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Fabrizi, R. Cerutti, F.M. Donato, P. Messa" "autores" => array:4 [ 0 => array:4 [ "nombre" => "F." "apellidos" => "Fabrizi" "email" => array:1 [ 0 => "fabrizio.fabrizi@policlinico.mi.it" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "R." "apellidos" => "Cerutti" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "F.M." "apellidos" => "Donato" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "P." "apellidos" => "Messa" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Division of Nephrology, Dialysis and Renal Transplantation, Maggiore Policlinico Hospital and Cà Granda IRCCS Foundation, Milano, Italy" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Division of Gastroenterology and Hepatology, Maggiore Policlinico Hospital and Ca' Granda IRCCS Foundation, Milano, Italy" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "University School of Medicine, Milano, Italy" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "La infección por VHB es un factor de riesgo de enfermedad renal crónica: revisión sistemática y metaanálisis" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1700 "Ancho" => 2623 "Tamanyo" => 232651 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Flow diagram of study selection.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">It is currently estimated that around 257 million people worldwide are affected by hepatitis B virus (HBV) infection.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Liver-related complications such as cirrhosis and hepatocellular carcinoma are important causes of death among patients with chronic hepatitis B (CHB).<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Patients with CHB have numerous extra-hepatic co-morbidities, and significant associations between CHB and kidney function impairment,<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,3</span></a> as well as an increased risk of osteoporosis,<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> have been recently suggested. The diagnosis and treatment of CHB are frequently delayed<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>; thus, at present CHB patients tend to be older in age and have more co-morbidities which can complicate clinical management.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Chronic kidney disease (CKD) is a significant global public health issue, and presents numerous risk factors – some conventional and others unconventional in nature. Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections have been included in the latter group; in fact, studies performed in the last decade have associated chronic HCV infection with the risk of CKD in the general population<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> and among HIV-infected individuals.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> In addition, a link between HBV infection and a higher risk of developing reduced glomerular filtration rate (GFR) has also been observed.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,3</span></a> Extra-hepatic manifestations of CHB have been observed in up to 20% of patients infected with HBV, in both acute and chronic infections. The association between HBV infection and glomerular disease has been already addressed by various investigators.<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8,9</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The recent publication of numerous and extensive surveys on the relationship between HBV infection and frequency of CKD (reduced estimated GFR and/or detectable proteinuria) leads us to review once again the evidence on this point. We have performed a systematic review of the medical literature with a meta-analysis of clinical observational studies to assess whether HBV-infected individuals in the adult general population are at increased risk for the development and progression of CKD.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Material and methods</span><p id="par0020" class="elsevierStylePara elsevierViewall">This work is in agreement with the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement (Supplementary file 1).<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Data sources and searches</span><p id="par0025" class="elsevierStylePara elsevierViewall">Two authors (F.F. and R.C.) independently reviewed English-language citations from the national Library of Medicine’s Medline database dating from 1970 until February 28, 2019. Data on HBsAg status were not available before 1970, when the first HBsAg assay was manufactured. We conducted our search via four Medline database engines (Embase, Grateful Med, Ovid, and PubMed). Our search was limited to human studies and we applied the following algorithm to medical subject headings and free text words: (“HEPATITIS B”; “HEPATITIS B VIRUS INFECTION”; “HBsAg POSITIVE STATUS”; oy “HBc ANTIBODY POSITIVE STATUS”) and (“CHRONIC KIDNEY DISEASE”; “CKD”; “END-STAGE KIDNEY DISEASE”; “ESKD”; “END-STAGE RENAL DISEASE”; “ESRD”; “LOW GLOMERULAR FILTRATION RATE”; “RENAL IMPAIRMENT”; “RENAL INSUFFICIENCY”; “RENAL FAILURE”; or “PROTEINURIA”) and (“RELATIVE RISK”; “RISK RATIO”; “RR”; “ODDS RATIO”; “OR”; “HAZARD RATIO”; “HR”; or “INCIDENCE”). An additional search was performed with electronic searches of the Cochrane Library, manual searches of selected specialty journals were performed to identify all pertinent literature, and reference lists from qualitative topic reviews and published clinical studies were also searched as it was previously demonstrated that a Medline search alone might not be sensitive enough.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Data on study design, study period, patient characteristics, HBV prevalence, and kidney disease outcomes were abstracted. Authors of selected papers were contacted to obtain missing data and only data from individuals with known HBV status were included in the meta-analysis. Consensus was reached for all data. The studies were compared to eliminate duplicate reports for the same patients, which included contacting investigators when necessary. Eligibility and exclusion criteria were pre-specified.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Study selection</span><p id="par0030" class="elsevierStylePara elsevierViewall">Studies were included if they met the following inclusion criteria:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0035" class="elsevierStylePara elsevierViewall">They presented original data from cohort, case-control, or cross-sectional studies;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0040" class="elsevierStylePara elsevierViewall">The outcome of interest was clearly defined as incidence or prevalence of CKD, i.e., reduced GFR and/or detectable proteinuria in the adult general population;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0045" class="elsevierStylePara elsevierViewall">They provided adjusted risk estimates (hazard ratio [HR], odds ratio [OR]) and confidence intervals (CI) or enough data for these to be calculated.</p></li></ul></p><p id="par0050" class="elsevierStylePara elsevierViewall">If data on the same population were duplicated in more than one study, the most recent study was included in the analysis. We included studies wherein HBV infection was diagnosed by testing for HBsAg in serum and/or HBc antibody. Information on HBV serological status was collected at the time of enrolment. Surveys based on administrative codes (i.e., ICD-9) were also considered.</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Ineligible studies</span><p id="par0055" class="elsevierStylePara elsevierViewall">Studies were excluded if they reported inadequate data on the association between CKD and HBV seropositive status (e.g., incomplete information on HBV status or renal outcomes). Unpublished studies, studies that were only published in abstract form or as interim reports were excluded; letters and review articles were not considered for this systematic review.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Quality assessment</span><p id="par0060" class="elsevierStylePara elsevierViewall">Study quality was assessed using a five-point binary scale specifically developed for this study. The scale is based on the Newcastle/Ottawa Scale (NOS) with modifications in view of standard guidelines and our own judgment.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> The Newcastle-Ottawa Scale is a scoring system that assesses every aspect of an observational epidemiologic study from a methodological point of view. For this meta-analysis, we adopted those elements that were common to all epidemiologic designs and thus shortened the scale considerably. We adopted the following criteria labelled as ‘yes’ (1) or ‘no’ (2): (1) whether assessment of HBV infection was based on laboratory data (yes) or administrative codes or others (no); (2) whether the diagnosis of CKD was established by assessment of GFR and proteinuria with laboratory data (yes) or administrative codes or others (no); (3) whether the results of the confounding assessment were adjusted at least for age and gender, either in the design phase or in the analysis (yes), or not (no); (4) whether the non-exposed cohort was drawn from the same community as the exposed cohort (yes) or not (no); (5) whether the target population was clearly defined (yes), or on the contrary, was based on convenience sampling of subjects such as patients from a single consultation or volunteers or not explained (no). Throughout this assessment, when the information for a specific item was not provided by the authors, we labelled this item as ‘no’. Data extraction and quality scoring were performed independently by two reviewers (F.F. and F.M.D.) and the results were merged by consensus. The complete protocol for quality scoring is available on-line (Supplementary file 2). We carried out a pooled analysis on those studies that fulfilled at least three criteria and compared them with those that scored fewer than three. The evaluation of study quality did not include the quality of studies enrolled in the meta-analysis.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Outcomes measures</span><p id="par0065" class="elsevierStylePara elsevierViewall">We performed separate meta-analyses according to the outcome. One meta-analysis included cohort studies addressing the incidence of CKD or end-stage renal disease (ESRD), while another considered cross-sectional (or case-control) studies assessing the prevalence of CKD. An additional meta-analysis was performed to evaluate the prevalence of proteinuria. Staging of CKD was categorized according to the Kidney Disease Outcomes Quality Initiative (K/DOQI) definition, and the 4-variable MDRD equation or other formulas devised to estimate GFR on the basis of serum creatinine levels were adopted.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> The primary endpoint was to provide adjusted estimates of the risk (and 95% confidence intervals, CIs) of incidence (or prevalence) of CKD in the general population according to HBV serological status. A multivariate analysis was carried out to estimate the independent effect of HBV positive serological status on the frequency of CKD after adjusting for potential confounders (covariates) (e.g., age, gender, race/ethnicity, diabetes mellitus, and others). The cohort studies used the Cox regression analysis to assess the independent predictors of CKD incidence. Multiple logistic regression analyses were performed in cross-sectional surveys. An additional endpoint was the adjusted estimate of the risk (and 95% CIs) of prevalence of proteinuria in the adult general population according to HBV serological status. The Cox proportional hazards regression analysis was performed to evaluate the effect of HBV positive serological status per se on the incidence of CKD after adjustment for differential follow-up time and distribution of potential confounders.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Data synthesis and analysis</span><p id="par0070" class="elsevierStylePara elsevierViewall">We weighted the study-specific log OR for case-control and cross-sectional studies, and log hazard ratios for cohort studies by the inverse of their variance to obtain a pooled effect estimate and its 95% CIs. For each study, we adopted the estimate of the effect measure that was adjusted for the largest number of confounders. We present both fixed-effects and random-effects pooled estimates but used and reported the latter when heterogeneity occurred. We used the random-effects approach, as described by DerSimonian and Laird.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> The Cochrane <span class="elsevierStyleItalic">Q</span>-test was used to quantify heterogeneity.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> The <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span> statistic, which is the percentage of total variation across studies due to heterogeneity rather than chance, was also calculated.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> The null hypothesis of this test is the absence of heterogeneity. We explored the origin of heterogeneity by restricting the analysis to subgroups of studies defined by study characteristics such as country of origin, CKD stage, and others. Heterogeneity was also evaluated by meta-regression in order to look at the effect of potential and continuous covariates on the outcome of interest. Subgroup or stratified analyses and meta-regression were pre-specified. We performed random-effects meta-regression using the method of moments or maximum likelihood approaches where appropriate, with a single predictor allowed in each model (simple meta-regression). Publication bias was calculated using Egger’s test for funnel plot asymmetry. All analyses were performed with statistical package Comprehensive Meta-Analysis (CMA), version 2.0 (Biostat Inc., USA, 2005). A 5% significance level was adopted for risk. Every estimate was provided with its 95% CI.</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Results</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Literature review</span><p id="par0075" class="elsevierStylePara elsevierViewall">As shown in <a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>, we retrieved 722 articles of which 152 full-text papers were evaluated for eligibility. The complete list of articles is available by request from one of the authors (F.F.). Thirty-tree studies met our inclusion criteria and were published in 26 papers (4,604,406 unique patients), carried out on two continents.<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">17–42</span></a> We identified case-control (<span class="elsevierStyleItalic">n</span> = 5), cohort (<span class="elsevierStyleItalic">n</span> = 11), and cross-sectional (<span class="elsevierStyleItalic">n</span> = 17) studies that gave information on the risk of CKD in the same population. Some studies therefore contributed data on more than one kidney disease outcome, but each cohort was represented just once in any meta-analysis. There was 100% agreement between reviewers with respect to the final inclusion and exclusion of studies reviewed based on the predefined inclusion and exclusion criteria. Diagnosis of HBV infection was made by detecting the presence of hepatitis B virus surface antigen (HBsAg) in serum. In a few reports, the diagnosis of HBV infection was made through administrative databases (ICD-9 codes). One study addressed the rate of HBV infection by detecting HBcAb positive serological status while another survey identified HBV infection by patient medical history.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Patient and study characteristics</span><p id="par0080" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRefs" href="#tbl0005">Tables 1–4</a> and Supplementary Tables 1–2 (Supplementary file n.2) report some salient demographic and clinical characteristics of the subjects enrolled in the included studies. The mean age of patient cohorts ranged from 18.9 <span class="elsevierStyleUnderline">+</span> 0.5 to 72 years. The gender distribution ranged between 17.5% and 67.6% male. Eleven reports were from Taiwan, eight from China, two from Korea, Hong Kong and the USA, respectively, and one from Japan. The average follow-up ranged between 2 and 9.1 years in the cohort studies.</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0085" class="elsevierStylePara elsevierViewall">The quality scores ranged from 3 to 5 (cohort studies) and 4–5 (cross-sectional studies) (Supplementary file n.3).</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Summary estimate of outcome: incidence of CKD</span><p id="par0090" class="elsevierStylePara elsevierViewall">When all studies (<span class="elsevierStyleItalic">n</span> = 33) were analysed together (with pooled ORs expressed as HRs) a significant relationship between HBV and CKD risk in the general population was demonstrated (<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>). Significant heterogeneity was noted (<span class="elsevierStyleItalic">Q</span> value by chi-squared test, 227.5, <span class="elsevierStyleItalic">p</span> < 0.0001).</p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">Eleven cohort studies (<span class="elsevierStyleItalic">n</span> = 1,056,645 unique patients) gave information on the incidence of CKD (or ESRD) among HBV-positive patients. The relationship between HBV positive serological status and increased incidence of CKD was significant; the adjusted HR with HBV across the surveys was 1.40 (95% CI, 1.16; 1.69, <span class="elsevierStyleItalic">p</span> < 0.0001) (<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>). There was heterogeneity across the studies (<span class="elsevierStyleItalic">p</span> = 0.0001). The funnel plot (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>) and the corresponding results of the Egger’s test did not show evidence of publication bias (<span class="elsevierStyleItalic">p</span> = 0.127).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">As listed in <a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>, the association between positive HBV serological status and higher risk of CKD persisted (with pooled ORs expressed as HRs) when case-control (CC) studies alone (<span class="elsevierStyleItalic">n</span> = 4,315,277 patients) were considered and when CC and cohort studies were evaluated together (aHR of 1.39, 95% CI, 1.21; 1.59) (<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>).</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Summary estimate of outcome: prevalence of CKD</span><p id="par0105" class="elsevierStylePara elsevierViewall">Ten (3,222,545 patients) studies with cross-sectional designs addressed the prevalence of CKD, or reduced GFR, in HBV-infected patients. The association between HBV positive serological status and the prevalence of CKD was not significant, with an adjusted OR with HBV across the studies of 1.04 (95% CI, 0.90; 1.21), <span class="elsevierStyleItalic">p</span> < 0.055. Heterogeneity was observed (<span class="elsevierStyleItalic">Q</span>-value by chi-squared test, 68.09, <span class="elsevierStyleItalic">p</span> < 0.0001).</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Summary estimate of outcome: prevalence of proteinuria</span><p id="par0110" class="elsevierStylePara elsevierViewall">Eight studies (3,205,142 unique patients) evaluated the prevalence of proteinuria according to HBV positive serological status. Most (<span class="elsevierStyleItalic">n</span> = 7) studies had a cross-sectional design (<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>). No link between HBV infection and proteinuria was observed (<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>).</p><p id="par0115" class="elsevierStylePara elsevierViewall">Four studies defined proteinuria by semiquantitative analysis (urine protein dipstick test) and four measured albuminuria by spot urine albumin/creatinine ratio (<a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>).</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Sensitivity analysis</span><p id="par0120" class="elsevierStylePara elsevierViewall">To further evaluate the possibility that our results could be due to publication bias, we assumed that cross-sectional studies are the study type that is most likely to be rejected by journals in case of null results. We recalculated our pooled estimates under the following extreme assumptions: (1) published cross-sectional studies evaluating the impact of HBV on the risk of CKD in the adult general population are only half of the studies published on this point; (2) all unpublished studies found an OR of 1; (3) the unpublished studies gave the same prevalence of CKD as the average of the published studies. Under these extreme assumptions, the random effects pooled estimates showed increased risk [with pooled ORs expressed as relative risks (RRs)], aRR, 1.08 (95% CI, 1.02; 1.15) (<span class="elsevierStyleItalic">p</span> = 0.013).</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Meta-regression analysis</span><p id="par0125" class="elsevierStylePara elsevierViewall">As shown in <a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a> meta-regression demonstrated a positive impact of HBsAg positive serological status on the outcome of interest (adjusted HR of CKD incidence among HBV-positive patients) (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>). No link between the outcome of interest and a number of continuous variables (<a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a>) was observed.</p><elsevierMultimedia ident="tbl0030"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Discussion</span><p id="par0130" class="elsevierStylePara elsevierViewall">The association between HBV infection and glomerular damage was first reported by Combes et al. in 1971 in a patient with nephrotic syndrome due to membranous nephropathy and CHB.<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> Since then, further glomerular diseases such as minimal change disease, IgA nephropathy, membranoproliferative glomerulonephritis, and mesangial nephritis have been associated with chronic hepatic disease and some antigens such as HBsAg, HBeAg, and HBcAg. These disorders are frequent in Asian countries and uncommon in European areas.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> A systematic review of ours with a meta-analysis of observational studies had previously shown an independent impact of positive HBsAg serological status on the incidence of CKD in the general population.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Numerous and larger studies have been subsequently published on this issue. Accordingly, we have again summarized the scientific evidence and carried out a meta-analysis on exposure to HBV infection and the risk CKD among adults.</p><p id="par0135" class="elsevierStylePara elsevierViewall">This meta-analysis (<span class="elsevierStyleItalic">n</span> = 33, 7,849,849 patients) includes more than twice the number than our previous meta-analysis and highlights the association between positive serological status for HBV infection and greater incidence of CKD; pooling results from 11 cohort studies gave an adjusted HR of 1.40 (95% CI, 1.16; 1.69, <span class="elsevierStyleItalic">p</span> < 0.0001). The occurrence of significant heterogeneity clearly precluded more definitive conclusions, even if our stratified analysis showed homogeneous results in some comparisons.</p><p id="par0140" class="elsevierStylePara elsevierViewall">The relationship between HBV infection and CKD appears complex and bidirectional in nature – some forms of renal disease are induced by HBV infection and patients with CKD are at increased risk for acquiring HBV. Numerous findings suggest HBV plays a pivotal role in the acquisition and progression of CKD. In the HARPE survey (<span class="elsevierStyleItalic">n</span> = 260 patients), a total of 64.6% patients were found to have kidney disease; the prevalence of proteinuria and haematuria was 38.1% and 20.6%, respectively.<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> According to a retrospective cohort of 815 patients followed for a median follow-up of 4 years in the US, HBV patients not receiving antiviral therapy experienced age-related decline in eGFR at a rate comparable to that of the general population. However, renal function in HBV patients treated with NUCs declined more rapidly than expected and the loss was not entirely attributable to the antiviral agents per se.<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> Studies performed on liver transplant recipients or patients with normal function concluded that telbivudine (alone or with add-on adefovir therapy) can improve renal function during CHB treatment and this result has been linked to its antiviral activity. The improvement of eGFR induced by telbivudine was durable, unique and unrelated to HBV DNA titres.<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">45,46</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Chronic kidney disease is a global public health problem.<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> In the US, around 10% of non-institutionalized adults are estimated to have CKD; outcomes of CKD include not only progression to kidney failure, but complications such as reduced kidney function and increased risk of cardiovascular disease. Patients with CKD are more likely to die, mostly from CKD, than to develop kidney failure. Chronic hepatitis B is an inflammatory condition and various diseases with chronic low-grade inflammation have been reported to increase the risk of atherosclerosis.<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> A few pieces of evidence support a relationship between HBV and atherosclerotic disease in humans<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">49,50</span></a> Patients with CHB have higher levels of fasting insulin, HOMA-IR index, and a lower QUICKI index.<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> A case report from Korean authors reported the case of a 34-year-old man with chronic HBV and multiple cerebral arterial stenosis without any risk factor for atherosclerosis.<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> Another study from Turkey showed that HBsAg carriers have a higher mean platelet volume which is considered to be an emerging risk factor for atherothrombosis.<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">The current meta-analysis has numerous limitations. Firstly, the majority of studies came from Asia – so studies from other continents are required. The low prevalence of HBV in the general European population clearly hampers the implementation of such surveys. Secondly, a number of studies included in this systematic review had a cross-sectional design; these studies showed no significant link between exposure to HBV and risk of CKD. Thus, there is evidence that our findings may be impacted by study design. Thirdly, our study is a systematic review of observational studies (such as cohort or case-control studies), as ethical and budgetary constraints often limit the application of experimental study designs in health research. Due to their lack of randomization, the estimated associations between the outcome and the exposure can be affected by unmeasured confounding factors which bias estimates from their true values. For example, information on the viral characteristics of HBV (i.e., HBV DNA or HBV genotypes) or recreational drug use, which are potential confounders, was incomplete in the studies retrieved for our meta-analysis. The significance of a residual confounding effect in observational studies (and meta-analyses) remains a matter of discussion among statisticians and meta-analysts; simulation approaches have been developed to this aim but were inconclusive.<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> New methods for managing confounding effects are under development.<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">In conclusion, this meta-analysis of observational studies seems to suggest a relationship between exposure to HBV and greater incidence of low eGFR and/or end-stage renal disease in the general population. Future studies are required to confirm these results, and should minimise measurement error in the exposure and misclassification bias in the outcome. In addition, cross-sectional designs should be avoided. We suggest an assessment of kidney function and a urine test at the beginning and during follow-up in all HBsAg-positive patients.</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Conflicts of interests</span><p id="par0160" class="elsevierStylePara elsevierViewall">The authors declare that there are no conflicts of interests.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres1616870" "titulo" => "Abstract" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Aim" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Material and methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1445024" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1616871" "titulo" => "Resumen" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivo" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Material y métodos" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1445023" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Material and methods" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Data sources and searches" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Study selection" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Ineligible studies" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Quality assessment" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Outcomes measures" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Data synthesis and analysis" ] ] ] 6 => array:3 [ "identificador" => "sec0045" "titulo" => "Results" "secciones" => array:7 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "Literature review" ] 1 => array:2 [ "identificador" => "sec0055" "titulo" => "Patient and study characteristics" ] 2 => array:2 [ "identificador" => "sec0060" "titulo" => "Summary estimate of outcome: incidence of CKD" ] 3 => array:2 [ "identificador" => "sec0065" "titulo" => "Summary estimate of outcome: prevalence of CKD" ] 4 => array:2 [ "identificador" => "sec0070" "titulo" => "Summary estimate of outcome: prevalence of proteinuria" ] 5 => array:2 [ "identificador" => "sec0075" "titulo" => "Sensitivity analysis" ] 6 => array:2 [ "identificador" => "sec0080" "titulo" => "Meta-regression analysis" ] ] ] 7 => array:2 [ "identificador" => "sec0085" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0090" "titulo" => "Conflicts of interests" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-03-16" "fechaAceptado" => "2019-10-06" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1445024" "palabras" => array:5 [ 0 => "Chronic kidney disease" 1 => "End-stage renal disease" 2 => "Glomerular filtration rate" 3 => "Hepatitis B virus" 4 => "Meta-analysis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1445023" "palabras" => array:5 [ 0 => "Enfermedad renal crónica" 1 => "Enfermedad renal terminal" 2 => "Tasa de filtración glomerular" 3 => "Virus de la hepatitis B virus" 4 => "Metaanálisis" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background</span><p id="spar0165" class="elsevierStyleSimplePara elsevierViewall">The activity of hepatitis B virus (HBV) as a risk factor for the incidence and progression of chronic kidney disease (CKD) has not been clarified.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Aim</span><p id="spar0170" class="elsevierStyleSimplePara elsevierViewall">We evaluated the impact of infection with HBV on the risk of CKD in the general population.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Material and methods</span><p id="spar0175" class="elsevierStyleSimplePara elsevierViewall">We carried out a systematic review of the published medical literature to assess whether a relationship between hepatitis B infection and an increased risk of CKD in the adult general population occurs. We adopted the random effects model of DerSimonian and Laird to provide a summary estimate of the risk of chronic kidney disease (defined by lowered glomerular filtration rate and/or detectable proteinuria) with HBV infection across the published studies. Meta-regression and stratified analyses were also performed.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><p id="spar0180" class="elsevierStyleSimplePara elsevierViewall">We retrieved 33 studies (n = 7,849,849 patients) published in 26 different articles, and separate meta-analyses were performed according to the outcome. Pooling results from cohort studies (11 studies, n = 1,056,645 patients) demonstrated a relationship between positive HBV serologic status and increased incidence of CKD, the summary estimate for adjusted HR with HBV across the surveys, 1.40 (95% CI, 1.16−1.69) (P < .001). Between-study heterogeneity was noted (Q value, 49.5, P < .0001). No relationship between HBV and prevalence of CKD was noted in the subset of cross-sectional studies (10 studies; n = 3,222,545 patients), adjusted OR, 1.04 (95% IC 0.90–1.218; P = .5). Meta-regression analysis reported a relationship between positive HBsAg status and incidence of CKD in the general population (P < .015).</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conclusions</span><p id="spar0185" class="elsevierStyleSimplePara elsevierViewall">It appears that exposure to HBV infection seems to be associated with an increased risk of developing CKD in the adult general population. Studies aimed to understand the mechanisms responsible of such association are under way.</p></span>" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Aim" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Material and methods" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0025" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Antecedentes</span><p id="spar0190" class="elsevierStyleSimplePara elsevierViewall">El papel del virus de la hepatitis B (VHB) como factor de riesgo en la incidencia y progresión de la enfermedad renal crónica (ERC) no ha sido clarificado.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Objetivo</span><p id="spar0195" class="elsevierStyleSimplePara elsevierViewall">Evaluamos el impacto producido por la infección con el VHB sobre el riesgo de la ERC en la población general.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Material y métodos</span><p id="spar0200" class="elsevierStyleSimplePara elsevierViewall">Llevamos a cabo una revisión sistemática de la literatura médica publicada a fin de evaluar si existe, en la población adulta general, una relación entre la infección por el VHB y un aumento del riesgo de ERC. Adoptamos el modelo de efectos aleatorios de DerSimonian y Laird para proporcionar una estimación resumida del riesgo de ERC (definida por una tasa de filtración glomerular reducida y/o una proteinuria detectable) por infección con el VHB en los estudios publicados. También se realizaron metarregresiones y análisis estratificados.</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Resultados</span><p id="spar0205" class="elsevierStyleSimplePara elsevierViewall">Recogimos 33 estudios (n = 7.849.849 pacientes) publicados en 26 artículos y se realizó un metaanálisis por separado conforme a los resultados. La agrupación de los resultados de los estudios de cohortes (11 estudios, n = 1.056.645 pacientes) demostró una relación entre un estatus serológico VHB positivo y el aumento de la incidencia de la ERC, con una estimación resumida para la HR ajustada con VHB en todas las encuestas del 1,40 (IC 95% 1,16–1,69; p < 0,001). Se observó heterogeneidad entre estudios (valor Q: 49,5; p < 0,0001). En el subconjunto de estudios transversales no se detectó relación entre el VHB y la prevalencia de la ERC (10 estudios; n = 3.222.545 pacientes; OR ajustada 1,04; IC 95% 0,90−1,218; p = 0,5). Los análisis de metarregresión informaron de una relación entre el estatus HBcAg positivo y la incidencia de ERC en la población general (p < 0,015).</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusiones</span><p id="spar0210" class="elsevierStyleSimplePara elsevierViewall">Parece que la exposición a la infección por VHB está asociada con un aumento en el riesgo de desarrollar ERC en la población adulta general. Se están realizando estudios destinados a comprender los mecanismos responsables de dicha asociación.</p></span>" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0030" "titulo" => "Antecedentes" ] 1 => array:2 [ "identificador" => "abst0035" "titulo" => "Objetivo" ] 2 => array:2 [ "identificador" => "abst0040" "titulo" => "Material y métodos" ] 3 => array:2 [ "identificador" => "abst0045" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0050" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Fabrizi F, Cerutti R, Donato FM, Messa P. La infección por VHB es un factor de riesgo de enfermedad renal crónica: revisión sistemática y metaanálisis. Rev Clin Esp. 2021;221:600–611.</p>" ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "<p id="par0170" class="elsevierStylePara elsevierViewall">The following are Supplementary data to this article:<elsevierMultimedia ident="upi0005"></elsevierMultimedia><elsevierMultimedia ident="upi0010"></elsevierMultimedia></p>" "etiqueta" => "Appendix A" "titulo" => "Supplementary data" "identificador" => "sec0100" ] ] ] ] "multimedia" => array:11 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [