></span><span id="s0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0075">Impact of HCV upon CKD&#58; additional data</span><p id="p0080" class="elsevierStylePara elsevierViewall">Chronic kidney disease affects 4&#37;-13&#37; of the Western adult population and over 25&#37; of individuals older than 65 years&#46; Recent data emphasized the rising prevalence of CKD in the general population&#44; this is related to the rising epidemic of its risk factors such as overweight&#44; diabetes mellitus&#44; arterial hypertension&#44; smoking&#44; and ageing&#46; The high morbidity&#44; mortality and health care costs associated with CKD have led investigators to search for non-traditional risk factors such as chronic hepatitis C virus infection&#46; Hepatitis C virus infection is endemic worldwide&#44; with an estimated global prevalence of 3&#37; &#40;approximately 170 million infected people&#41;&#46; Hepatitis C virus has hepatic and extra-hepatic manifestations and has been implicated in perturbation of multiple organ systems including the ocular&#44; skeletal&#44; nervous&#44; cardiovascular systems and skin&#46; In addition&#44; HCV has a deleterious impact on psyco-social status&#46;</p><p id="p0085" class="elsevierStylePara elsevierViewall">Renal involvement by hepatitis C virus was first reported more than two decades ago&#59; the knowledge of the association between HCV and chronic kidney disease &#40;low eGFR or abnormal proteinuria&#41; in the adult general population was limited and controversial until a few years ago&#46; A growing body of evidence has recently highlighted the detrimental role of HCV infection on the risk of chronic kidney disease&#46; Cohort studies performed in various patient groups<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">38-43&#44;47&#44;48</span></a> demonstrated a significant relationship between anti-HCV positive serologic status and accelerated progression of chronic kidney disease&#46; Soma&#44; <span class="elsevierStyleItalic">et al&#46;</span> evaluated 123 patients &#40;24 anti-HCV seropositive&#41; with type 2 diabetic-related nephropathy over a 27-month follow-up&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">47</span></a> In their multiple linear regression analysis adjusted for the effect of several covariates &#40;age&#44; gender&#44; blood pressure&#44; gli-catedhaemoglobin&#44; urinary protein excretion&#44; and histologic parameters&#41; urinary protein excretion &#40;P &#61; 0&#46;011&#41;&#44; severe arteriolar hyalinosis &#40;P &#61; 0&#46;006&#41;&#44; and anti-HCV positive &#40;P &#60; 0&#46;001&#41; serologic status were significantly associated with a decline of renal function as reflected by the slope of reciprocal serum creatinine &#40;1&#47;Scr&#41;&#46;</p><p id="p0090" class="elsevierStylePara elsevierViewall">Noureddine and coworkers<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">49</span></a> at the Indiana University School of Medicine retrospectively identified 111 patients &#40;21&#37; showing anti-HCV antibody in serum&#41; with primary glomerulonephritis on kidney biopsy over 4 years&#44; and evaluated the progression of CKD over time&#46; The hepatitis C-positive subjects were more likely to be African American &#40;P &#61; 0&#46;031&#41;&#44; followed for fewer days &#40;P &#61; 0&#46;007&#41; and have diabetes and focal segmental glomerulosclerosis on biopsy &#40;P &#60; 0&#46;001&#41;&#46; Longitudinal follow-up of CKD progression using multiple creatinine measures analyzed by repeated measures ANCOVA demonstrated an increase in serum creatinine of 1&#46;3 mg&#47;dL&#47;year for hepatitis C subjects compared to either hepatitis C-negative or those not tested &#40;P &#60; 0&#46;001&#41;&#46;</p><p id="p0095" class="elsevierStylePara elsevierViewall">Ble&#44; <span class="elsevierStyleItalic">et al&#46;</span><a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">50</span></a> discovered that a sustained viral response was associated with improved kidney function among liver transplant recipients treated for HCV infection&#46; All treated LT recipients with a minimum observation period of at least 1 year since the end of antiviral treatment &#40;n &#61; 175 LT patients&#41; were identified&#46; In the subset of patients &#40;n &#61; 99&#41; with stage 2 CKD before antiviral treatment&#44; the median changes in the MDRD-4 values before treatment to 1&#44; 3&#44; and 5 years after treatment were -0&#46;5&#44; 4&#46;5&#44; and 9&#46;4 mL&#47;min for the SVR patients and -1&#44; -0&#46;3&#44; and -1&#46;5 mL&#47;min for the non-responder recipients &#40;NRs&#41; &#40;P &#61; 0&#46;6&#44; P &#61; 0&#46;06&#44; and P &#61; 0&#46;004&#44; respectively&#41;&#46; In the multivariate analysis&#44; there was a relationship between kidney dysfunction at the last follow-up and NRs &#91;relative risk &#40;RR&#41; 3&#46;8&#59; 95&#37; confidence intervals &#40;CIs&#41; &#61; 1&#46;3&#59; 11&#46;23&#44; P &#61; 0&#46;01&#93;&#44; MDRD-4 values at the end of treatment &#40;EOT&#41; &#40;RR &#61; 1&#46;022&#44; 95&#37; CI &#61; 1&#46;001&#59; 1&#46;04&#44; P &#61; 0&#46;04&#41;&#44; and female gender &#40;RR &#61; 5&#46;6&#44; 95&#37; CI &#61; 1&#46;84&#59; 17&#46;5&#44; P &#61; 0&#46;002&#41;&#46;</p><p id="p0100" class="elsevierStylePara elsevierViewall">Another piece of evidence regarding the link between chronic HCV and CKD comes from additional epidemio-logical studies&#46; Various authors found that the prevalence of anti-HCV antibody was significantly higher in patients with chronic kidney disease before reaching end-stage renal disease than in a healthy population&#44; independent of blood transfusions&#46;<a class="elsevierStyleCrossRefs" href="#bib0260"><span class="elsevierStyleSup">51&#44;52</span></a> Iwasa&#44; <span class="elsevierStyleItalic">et al&#46;</span><a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">52</span></a> enrolled 400 patients who began regular haemodialysis between February 2003 and June 2007 at Tokyo University School of Medicine&#46; As healthy controls they used healthy blood donors &#40;n &#61; 70&#44;717&#41; with data were obtained from Tokyo Metropolitan Red Cross Blood Center&#46; The anti-HCV antibody prevalence rate among the patients who were new to haemodialysis was 7&#46;3&#37;&#44; as opposed to 0&#46;15&#37; in the healthy volunteers&#46; The prevalence of anti-HCV seropositive status in the 31-45-&#44; 46-60-&#44; and 61-year-old groups was significantly higher among the haemodialysis patients than among the healthy volunteers &#40;P &#61; 0&#46;0209&#44; P &#60; 0&#46;0001&#44; and P &#60; 0&#46;0001&#44; respectively&#41;&#46; Among the anti-HCV-antibody-positive patients&#44; 55&#46;2&#37; had received a blood transfusion&#46; The rate was significantly higher than among the anti-HCV-antibody-negative patients &#40;19&#46;4&#37;&#44; P &#60; 0&#46;0001&#41;&#46; The authors concluded that the frequency of anti-HCV antibody positivity was greater in patients new to haemodialysis than in healthy volunteers&#46; Older age&#44; blood transfusion&#44; male gender&#44; and diabetic ne-phropathy seemed to be risk factors for anti-HCV antibody positivity in Japan&#46;</p><p id="p0105" class="elsevierStylePara elsevierViewall">The relationship between anti-HCV antibody positive status and chronic kidney disease has been also addressed among HIV infected populations&#46; In the Women&#39;s Intera-gency HIV study&#44; anti-HCV positive serologic status was independently associated with a fully adjusted net decrease in eGFR of approximately 5&#37; per year &#40;95&#37; confidence interval&#44; 3&#46;2 to 7&#46;2&#41; relative to women who were seronega-tive&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">53</span></a> One systematic review had been already published on the impact of HIV&#47;HCV co-infection on the incidence of CKD&#59;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">54</span></a> we performed a meta-analysis and retrieved 19 studies &#40;n &#61; 146&#44;1151 unique patients with HIV infec-tion&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">55</span></a> Aggregation of longitudinal studies &#40;n &#61; 8&#59; n &#61; 105&#44;462 unique patients&#41; showed a link between anti-HCV positive serologic status and increased risk of reduced glomerular filtration rate among HIV-infected patients&#44; the summary estimate for adjusted hazard ratio &#40;aHR&#41; was 1&#46;64 &#40;95&#37; CI&#44; 1&#46;28&#59; 2&#46;0&#44; P &#60; 0&#46;001&#41; of incidence of CKD in HIV-HCV co-infected individuals compared with mono-infected HIV positive individuals&#46; No between-studies heterogeneity was found &#40;P-value by Q test &#61; 0&#46;08&#41;&#46; Anti-HCV antibody positive serologic status was an independent risk factor for proteinuria in HIV-infected population&#59; adjusted effect estimate&#44; 1&#46;23 &#40;95&#37; CI&#44; 1&#46;18&#59; 1&#46;28&#44; P &#61; 0&#46;001&#41; &#40;n &#61; 6 studies&#44; n &#61; 26&#44;835 unique patients&#41;&#46; In meta-regression&#44; we noted the impact of ageing &#40;P &#61; 0&#46;0001&#41; upon the adjusted hazard ratio of incidence of reduced glomerular filtration rate among HCV-HIV co-infected populations&#46;</p><p id="p0110" class="elsevierStylePara elsevierViewall">HCV co-infection appears as a risk factor for increased healthcare resource utilization in HIV-infected individuals in the USA&#59; multivariate Poisson model showed that HCV co-infection was associated with higher frequency of emergency department visits&#44; aRR 2&#46;07 &#40;95&#37; CI 1&#46;49&#59; 2&#46;89&#41;&#44; P &#60; 0&#46;001&#46; In addition to liver injury&#44; renal disease &#40;37&#37; <span class="elsevierStyleItalic">vs&#46;</span> 12&#37;&#41; played a larger role&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">56</span></a></p><p id="p0115" class="elsevierStylePara elsevierViewall">Classically&#44; HCV infection predisposes to cryoglob-ulinemicmembrano-proliferative glomerulonephritis or non-cryoglobulinemic glomerular disease&#59; however&#44; HCV-positive individuals may also be at risk for kidney injury secondary to end-stage liver disease&#44; injecting drug use&#44; concomitant HIV or HBV co-infection&#46; Also&#44; an accelerated atherosclerosis may increase the risk of developing kidney disease among HCV-infected individuals&#46; The data reported above promote the screening for CKD among HCV-infected individuals even in the absence of traditional risk factors for kidney disease&#46;</p></span><span id="s0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0080">HCV&#44; metabolic changes and chronic kidney disease</span><p id="p0120" class="elsevierStylePara elsevierViewall">Data from the 1988 to 1994 NHANES &#40;National Health and Nutrition Examination Survey&#41; have shown a significant and independent relationship between insulin resistance&#44; diabetes mellitus and HCV infection&#46; The rapid increase in the prevalence of obesity has been cited to explain the absence of relationships between insulin resistance&#44; HCV&#44; and diabetes in later NHANES surveys &#40;1998-2008&#41;&#46; Multiple additional studies have suggested a link between chronic HCV&#44; insulin resistance&#44; type 2 diabetes mellitus&#44; and subsequent steatosis&#46; In their longitudinal study on 4&#44;958 individuals from southern Taiwan&#44; Wang&#44; <span class="elsevierStyleItalic">et al&#46;</span> found that anti-HCV positive serologic status &#40;hazard ratio&#44; 1&#46;7&#44; 95&#37; CI&#44; 1&#46;3-2&#46;1&#41;&#44; HBV&#47;HCV co-infection &#40;hazard ratio &#61; 1&#46;7&#41;&#44; overweight&#44; obesity&#44; and ageing were significantly associated with diabetes &#40;P &#60; 0&#46;05&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">57</span></a> The authors concluded that HCV infection is an independent risk factor for diabetes&#44; especially for HCV positive patients who are younger or have a greater body mass index&#46; Clearance of HCV RNA from serum by combined antiviral therapy &#40;pegylated interferon and ribavirin&#41; reduced insulin resistance at 12 and 24 weeks and at the end of antiviral therapy &#40;24 or 48 weeks&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">58</span></a></p><p id="p0125" class="elsevierStylePara elsevierViewall">Another metabolic consequence of chronic HCV is hepatic steatosis&#46; Hepatic steatosis is a distinguishable feature of HCV infection&#46; It remain uncertain whether steatosis is directly related to the presence of HCV or results from host-related factors&#46; Growing experimental and epidemiological data suggests that HCV infection&#44; non-alcoholic fatty liver disease and CKD share common pathogenic mechanisms and interactions&#46; NAFLD encompasses a histologic spectrum ranging from simple steatosis to non-alcoholic steato-hepatitis NASH&#44; the latter with or without advanced fibrosis&#46; In a recent systematic review with meta-analysis of clinical studies &#40;n &#61; 32 studies&#44; n &#61; 63&#44;902 participants&#41;&#44; Musso&#44; <span class="elsevierStyleItalic">et al&#46;</span> found that NAFLD was associated with a greater risk of prevalent &#40;Odds Ratio&#44; 2&#46;12&#44; 95&#37; CI&#44; 1&#46;69&#59; 2&#46;66&#41; and incident &#40;HR&#44; 1&#46;79&#44; 95&#37; CI&#44; 1&#46;65&#59; 1&#46;95&#41; chronic kidney disease&#46; These associations remained statistically significant in diabetic and non-diabetic individuals&#44; as well as in studies adjusting for conventional risk factors for CKD and were independent from insulin resistance and obesity&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">59</span></a></p></span><span id="s0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0085">Anti-HCV therapy and extra-hepatic outcomes</span><p id="p0130" class="elsevierStylePara elsevierViewall">Of note&#44; antiviral therapy towards HCV significantly improves hepatic and extra-hepatic outcomes in the general population<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">60</span></a> and among patients co-infected with HIV and HCV&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">61</span></a> A population-based study in Taiwan has retrospectively shown that interferon-based therapy &#40;IBT&#41; reduces the risk of stroke in patients with chronic hepatitis C&#46; 208 patients who received IBT for more than 3 months were included in the IBT cohort&#44; and 2&#44;875 subjects who did not receive IBT between 2004 and 2008 were included in the non-IBT cohort&#46; The median duration of follow-up was 4&#46;78 years&#46; Use of IBT &#40;defined as treatment with in-terferon alpha&#44; pegylated interferon alpha-2a or pegylated interferon alpha-2b for at least 3 months&#41; significantly reduced the risk of stroke in HCV patients &#40;adjusted HR &#61; 0&#46;39&#44; 95&#37; CI &#61; 0&#46;16&#59; 0&#46;95&#44; P &#61; 0&#46;039&#41; after adjusting for known prognostic factors &#40;age&#44; gender&#44; co-morbidities&#44; health behaviour&#44; and drugs&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">60</span></a></p><p id="p0135" class="elsevierStylePara elsevierViewall">According to an updated review&#44; a total of six studies have addressed the impact of IFN-based regimens on the progression of chronic kidney disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">43&#44;62-66</span></a> In five<a class="elsevierStyleCrossRefs" href="#bib0220"><span class="elsevierStyleSup">43&#44;62-65</span></a> multivariate analysis suggested that treatment of HCV infection may improve per se renal survival &#40;<a class="elsevierStyleCrossRef" href="#t0015">Table 2</a>&#41;&#46; In the nationwide cohort study based on the Taiwan National Health Insurance Research Database &#40;NHIRD&#41;&#44; a total of 12&#44;384 eligible patients who had received antiviral treatment &#40;pegylated interferon plus ribavirin&#41; towards HCV were matched 1&#58; 2 with 24&#44;768 untreated controls&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">62</span></a> The treated and untreated cohorts were followed for a mean duration of 3&#46;3 <span class="elsevierStyleBold">&#40;&#43;</span>2&#46;5&#41; and 3&#46;2 <span class="elsevierStyleBold">&#40;&#43;</span>2&#46;4&#41; years&#44; respectively&#46; The calculated 8-year cumulative incidences of end-stage renal disease between treated and untreated patients were 0&#46;15&#37; <span class="elsevierStyleItalic">vs&#46;</span> 1&#46;32&#37; &#40;P &#60; 0&#46;001&#41;&#46; Multivariate-adjusted Cox regression revealed that antiviral treatment was associated with lower risk of end-stage renal disease &#40;HR&#44; 0&#46;15&#59; 95&#37; CI&#44; 0&#46;07&#59; 0&#46;31&#44; P &#60; 0&#46;001&#41;&#46; Antiviral treatment was also associated with an adjusted HR of 0&#46;77 &#40;95&#37; CI&#44; 0&#46;62&#59; 0&#46;97&#44; P &#61; 0&#46;026&#41; for acute coronary syndrome&#44; and 0&#46;62 &#40;95&#37; CI&#44; 0&#46;46&#59; 0&#46;83&#44; P &#61; 0&#46;001&#41; for ischemic stroke&#46; These associations were invalid in incompletely treated patients &#40;duration of antiviral treatment&#44; &#60; 16 weeks&#41;&#46; Various confounders entered the multivariate analysis&#44; including death as a competing cause of risk&#46; An important limitation of the current study is that the NHIRD does not contain information regarding virology such as the viral genotype&#44; the sustained viral response to antiviral therapy&#44; and the HCV viral load&#46;</p><elsevierMultimedia ident="t0015"></elsevierMultimedia><p id="p0140" class="elsevierStylePara elsevierViewall">Another survey from the NHIRD database&#44; a single payer system that covers nearly the entire population of Taiwan&#44; compared the risk of chronic kidney disease in patients &#40;n &#61; 919&#41; who received three months or more of interferon-based therapy with controls &#40;n &#61; 3&#44;676 patients&#59; untreated cohort&#41; matched by propensity score&#46; The adjusted HR for CKD in patients treated with inter-feron-based therapy was 0&#46;42 &#40;95&#37; CI&#44; 0&#46;20&#59; 0&#46;92&#44; P &#61; 0&#46;03&#41;&#46; Multivariable stratified analysis revealed that the greater risk reduction of CKD occurred among HCV-in-fected patients with hyperlipidemia&#44; diabetes mellitus&#44; arterial hypertension&#44; and those without coronary artery disease&#46;<a class="elsevierStyleCrossRef" href="#bib0320"><span class="elsevierStyleSup">63</span></a></p><p id="p0145" class="elsevierStylePara elsevierViewall">Improved renal &#40;and cardiovascular&#41; outcomes after antiviral treatment for hepatitis C virus infection have been observed in diabetic patients residents in Taiwan&#44; according to the NHIRD&#46; A total of 1&#44;411 eligible patients who received pegylated interferon plus ribavirin &#40;treated cohort&#41;&#44; and matched 1&#58;1 with 1&#44;411 untreated controls by propensity scores were enrolled&#46; The authors included an additional group of 5&#44;644 diabetic patients without HCV infection &#40;uninfected cohort&#41; matched 4&#58;1 with the treated cohort&#46; From 2003 to 2011&#44; the 8-year cumulative incidences of end-stage renal disease in the treated&#44; untreated&#44; and uninfected cohorts were 1&#46;1&#37; &#40;95&#37; CI&#44; 0&#46;3&#59; 2&#46;0&#41;&#44; 9&#46;3&#37; &#40;95&#37; CI&#44; 5&#46;94&#59; 12&#46;7&#41;&#44; and 3&#46;3&#37; &#40;95&#37; CI&#44; 2&#46;3&#59; 4&#46;3&#41; &#40;P &#60; 0&#46;001&#41;&#46; As compared with the untreated cohort&#44; antiviral treatment was associated with multivariate-adjusted hazard ratio of 0&#46;16 &#40;95&#37; CI&#44; 0&#46;07&#59; 0&#46;33&#41; for ESRD and 0&#46;53 &#40;95&#37; CI&#44; 0&#46;3&#59; 0&#46;93&#41; for ischemic stroke&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">64</span></a></p><p id="p0150" class="elsevierStylePara elsevierViewall">Similar findings have been obtained from studies performed in other countries&#46; Arase<span class="elsevierStyleItalic">&#44; et al</span>&#46; retrospectively followed 650 HCV-infected&#44; liver cirrhotic patients who were treated with interferon and had an estimated glomer-ular filtration rate &#40;eGFR&#41; of &#62; 60 mL&#47;min per 1&#46;73m<span class="elsevierStyleSup">2</span> after termination of interferon therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">65</span></a> The cumulative development rate of end-stage renal disease was determined to be 0&#46;4&#37; at the 5th year&#44; 1&#46;6&#37; at the 10th year and 2&#46;8&#37; at the 15th year by Kaplan-Meier method&#46; Multivari-ate Cox proportional hazard analysis showed that ageing&#44; diabetes&#44; hypertension&#44; and non-clearance of HCV &#40;HR&#44; 2&#46;67&#59; 95&#37; CI&#44; 1&#46;34&#59; 5&#46;32&#59; P &#61; 0&#46;005&#41; were risk factors for CKD&#46; In a hospital-based study from the US&#44; 552 HCV-infected American patients were retrospectively evaluated and 159 received IFN therapy during a 7-year follow-up&#46; The prevalence of CKD in the anti-HCV positive group was greater compared to controls &#40;313 patients without HCV infection matched for age&#44; race&#44; gender&#41;&#44; 9&#46;6&#37; <span class="elsevierStyleItalic">vs&#46;</span> 5&#46;1&#37;&#44; P &#61; 0&#46;02&#46; Multivariate logistic regression analysis&#44; performed in patients with serum positive for antibody for HCV&#44; showed that history of IFN treatment was an independent negative predictor for CKD &#40;OR&#44; 0&#46;18&#59; 95&#37; CI&#44; 0&#46;06&#59; 0&#46;56&#44; P &#60; 0&#46;003&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">65</span></a></p><p id="p0155" class="elsevierStylePara elsevierViewall">The Italian multicenter survey demonstrated conflicting findings&#46; The impact of sustained viral response to hepatitis C virus therapy on the outcome of extra-hepatic complications &#40;occurrence of CKD&#44; diabetes&#44; and cardiovascular disease&#41; was addressed in a cohort of human immunodeficiency virus &#8211;infected patients&#46; A total of 1&#44;676 patients from the Italian Management of Standardized Evaluation of Retroviral HIV Infection &#40;MASTER&#41; cohort were included&#44; 340 &#40;20&#46;3&#37;&#41; patients initiated an interferon-based regimen and 102 &#40;30&#37;&#41; achieved SVR during the observation period&#46; In the Cox regression model for treated patients&#44; there was no association between SVR and lower risk of CKD&#44; 1&#46;05 &#40;0&#46;29&#59; 3&#46;9&#41; &#40;NS&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">66</span></a></p><p id="p0160" class="elsevierStylePara elsevierViewall">Theoretically&#44; a randomised-placebo controlled trial is the ideal design to clarify how antiviral treatment improves extra-hepatic outcomes of HCV&#46; On the other hand&#44; critical events commonly take time to develop&#44; as they occur at a low incidence in an average-risk population&#46; A great sample size with a long follow-up would be required&#59; in addition&#44; randomisation to placebo can hardly be considered as ethically acceptable nowadays for HCV-infected patients&#44; as safe and effective drugs for anti viral therapy of HCV are currently available&#46; The mechanisms underlying such relationships remain unclear&#59; it has been suggested that HCV promotes atherogenesis through direct and indirect mechanisms&#46; Clinical trials are in progress to assess whether the clearance of HCV RNA from serum by direct-acting antiviral drugs &#40;DAAs&#41; &#40;<a class="elsevierStyleCrossRef" href="#f0015">Figure 2</a>&#41; &#40;instead of IFN-based therapies&#41; reduces the frequency of cardiovascular disease in dialysis patients and chronic kidney disease in the adult general population&#46;</p><elsevierMultimedia ident="f0015"></elsevierMultimedia></span><span id="s0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0090">Discussion and Conclusions</span><p id="p0165" class="elsevierStylePara elsevierViewall">Many epidemiological and experimental data have been recently accumulated suggesting that active HCV infection is linked to an increased incidence or progression of CKD in the adult general population&#46; Also&#44; it appears that a greater CV risk exists in patients on maintenance dialysis with active HCV&#46; However&#44; despite the growing evidence&#44; it has not been definitively established whether causal relationships occur&#46; The evidence reported above suggest that patients with HCV should be screened for CKD even in the absence of conventional risk factors for CKD&#46; We urgently need randomized&#44; double-blind&#44; placebo-controlled trials regarding the impact of the treatment for liver disease in HCV-posi-tive patients on the incidence and progression of CKD in the general population&#46; Clinical trials are ongoing to assess whether the clearance of HCV RNA from serum by direct-acting antiviral drugs reduces all-cause or disease-specific &#40;cardiovascular&#41; mortality among patients on maintenance dialysis&#46;</p></span></span><span id="s0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0095">Abbreviations</span><p id="p0170" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="l0010"><li class="elsevierStyleListItem" id="u0010"><span class="elsevierStyleLabel">&#8226;</span><p id="p0175" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">CDC&#58;</span> Centers for Disease Control and Prevention&#46;</p></li><li class="elsevierStyleListItem" id="u0015"><span class="elsevierStyleLabel">&#8226;</span><p id="p0180" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">CI&#58;</span> confidence intervals&#46;</p></li><li class="elsevierStyleListItem" id="u0020"><span class="elsevierStyleLabel">&#8226;</span><p id="p0185" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">CKD&#58;</span> chronic kidney disease&#46;</p></li><li class="elsevierStyleListItem" id="u0025"><span class="elsevierStyleLabel">&#8226;</span><p id="p0190" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">CV&#58;</span> cardiovascular&#46;</p></li><li class="elsevierStyleListItem" id="u0030"><span class="elsevierStyleLabel">&#8226;</span><p id="p0195" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">DAAs&#58;</span> direct-acting antiviral agents&#46;</p></li><li class="elsevierStyleListItem" id="u0035"><span class="elsevierStyleLabel">&#8226;</span><p id="p0200" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">eGFR&#58;</span> estimated glomerular filtration rate&#46;</p></li><li class="elsevierStyleListItem" id="u0040"><span class="elsevierStyleLabel">&#8226;</span><p id="p0205" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">ESRD&#58;</span> end-stage renal disease&#46;</p></li><li class="elsevierStyleListItem" id="u0045"><span class="elsevierStyleLabel">&#8226;</span><p id="p0210" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">HBV&#58;</span> hepatitis B virus&#46;</p></li><li class="elsevierStyleListItem" id="u0050"><span class="elsevierStyleLabel">&#8226;</span><p id="p0215" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">HCV&#58;</span> hepatitis C virus&#46;</p></li><li class="elsevierStyleListItem" id="u0055"><span class="elsevierStyleLabel">&#8226;</span><p id="p0220" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">HCV RNA&#58;</span> hepatitis C virus viremia&#46;</p></li><li class="elsevierStyleListItem" id="u0060"><span class="elsevierStyleLabel">&#8226;</span><p id="p0225" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">HD&#58;</span> haemodialysis&#46;</p></li><li class="elsevierStyleListItem" id="u0065"><span class="elsevierStyleLabel">&#8226;</span><p id="p0230" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">HIV&#58;</span> human immunodeficiency virus&#46;</p></li><li class="elsevierStyleListItem" id="u0070"><span class="elsevierStyleLabel">&#8226;</span><p id="p0235" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">HR&#58;</span> hazard ratio&#46;</p></li><li class="elsevierStyleListItem" id="u0075"><span class="elsevierStyleLabel">&#8226;</span><p id="p0240" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">HD&#58;</span> haemodialysis&#46;</p></li><li class="elsevierStyleListItem" id="u0080"><span class="elsevierStyleLabel">&#8226;</span><p id="p0245" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">I</span><span class="elsevierStyleSup"><span class="elsevierStyleBold">2</span></span><span class="elsevierStyleBold">&#58;</span> ratio of true heterogeneity to total variation in observed effects&#46;</p></li><li class="elsevierStyleListItem" id="u0085"><span class="elsevierStyleLabel">&#8226;</span><p id="p0250" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">NA&#58;</span> not available&#46;</p></li><li class="elsevierStyleListItem" id="u0090"><span class="elsevierStyleLabel">&#8226;</span><p id="p0255" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">NAFLD&#58;</span> non-alcoholic fatty liver disease&#46;</p></li><li class="elsevierStyleListItem" id="u0095"><span class="elsevierStyleLabel">&#8226;</span><p id="p0260" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">NASH&#58;</span> non-alcoholic steato-hepatitis&#46;</p></li><li class="elsevierStyleListItem" id="u0100"><span class="elsevierStyleLabel">&#8226;</span><p id="p0265" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">RCT&#58;</span> randomized clinical trial&#46;</p></li><li class="elsevierStyleListItem" id="u0105"><span class="elsevierStyleLabel">&#8226;</span><p id="p0270" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">SVR&#58;</span> sustained virological response&#46;</p></li></ul></p></span></span>"
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          "titulo" => "Keywords"
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          "titulo" => "Introduction"
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          "titulo" => "Material and Methods"
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            0 => array:2 [
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              "titulo" => "Data Sources and Searches"
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          "identificador" => "s0025"
          "titulo" => "Results"
          "secciones" => array:7 [
            0 => array:2 [
              "identificador" => "s0030"
              "titulo" => "HCV and survival among patients on dialysis"
            ]
            1 => array:2 [
              "identificador" => "s0035"
              "titulo" => "HCV and survival among patients with intact kidney function"
            ]
            2 => array:2 [
              "identificador" => "s0040"
              "titulo" => "Impact of HCV upon CKD&#58; data from the general population"
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              "titulo" => "Impact of HCV upon CKD&#58; additional data"
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              "identificador" => "s0050"
              "titulo" => "HCV&#44; metabolic changes and chronic kidney disease"
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            5 => array:2 [
              "identificador" => "s0055"
              "titulo" => "Anti-HCV therapy and extra-hepatic outcomes"
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              "identificador" => "s0060"
              "titulo" => "Discussion and Conclusions"
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        5 => array:2 [
          "identificador" => "s0065"
          "titulo" => "Abbreviations"
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        6 => array:1 [
          "titulo" => "References"
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    "fechaRecibido" => "2017-03-03"
    "fechaAceptado" => "2017-04-05"
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec1117794"
          "palabras" => array:4 [
            0 => "Hepatitis C virus"
            1 => "Dialysis"
            2 => "Chronic kidney disease"
            3 => "Direct-acting antiviral agents"
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    "resumen" => array:1 [
      "en" => array:3 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abs0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0015">Introduction</span><p id="sp0030" class="elsevierStyleSimplePara elsevierViewall">Evidence has been accumulated during the last decade showing that HCV infection plays an important activity at hepatic and extra-hepatic level&#46; Chronic HCV is associated with a large spectrum of extra-hepatic manifestations including lympho-pro-liferative diseases and metabolic abnormalities &#40;such as insulin resistance and fatty liver disease&#41;&#46;</p></span> <span id="abs0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0020">Material and methods</span><p id="sp0035" class="elsevierStyleSimplePara elsevierViewall">We have performed an extensive review of the medical literature regarding the increased risk of cardiovascular and kidney disease that has been observed in various groups of HCV-infected patients&#46; The potential link between such increased risk and the metabolic consequences of chronic HCV infection has been explored&#46;</p></span> <span id="abs0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0025">Results</span><p id="sp0040" class="elsevierStyleSimplePara elsevierViewall">According to a systematic review with a meta-analysis of longitudinal studies &#40;n &#61; 9 clinical observational studies&#59; n &#61; 1&#44;947&#44;034 unique patients&#41;&#44; we found a strong relationship between positive anti-HCV serologic status and increased incidence of chronic kidney disease in the adult general population&#44; the summary estimate for adjusted hazard ratio was 1&#46;43 &#40;95&#37; confidence intervals&#44; 1&#46;23&#59; 1&#46;63&#44; P &#61; 0&#46;0001&#41; &#40;random-effects model&#41; in anti-HCV positive patients&#46; In another meta-analysis of clinical observational studies &#40;n &#61; 145&#44;608 unique patients on long term dialysis&#59; n &#61; 14 observational studies&#41;&#44; anti-HCV sero-positive status was an independent and significant risk factor for death in patients on maintenance dialysis&#46; The summary estimate for adjusted relative risk &#40;all-cause mortality&#41; was 1&#46;35 with a 95&#37; confidence interval &#40;CI&#41; of 1&#46;25&#59; 1&#46;47 &#40;P &#60; 0&#46;01&#41; in anti-HCV positive patients on maintenance dialysis&#46; An updated and stratified analysis &#40;n &#61; 4 studies&#44; n &#61; 91&#44;916 patients on maintenance dialysis&#41; resulted in an adjusted HR for cardiovascular mortality among anti-HCV positive patients of 1&#46;21 &#40;95&#37; CI&#44; 1&#46;06&#59; 1&#46;39&#41; &#40;P &#60; 0&#46;01&#41;&#59; the homogeneity assumption was not rejected&#46; The mechanisms underlying such relationships remain unclear&#59; it has been suggested that HCV promotes atherogenesis through direct and indirect mechanisms&#46;</p></span> <span id="abs0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0030">Conclusions</span><p id="sp0045" class="elsevierStyleSimplePara elsevierViewall">Clinical trials are under way to assess whether the clearance of HCV RNA from serum by direct-acting antiviral drugs reduces all-cause or disease-specific &#40;cardiovascular&#41; mortality among patients on maintenance dialysis&#46;</p></span>"
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          "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">Adjusted CV risk in HCV positive vs&#46; -negative dialysis patients&#58; Confidence Intervals Graph&#46;</p>"
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          "en" => "<p id="sp0015" class="elsevierStyleSimplePara elsevierViewall">The hepatitis C virus genome and the DAAs &#40;DAAs&#58; Direct &#8211; acting antiviral agents&#41;&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Author&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Year&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Country&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Prevalence&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Reference &#40;n&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Alashek N&#44; <span class="elsevierStyleItalic">et al&#46;</span>&nbsp;\t\t\t\t\t\t\n
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                  \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">2012&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Lybia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">31&#46;1&#37; &#40;738&#47;2&#44;382&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><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">Su Y&#44; <span class="elsevierStyleItalic">et al&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2013&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">China&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&#46;1&#37; &#40;131&#47;2&#44;120&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
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                  \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">Unmate I&#44; <span class="elsevierStyleItalic">et al&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nigeria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#37; &#40;15&#47;100&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><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">Zahran A&#44; <span class="elsevierStyleItalic">et al&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Egypt&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">49&#46;6&#37; &#40;255&#47;514&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><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">Lioussfi Z&#44; <span class="elsevierStyleItalic">et al&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Morocco&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">60&#37; &#40;40&#47;67&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><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">Dumaidi K&#44; <span class="elsevierStyleItalic">et al&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Palestine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">27&#37; &#40;40&#47;148&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><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">Schiller A&#44; <span class="elsevierStyleItalic">et al&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Romania&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">32&#37; &#40;194&#47;600&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><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">Duong M&#44; <span class="elsevierStyleItalic">et al&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vietnam&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&#37; &#40;8&#47;113&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><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">Vidales-Braz B&#44; <span class="elsevierStyleItalic">et al&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Brasil&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&#46;2&#37; &#40;58&#47;318&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><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">Aman K&#44; <span class="elsevierStyleItalic">et al&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yemen&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">40&#46;2&#37; &#40;88&#47;219&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><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">Malhotra R&#44; <span class="elsevierStyleItalic">et al&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">India&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">33&#46;5&#37; &#40;88&#47;262&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><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">Halle M&#44; <span class="elsevierStyleItalic">et al&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cameroon&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">20&#46;6&#37; &#40;20&#47;97&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">16&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><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">Hasanjani M&#44; <span class="elsevierStyleItalic">et al&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Iran&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#46;3&#37; &#40;40&#47;482&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" 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">Authors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Reference year&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Country&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Patients&#44; n&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Anti-HCV positive&#44; n&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Study&#44; type&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" 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">Satapathy S&#44; <span class="elsevierStyleItalic">et al&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2011&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">US&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">865&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">552 &#40;63&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cohort&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><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">Arase Y&#44; <span class="elsevierStyleItalic">et al&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2011&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Japan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">650&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">650 &#40;100&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cohort&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><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">Hsu Y&#44; <span class="elsevierStyleItalic">et al&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2014&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Taiwan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&#44;466&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#44;822 &#40;33&#46;3&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Case control&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><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">Hsu Y&#44; <span class="elsevierStyleItalic">et al&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Taiwan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">37&#44;152&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">37&#44;152 &#40;100&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Case control&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><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">Chen Y&#44; <span class="elsevierStyleItalic">et al&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2015&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Taiwan&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&#44;595&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">919 &#40;20&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Case control&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><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">Leone S&#44; <span class="elsevierStyleItalic">et al&#46;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Italy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;676&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#44;676 &#40;100&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cohort&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="sp0025" class="elsevierStyleSimplePara elsevierViewall">Clinical studies addressing the association between interferon-based regimens for HCV and the risk of chronic kidney disease in the general population&#46;</p>"
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      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
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          "bibliografiaReferencia" => array:66 [
            0 => array:3 [
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              "referencia" => array:1 [
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                  "contribucion" => array:1 [
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            3 => array:3 [
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                          "etal" => false
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                  "host" => array:1 [
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            4 => array:3 [
              "identificador" => "bib0030"
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                0 => array:2 [
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "Alashek W&#46;"
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                    0 => array:2 [
                      "doi" => "10.1186/1471-2334-12-265"
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                        "tituloSerie" => "BMC Infect Dis"
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                  "contribucion" => array:1 [
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                      "titulo" => "Prevalence and risk factors of hepatitis C and B virus infections in hemodialysis patients and their spouses&#58; a multi-center study in Beijing&#44; China"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:7 [
                            0 => "Su Y&#46;"
                            1 => "Yan R&#46;"
                            2 => "Duan Z&#46;"
                            3 => "Norris J&#46;"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
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                      "Revista" => array:6 [
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Risk factors for hepatitis C virus seropositivity among hemodialysis patients receiving care at kidney centre in a tertiary health facility in Maiduguri&#44; Nigeria"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "Unmate I&#46;"
                            1 => "Denue B&#46;"
                            2 => "Kida I&#46;"
                            3 => "Ohioma O&#46;"
                            4 => "Baba D&#46;"
                            5 => "Goni W&#46;"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
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                      "Revista" => array:5 [
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                        "paginaInicial" => "305"
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            7 => array:3 [
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prevalence of seroconversion of hepatitis C virus among hemodialysis patients in Menoufia Governorate&#44; Egypt"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "Zahran A&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Arab J Nephrol Transplant"
                        "fecha" => "2014"
                        "volumen" => "7"
                        "paginaInicial" => "133"
                        "paginaFinal" => "135"
                        "link" => array:1 [
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            8 => array:3 [
              "identificador" => "bib0050"
              "etiqueta" => "9&#46;"
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                0 => array:2 [
                  "contribucion" => array:1 [
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                      "titulo" => "Viral hepatitis C and B among dialysis patients at the Rabat University Hospital&#58; prevalence and risk factors"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:7 [
                            0 => "Lioussfi Z&#46;"
                            1 => "Errami Z&#46;"
                            2 => "Radoui A&#46;"
                            3 => "Rhou H&#46;"
                            4 => "Ezzaitouni F&#46;"
                            5 => "Ouzed-doun N&#46;"
                            6 => "Bayahia R&#46;"
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                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Saudi J Kidney Dis Transpl"
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                        "volumen" => "25"
                        "paginaInicial" => "672"
                        "paginaFinal" => "679"
                        "link" => array:1 [
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            9 => array:3 [
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                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Prevalence of occult HBV among haemodialysis patients in two districts in the northern part of the West Bank&#44; Palestine"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "Dumaidi K&#46;"
                            1 => "Al-Jawabreh A&#46;"
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/jmv.24008"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Med Virol"
                        "fecha" => "2014"
                        "volumen" => "86"
                        "paginaInicial" => "1694"
                        "paginaFinal" => "1699"
                        "link" => array:1 [
                          0 => array:2 [
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                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0060"
              "etiqueta" => "11&#46;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatitis B and C virus infection in the hemodi-alysis population from three Romanian regions"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:7 [
                            0 => "Schiller A&#46;"
                            1 => "Timar R&#46;"
                            2 => "Siriopol D&#46;"
                            3 => "Timar B&#46;"
                            4 => "Bob F&#46;"
                            5 => "Schiller O&#46;"
                            6 => "Drug V&#46;"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1159/000371450"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nephron"
                        "fecha" => "2015"
                        "volumen" => "129"
                        "paginaInicial" => "202"
                        "paginaFinal" => "208"
                        "link" => array:1 [
                          0 => array:2 [
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Article information
ISSN: 16652681
Original language: English
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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

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Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos