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Association between Helicobacter pylori and end-stage renal disease: A meta-analysis

AIM To investigate the prevalence and association of Helicobacter pylori (H. pylori) with end-stage renal disease (ESRD). METHODS SA comprehensive literature search was completed from inception until October 2016. Studies that reported prevalence, relative risks, odd ratios, hazard ratios or standardized incidence ratio of H. pylori among ESRD patients were included. Participants without H. pylori were used as comparators to assess the association between H. pylori infection and ESRD. Pooled risk ratios and 95%CI was calculated using a random-effect model. Adjusted point estimates from each study were combined by the generic inverse variance method of DerSimonian and Laird. RESULTS Of 4546 relevant studies, thirty-seven observational studies met all inclusion criteria. Thirty-five cross-sectional studies were included in the analyses to assess the prevalence and association of H. pylori with ESRD. The estimated prevalence of H. pylori among ESRD patients was 44% (95%CI: 40%-49%). The pooled RR of H. pylori in patients with ESRD was 0.77 (95%CI: 0.59-1.00) when compared with the patients without ESRD. Subgroup analysis showed significantly reduced risk of H. pylori in adult ESRD patients with pooled RR of 0.71 (95%CI: 0.55-0.94). The data on the risk of ESRD in patients with H. pylori were limited. Two cohort studies were included to assess the risk of ESRD in patients with H. pylori. The pooled risk RR of ESRD in patients with H. pylori was 0.61 (95%CI: 0.03-12.20). CONCLUSION The estimated prevalence of H. pylori in ESRD patients is 44%. Our meta-analysis demonstrates a decreased risk of H. pylori in adult ESRD patients.


INTRODUCTION
Helicobacter pylori (H. pylori) is the most common chronic bacterial infection in the gastrointestinal tract of humans [1] . It has been estimated that the prevalence of H. pylori infection is up to thirty percent in adult aged 18 to 30 years and to fifty percent in those older than 60 years old [2] . Many studies demonstrated that H. pylori infection is associated with a peptic and duodenal ulcer, chronic gastritis, and gastric cancer [3,4] .
Recently, epidemiologic studies have demonstrated associations between H. pylori infection and extragastrointestinal organ involvements including coronary artery disease, dyslipidemia, insulin resistance, and hematologic disorders [5][6][7] . End-stage renal disease (ESRD) is a common and serious chronic disease worldwide that continues to increase in prevalence by approximately 21000 cases per year in the United States [8] . Although there is no visible evidence demonstrated that H. pylori infection is directly associated with renal disease, patients with ESRD usually have gastrointestinal problems such as gastritis, dyspeptic symptoms or ulcers [9][10][11] .
Interestingly, recent investigations have demonstrated an association between H. pylori infection and ESRD [12][13][14] . In addition, an increase in renal resistance index due to systemic inflammation state H. pylori infection was also described [15][16][17][18] . However, many studies reported the conflict data regarding the association between H. pylori infection in ESRD and also the prevalence of H. pylori infection in ESRD patients  . Thus, we conducted the systematic review and meta-analysis that summarized all available evidence to determine the prevalence of H. pylori infection among ESRD patients and the association between H. pylori infection and ESRD.

Literature search
Three investigators (Wijarnpreecha K, Thongprayoon C and Cheungpasitporn W) independently reviewed published studies indexed in MEDLINE and EMBASE database from their inception to October 2016 using the search strategy that included the terms for "Helicobacter", "hemodialysis", and "renal disease" as described in Item S1 in online Supplementary Data 1. A search for additional articles utilizing references from included studies was also performed. There was no confinement on language in the literature search.
We conducted this systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement.

Selection criteria
The inclusion criteria were: (1) observational studies appraising the association between H. pylori and ESRD and prevalence in hemodialysis; (2) prevalence, odds ratios, relative risks, or hazard ratios with 95%CI were presented; and (3) individuals without H. pylori were used as comparators in cohort studies while individuals without ESRD were used as comparators in the crosssectional and case-control studies. Wijarnpreecha K, Thongprayoon C and Cheungpasitporn W individually examined the titles and abstracts of the studies. After the first phase, the full text of the included studies was subsequently examined to ascertain if they met the inclusion criteria. Discrepancies were also settled by discussion with all investigators.

Data abstraction
A structured data collection form was utilized to obtain the data from included studies including title of the study, year of publication, country where the study was conducted, name of the first author, demographic of subjects, method used to diagnose H. pylori, prevalence of H. pylori, effect estimates (hazard ratios, odds ratios, relative risks) with 95%CI, and factors adjusted in the multivariate analysis. To ensure the certainty, this data extraction process was reviewed by all investigators. The quality of each study was individually appraised by each investigator. We utilized the validated Newcastle-Ottawa quality assessment scale for cohort and casecontrol studies [43] and modified Newcastle-Ottawa scale [44] for the cross-sectional study.

Statistical analysis
MetaXL software (EpiGear International Pty Ltd) [45] was used for meta-analysis of prevalence. Otherwise, data analysis was performed using the Review Manager 5.3 software from the Cochrane Collaboration (London, United Kingdom). Adjusted point estimates from each study were combined by the generic inverse variance method of DerSimonian and Laird, which assigned the weight of each study based on its variance [46] . We used a random-effect model due to the high likelihood of between-study variance from different study designs, populations, and H. pylori testing. Cochran's Q test and I 2 statistic were used to ascertain the between-study heterogeneity. A value of I 2 of 0%-25%, 25%-50%, 50%-75%, and > 75% embodied insignificant, low, moderate and high heterogeneity, respectively [47] .

RESULTS
Of 4546 potentially relevant articles, 4466 articles were excluded due to the title and abstract not meeting inclusion criteria. Subsequently, 43 articles were excluded (6 articles were not observational studies, and 37 articles did not describe the outcomes of interest). Finally, thirty-seven observational studies (2 cohort [14,48] and 35 cross-sectional studies [12,13,16,[49][50][51][52][53][54][55][56] ) met all inclusion criteria. The literature retrieval, review, and selection process are shown in Figure 1. The characteristics and quality assessment of the included cross-sectional studies are presented in Table 1 while the characteristics of the included cohort studies are shown in Table 2.

articles were included in the meta-analysis
Exclusion of 2592 duplications 4466 articles were excluded based on title and abstract review as they clearly did not fulfill the inclusion criteria on the basis of type of article and study design 6 articles were excluded because they were descriptive studies without comparators. 37 articles were excluded because they did not report the outcome of interest.  [55] United Kingdom 1990 Dialysis [34] The Netherland 1991 HD Antibody 13/30 (43%) 1.24 (0.58-2.64) S 3 C 1 O 2 Davenport et al [22] United Kingdom 1991 HD Antibody [16] Finland 1991 HD Histology [27] Germany 1993 HD Cumulative evaluation (urease, test, histology, culture and direct examiniation)
The data on the risk of ESRD in patients with H. pylori were limited. Two cohort [14,48]

Evaluation for publication bias
A funnel plot assessing publication bias for the association between H. pylori infection in overall ESRD subjects was demonstrated in Figure 4. The funnel plot of the association between H. pylori infection in overall ESRD subjects was symmetric and suggested no publication bias.

DISCUSSION
In this meta-analysis summarizing all presently Tsukada et al [41] Japan 2003 HD Histology 9/36 (25%) 0.28 (0.02-3.82) S 3 C 2 O 2 Olmos et al [37] Argentina  [21] South Korea 2010 HD Urease test and histology 12/33 (36%) 0.30 (0.12-0.74) S 3 C 0 O 2 Hooman et al [29] Iran 2011 HD -children Histology 19/68 (28%) 1.59 (0.65-3.92) S 3 C 0 O 2 Genç et al [24] Turkey 2013 HD and PDchildren   available data on the prevalence of H. pylori infection among ESRD patients and the association between H. pylori infection and ESRD, we demonstrated an estimated prevalence of H. pylori in ESRD patients of 44%. In addition, we found a 0.71-fold decreased risk of H. pylori in adult ESRD patients. Although the precise explanation of reduced risk of H. pylori among adult ESRD patients is still unclear, there are several plausible explanations for this association. First, it has been postulated in previous studies that administering antibiotics and antacid more frequently in ESRD patients may contribute to lower the prevalence of H. pylori infection [39,53] . Previous study proposed that ESRD patients may have a lower risk of H. pylori infection from routinely used of antacids to prevent renal osteodystrophy by reducing intestinal phosphate absorption [16] . Second, patients with ESRD have higher levels of inflammatory cytokines including tumor necrotic factor, interleukin-6 and -8 from infiltrative inflammatory cells in gastric mucosa [57] and chronic circulatory failure [58,59] could lead to gastric mucosal damage and progress to gastric atrophy or atrophic gastritis, increased in gastric pH mucosa, and eventually eradication of H. pylori infection [60][61][62] . Although the included studies in this meta-analysis are almost of good quality, there are several limitations to this study that need to be addressed. Firstly, there was a statistical heterogeneity in the completed analysis. Possible sources of this heterogeneity include differences in confounder-adjusted methods (e.g., age, gender, ethnicity and socioeconomic status), different test to detect H. pylori infection in each study, various grades of uremia. Secondly, our subgroup analysis revealed significantly decreased the risk of H. pylori infection among adult subjects with ESRD but not in children likely due to a limitation in some studies. Although the number of study assessing H. pylori in children was limited and the insignificant finding in ESRD children could be from the lack of power, further studies are required to determine the role of aging in the underlying pathogenesis of H. pylori infection  among ESRD patients. Lastly, this study is a metaanalysis of observational studies. Thus, our study demonstrated an association, but could not establish causality as unknown confounders could play a role in the association between prevalence of H. pylori among hemodialysis and association between H. pylori and ESRD.
In conclusion, our meta-analysis demonstrated an estimated prevalence of H. pylori in ESRD patients of 44%. In addition, our meta-analysis demonstrates a decreased risk of H. pylori in adult ESRD patients. ESRD could be a potential protective factor for H. pylori infection.

Background
Helicobacter pylori (H. pylori) is the most common chronic bacterial infection in the gastrointestinal tract of humans. Epidemiologic studies showed the link between H. pylori infection and extra-gastrointestinal tract including endstage renal disease (ESRD). However, many studies reported the conflict data regarding the association between H. pylori infection in ESRD and also the prevalence of H. pylori infection in ESRD patients.

Research frontiers
The results of those epidemiologic studies were inconsistent. To further investigate this possible association of H. pylori infection and ESRD and determine the prevalence of H. pylori among ESRD patients, the authors conducted this systematic review and meta-analysis of observational studies reporting the association between H. pylori and ESRD and prevalence of H. pylori among ESRD patients.

Innovations and breakthroughs
The authors found an estimated prevalence of H. pylori in ESRD patients of 44% (95%CI: 40%-49%). Moreover, the authors also found a decreased risk of H. pylori infection among adult ESRD patients with pooled RR of 0.71 (95%CI: 0.55-0.94).

Applications
This study demonstrated a significantly decreased risk of H. pylori infection among ESRD patients. This finding suggests that ESRD may be an independent potential protective factor for H. pylori infection.

Peer-review
This meta-analysis investigated the prevalence and association of H. pylori