The Association of Helicobacter pylori Eradication with the Occurrences of Chronic Kidney Diseases in Patients with Peptic Ulcer Diseases

The association of Helicobacter pylori eradication with the occurrence of renal dysfunction in patients with peptic ulcer diseases is still unclear. This study aimed to clarify the relevance of H. pylori eradication to the occurrence of chronic kidney diseases in patients with peptic ulcer diseases. Data that were available from 2000–2011 were extracted from the National Health Insurance Research Database in Taiwan, and all patients with peptic ulcer diseases (n = 208 196) were screened for eligibility. We divided randomly selected patients into an H. pylori eradication cohort (cohort A, n = 3593) and matched them by age and sex to a without H. pylori eradication cohort (cohort B, n = 3593). Subgroup analysis was further performed for H. pylori eradication within ≤ 90 days of the diagnosis date (early eradication, n = 2837) and within 91–365 days (non-early eradication, n = 756). Cox proportional hazards regression analysis was used to estimate the association of H. pylori eradication with the risk of developing chronic kidney diseases and mortality. We observed that there were more patients suffering from chronic kidney disease in cohort B than in the early eradication subgroup of cohort A (8.49% vs. 6.70%, respectively, p = 0.0075); the mortality rate was also higher in cohort B (4.76% vs. 3.70%, respectively, p = 0.0376). Old age, pulmonary disease, connective tissue disorders, and diabetes were risk factors for chronic kidney diseases but early H. pylori eradication was a protective factor against chronic kidney diseases (hazard ratio: 0.68, 95% confidence interval: 0.52–0.88, p = 0.0030), and death (hazard ratio: 0.69, 95% confidence interval: 0.49–0.96, p = 0.0297). In conclusion, our findings have important implications suggesting that early H. pylori eradication is mandatory since it is associated with a protective role against the occurrence of chronic kidney diseases.


Introduction
Helicobacter pylori is a spiral-shaped, microaerophilic Gram-negative flagellate bacterium that usually resides in the gastric mucosa [1,2]. H. pylori infection is a common bacterial infection of humans worldwide. Approximately 50% of the world's population is colonized with H. pylori, and the infection levels exceed 70% in some developing areas [3,4]. An association between H. pylori infection and the development of gastrointestinal diseases, such as peptic ulcer, gastric hyperplastic polyps, gastric adenoma, gastric cancer, and gastric mucosa associated-lymphoid tissue lymphoma, has been demonstrated [5,6].
However, the relevance of H. pylori infection and eradication to renal dysfunction is still unclear. The results of a previous study suggested that H. pylori infected patients with concomitant chronic kidney disease (CKD) and cardiovascular diseases risk factors were at higher risk of end stage renal disease (ESRD) than those with a singer factor [13]. However, little is known about whether eradication of the bacteria has any effect on renal function. Therefore, this nationwide cohort study aimed to investigate the association of H. pylori eradication with the occurrence of chronic kidney diseases in patients with peptic ulcer diseases (PUD).

Ethics Statement
The study protocol was approved by the institutional review board and the Ethics Committee of Chang Gung Memorial Hospital and Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. The Ethics Committee waived the requirement for informed consent for this study, and all of the data were analyzed anonymously.

Data Source
We used a database of a million patients who were randomly selected for analysis from 22.6 million of Taiwan's National Health Insurance (NHI) enrollees in 2000(NHI 2000. The Taiwan NHI was created by the Taiwan government as a single-payer health insurance program on March 1, 1995 [14]. The diagnoses used in the National Health Insurance Research Database (NHIRD) are coded according to the diagnostic criteria of the International Classifications of Diseases, Revision 9, Clinical Modification (ICD-9-CM). The data analysts were staff of Kaohsiung Medical Center, a site of the Collaboration Center of Health Information Application, Ministry of Health and Welfare. The cohort dataset of a million randomly selected individuals and the dataset of patients with recorded illnesses included individuals who were still alive in 2011. The recorded data for each individual included the enrollment files, claims data, serious illness files, and the drug prescription registry. In the cohort dataset, each patient's original identification number was anonymized and de-identified prior to retrieval of data for privacy purposes.

Study Subjects
In this population-based cohort study, patients with PUD (n = 208 196) were screened for eligibility, and those aged more than 18 years old were included (n = 202 708). Fig 1 shows the schematic flowchart of the study design. We used ICD-9-CM codes (531-534) to identify patients with PUD. The date of diagnosis with PUD was used as the index date. Patients who underwent H. pylori eradication within 365 days before the index date, patients who received renal transplantation (ICD-9-CM code V420), and patients who were diagnosed with prior PUD, CKD, pre-ESRD, ESRD (ICD-9-CM code 585), any malignancy, or had unavailable information about their sex or age were all excluded (n = 134 605).
We used ICD-9-CM codes to identify renal transplantation and CKD patients who were hospitalized at least once or presented for two or more outpatient visits at least 84 days apart. Patients who used erythropoietin (anatomical therapeutic chemical codes) or underwent arteriovenous shunt creation (ICD-9-CM codes 4470, details of inpatient orders codes 69032C and 69034C) were defined as pre-ESRD. Patients who received hemodialysis or peritoneal dialysis for at least 3 months were defined as ESRD.
We divided the patients into those with H. pylori eradication (cohort A, n = 3593) and without H. pylori eradication (n = 58916), and selected the same number of patients in cohort A from the non-eradication cohort to form the comparison cohort (cohort B, n = 3593) after matching by age and sex. Patients with H. pylori eradication performed within 365 days of the index date were included in cohort A.
H. pylori eradication triple or quadruple therapy was defined as proton-pump inhibitor (PPI) or histamine type 2 receptor antagonists (H 2 RA) plus clarithromycin or metronidazole plus amoxicillin or tetracycline, with or without bismuth. These drug combinations were prescribed within the same prescription order, and the duration of therapy was 7-14 days. Subgroup analysis was further performed according to the timing of H. pylori eradication after initial diagnosis. Early H. pylori eradication was defined as treatment 90 days after the index date (n = 2837) and non-early eradication was defined as those who received treatment > 90 days but 365 days after the index date (n = 756).

Comorbidities and Other Covariates
General health status was assessed by the Charlson co-morbidity index (CCI), which is the sum of the weighted scores of 17 co-morbid conditions and is widely used to control for confounding in epidemiological studies [15]. Exposure to nephrotoxic drugs such as nonsteroidal antiinflammatory drugs (NSAIDs), angiotensin converting enzyme inhibitors (ACEI), and angiotensin II receptor blockers (ARB) was defined as a patient having a prescription for any of them at least 1 day after the index date through the occurrence of any event related to this study, withdrawal from the NHI, the end of the study period, or death, whichever came first. The NHIRD database contains the details of every prescription, including the doses, frequencies, dates, and administration routes.

Outcome Measurements
The primary endpoint of this study was newly diagnosed CKD and the secondary endpoint was all-cause mortality. Newly diagnosed CKD was defined as having at least one record of CKD during hospitalization or during two or more outpatient visits that occurred at least 84 days apart.

Statistics
Categorical variables are presented as percentages. The X 2 test was used for categorical data. Cox proportional hazards regression analysis was used to estimate the association of H. pylori eradication with the risk of CKD and mortality. The Cox proportional hazards model was used to estimate the age-, sex-, comorbidity-, and nephrotoxicity drug-specific hazard ratio (HR) and 95% confidence interval (CI). We also used Kaplan-Meier curves to display the association of H. pylori eradication to the occurrence of CKD and mortality over time. All statistical analyses were conducted using the statistical software package SAS (version 9.3; SAS Institute Inc., Cary, NC, USA). A two-sided p value < 0.05 was considered significant.

Demographic Data
The demographic data of the two patient cohorts after matching by age and sex are shown in    (Tables 3 and 4). However, older age, pulmonary disease, connective tissue disorders, and diabetes were risk factors for CKD. In the mortality analysis, older age, male sex, congestive heart failure, connective tissue disorders, liver disease, diabetes, and acute kidney injury were risk factors for death. When we performed subgroup analysis to look at the possible effect of the timing of H. pylori eradication, we found that early H. pylori eradication was a protective factor against CKD (HR: 0.68, 95% CI: 0.52-0.88, p = 0.0030), and death (HR: 0.69, 95% CI: 0.49-0.96, p = 0.0297) compared to non-early H. pylori eradication (Tables 5 and 6).

Kaplan-Meier Analysis
Both the cumulative occurrence of CKD and the mortality rate were not significantly different (p = 0.8834 and p = 0.5132, respectively) between cohort A and cohort B at the last follow-up since the index date. On the other hand, the cumulative occurrence of CKD and the mortality rate were significantly different in the patients with early H. pylori eradication compared with non-early H. pylori eradication (p < 0.0001 and p = 0.0009 respectively) (Figs 2 and 3).

Discussion
There are reports on the association between H. pylori infection and ESRD but evidence of an effect of H. pylori eradication on kidney function is seldom reported. This study aimed to clarify the relevance of H. pylori eradication to the occurrence of chronic kidney diseases in patients with peptic ulcer diseases. Our study observed that H. pylori eradication within 90 days of diagnosis was associated with decreased rates of occurrence of CKD and mortality compared with those without early H. pylori eradication. Several studies have proven that gastric and extra-gastric H. pylori infection plays a role in the development of systemic disease such as renal dysfunction [16]. In addition, a retrospective cohort study reported that H. pylori infection may be a risk factor for subsequent ESRD but the authors did not investigate the possibility that eradication of the bacteria could be a protective factor [13]. Nozaki et al. found that H. pylori eradication at an early stage of inflammation (< 15 weeks) might be effective in preventing gastric carcinogenesis [17]. This might also imply that the timing of eradication could be crucial in minimizing the damage from inflammatory events initiated by H. pylori.
We defined the early H. pylori eradication therapy cohort as patients who received therapy within 90 days of initial diagnosis. The observations about preventing inflammation could partly explain the observation in the current study that early eradication of H. pylori was associated with a lower rate of occurrence of CKD as compared to those infected PUD subjects who did not received H. pylori eradication or had non-early eradication, after adjusting for age, sex, co-morbidities, and nephrotoxicity drugs. The presence of H. pylori is strongly associated with PUD. It has been found that H. pylori exists in > 90% of duodenal ulcer patients and 70-90% of gastric ulcer patients [18]. Before adjusting for confounding factors, we found that there was no significant difference in CKD or mortality rates between patients with H. pylori eradication 365 days of the index date and those without H. pylori eradication, whereas a significant decrease in the occurrence of CKD and mortality was noted for patients in the early H. pylori eradication group compared to those without H. pylori eradication. These results were similar after we adjusted for confounding factors. Previously, Wu et al. proved early H. pylori eradication was an independent protective factor against gastric cancer [19]. Likewise, we observed that early H. pylori eradication played a role in renoprotection in the current study.
It has also been reported that H. pylori infection can contribute to endothelial dysfunction, which is related to CKD development and renal function decline [20][21][22]. A possible mechanism for this could be that chronic H. pylori infection might induce a persistent systemic and vascular inflammation and hence result in the malabsorption of folate, vitamin B6, and vitamin B12, leading to failure of methylation by 5-methyl-tetrahydrofolic acid and, thus, to hyperhomocysteinanemia, which causes toxicity to endothelial cells. Moreover, it is also possible that H. pylori infection increases asymmetric dimethylarginine (ADMA) levels, causing deep metabolic modifications [23]. High plasma ADMA levels have been shown to contribute to the development of oxidative stress and interstitial and glomerular fibrosis, which are associated with endothelial dysfunction and CKD progression [24]. The optimal timing for eradication is an important issue. Decreasing H. pylori exposure duration would shorten the period of the above pathophysiologic processes, so we can infer that early H. pylori eradication would be associated with lower risks of CKD development.
Interestingly, our study also observed that pulmonary disease and connective tissue disorders could be related to CKD development. Similar results were reported for two other cohort studies. Chen et al. found that chronic obstructive pulmonary disease was a risk factor for the development of CKD [25]. Chiu et al. observed rheumatoid arthritis patients had a higher risk of developing CKD [26]. These findings imply that comorbidities could be additive factors for the occurrence of CKD.
The strength of our study is its large sample size obtained by enrollment of a nationally representative cohort. Detailed information regarding H. pylori eradication therapy, NSAIDs, ACEI, and ARB were obtained by linking to the NHI pharmacy database under the Reimbursement Policy requested by NHI to reduce the possibility of duplication or misclassification. Furthermore, many important covariates such as the underlying diseases were available in detail.
On the other hand, it is inevitable that our study has several limitations. First, H. pylori eradication has had a relatively high failure rate over the years in Taiwan [27][28][29]. However, the Taiwanese patients enrolled during our study period who received first line H. pylori therapy could be expected to achieve a > 90% eradication rate with standard triple therapy of prescriptions of twice daily treatment with PPI combined with clarithromycin 500 mg and amoxicillin 1 g for 1 week [30]. This high rate is probably due to the low clarithromycin drug resistance rate at the time. Second, we were unable to assess several important risk factors of CKD related to lifestyle such as obesity or cigarette smoking because this information was not recorded in the NHIRD database. Finally, we studied a population largely consisting of people from Han Chinese descent, so our results might not be generalizable to non-Asians.
In conclusion, our findings have important implications, suggesting that early H. pylori eradication 90 days of the index date is mandatory since it is associated with a protective role against the occurrence of chronic kidney diseases. Further studies, especially population-based studies, will be helpful to confirm our results.