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J Clinic Care Skill 2024, 5(3): 145-150 |
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Received: 2024/04/24 | Accepted: 2024/08/31 | Published: 2024/09/20
Received: 2024/04/24 | Accepted: 2024/08/31 | Published: 2024/09/20
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Abbasi Larki R, Azad A, Jannesar R, Manzouri L, Jahanbani S. The Effect of Helicobacter Pylori Infection Eradication on Glomerular Filtration Rate in Patients with Chronic Kidney Disease. J Clinic Care Skill 2024; 5 (3) :145-150
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1- Department of Nephrology, Faculty of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran
2- Department of Gastroenterology, Faculty of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran
3- Department of Pathology, Faculty of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran
4- Community and Preventive Medicine Social Determinants of Health Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
5- “Department of Internal Medicine, Faculty of Medicine,” and “Medicinal Plants Research Center”, Yasuj University of Medical Sciences, Yasuj, Iran
2- Department of Gastroenterology, Faculty of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran
3- Department of Pathology, Faculty of Medicine, Yasuj University of Medical Sciences, Yasuj, Iran
4- Community and Preventive Medicine Social Determinants of Health Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
5- “Department of Internal Medicine, Faculty of Medicine,” and “Medicinal Plants Research Center”, Yasuj University of Medical Sciences, Yasuj, Iran
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Introduction
Chronic kidney disease is a progressive disease with no cure and high morbidity and mortality that usually occurs in the adult population. Preservation of kidney function can improve outcomes and be achieved through non-pharmacological strategies (dietary and lifestyle modification) and chronic kidney disease-targeted and kidney disease-specific pharmacological interventions [1]. Patients require monitoring for complications of CKD such as hyperkalemia, metabolic acidosis, hyperphosphatemia, vitamin D deficiency, secondary hyperparathyroidism, and anemia [2]. In addition to physical, mental and emotional dimensions, quality of life, depression [3], sleep disorders [4], and reduced life expectancy affect both patients and caregivers [5]. A patient with CKD for a period equal to or longer than three months, a glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2 or a GFR greater than 60 mL/min/1.73 m2 and with evidence of structural damage He showed the kidney [6]. Some studies show that the prevalence of chronic kidney failure in Iran is increasing [3]. The final stage of this disease ESRD (End Stage Renal) is irreversible kidney loss and patients permanently need alternative treatments such as kidney transplants or dialysis [3]. Reduction in the glomerular filtration rate and progressing to the dialysis stage impose on patients many emotional and financial burdens as well as loss of quality life [7]. The following risk factors play a role in the development and progression of CKD: Female gender, high BMI, race with high prevalence in people of Black and South Asian origin, old age, increased waist circumference, arterial hypertension, and some comorbidities such as diabetes [8]. Unfortunately, the current global increase in type-II diabetes also contributes to the rising prevalence of CKD. The previous studies reported the prevalence of H. pylori infection among patients with CKD range between 20 and 60% [9].
Helicobacter pylori (H. pylori) is a gram-negative spiral rod and its infection is common, that is commonly found in the stomach [10]. The prevalence of this disease is related to age, ethnicity, related diseases, geographical areas, socio-economic status, and health conditions [11].
The transmission of this bacterium occurs via the fecal-oral, and oral-oral routes [12]. There is a direct relationship between Helicobacter pylori infection and its transmission with water pollution, low-quality lifestyle, poor diet, smoking and lack of physical activity [13]. The global prevalence of Helicobacter pylori infection in adults has decreased from 50 to 55% to 43% [14, 15] which is mostly attributed to the improvement of socio-economic status, living standards and health conditions, increasing the use of antibiotics including eradication treatment [11].
Recent evidence has proposed the implication of H. pylori in a variety of extra gastric diseases, such as neurological diseases [16], coronary heart disease [17], and glaucoma [18]. Furthermore, a concurrence between H. pylori infection and a number of diseases such as biliary, pancreatic and colon diseases has been reported [19-21]. The suggested mechanism for these diseases is that chronic infection by H. pylori causes chronic inflammation with a low degree as a biological response. Inflammatory factors produced by the gastric mucosa such as tumor necrosis (TNF) and cytokines (IL) are induced in gastritis, diabetes, metabolic syndrome, atherosclerosis and obesity, which are secreted into blood circulation and metabolic profiles [13, 22].
Some evidence emphasizes the association between H. pylori infection and the upcoming development of end-stage renal disease (ESRD). A large nation-based study indicated that concomitant H. pylori infection with CKD puts patients at increased risk of progression to ESRD [23, 24]. The common feature of all the indicated pathological diseases is the presence of a low-grade systemic inflammation [16].
Despite the well-studied effects of H. pylori infection on other organs of the body, no conclusive evidence was shown to indicate that this pathogen may secondarily lead to diminished renal function. The results of some studies indicated a lower prevalence rate of H. pylori infection in CKD or ESRD patients [25, 26]. Increased inflammatory cytokines in patients with CKD leads to gastric mucosal damage, which in turn makes it difficult for H. pylori to survive [25]. Furthermore, a recent meta-analysis estimated the prevalence on H. pylori infection in 44% of the ESRD and 53% in non-dialysis-dependent CKD patients. They concluded that H. pylori infection has a protective role in ESRD [27]. In peptic ulcer disease (PUD) patients with CKD and ESRD, a lower rate of infection with this pathogen has been reported [26]. A possible explanation for this report is the severe inflammation and progressive gastric atrophy due to uremic milieu and dialysis which restrain the pathogen from surviving in the gastric environment [28]. The prevalence of ESRD in H. pylori positive cases has been described 3.72 times higher than in non-infected cases in some other studies. They concluded that H. pylori could be a predisposing factor in the progression of renal failure [23]. In Turkey, the prevalence was reported even higher, around 66% [27], while in Iran, the concurrence of H. pylori infection and ESRD was estimated between 28% to 67% [24, 29, 30].
Moreover, an association between H. pylori infection and a series of inflammatory and immunological events has been described. Hence, H. pylori trigger a cascade of local and systemic immunological and inflammatory responses believed to be the source of extra-gastric complications of this infection [31]. The release of inflammatory cytokines could be independently associate with the weakness and lack of energy experienced by CKD patients. Thus, it is assumed that H. pylori eradication further enhances the quality of life in this group of patients [22]. Recent studies have shown the importance of studying gastrointestinal diseases and outside gastrointestinal diseases associated with H. pylori infections [16]. Knowing the factors affecting this disease helps us take effective measures to prevent, treat and reduce complications and reduce costs because effective treatment for advanced kidney disease includes dialysis and kidney transplantation both of which are costly. On the other hand, due to the conflicting results of different studies on the exact effect of H. pylori infection on CKD patients, this study aimed to determine the effect of Helicobacter pylori infection eradication on glomerular filtration rate in patients with chronic kidney disease.
Materials and Methods
Study design
The present study was an interventional study involving a group of patients with H. pylori infection. After 6 months of follow-up, H. pylori infection was eradicated in some patients (group A), while it persisted in others (group B). Therefore, we compared GFR within and between the two groups at baseline and 6 months after.
Participants, eligibility criteria, and settings
The study population consisted of patients referred to an outpatient nephrology clinic in Yasuj, Iran from August to January 2016. Inclusion criteria included patients aged between 18 to 70 years, diagnosed with CKD with a GFR between 30 to 60 mL/min, a positive stool antigen test for H. pylori infection, and a negative pregnancy test at the time of the study, without renal malignancy, or a history of transplantation. However, those who had undergone surgery for any reason or had a history of hospitalization, myocardial infarction, stroke, acute kidney injury (AKI), and hypertension crisis in the past 6 months were excluded. Furthermore, enrolled patients had not taken any of the following medications during the past two months: Anti-Helicobacter pylori antibiotics, anti-acids, proton pump inhibitors (PPIs), and non-steroidal anti-inflammatory drugs (NSAIDs).
Sample size
The sampling method in this study was convenience sampling. A total of 270 eligible patients with CKD and GFR between 30 to 60 mL/min who were referred to the Nephrology Clinic affiliated to Yasuj University of Medical Sciences, Yasuj, Iran, (from August 2016 to January 2017) were recruited for the present study. They were referred to the laboratory for fecal antigen testing, however, only 79 patients with a positive fecal antigen test were included in the study.
Laboratory measurements
For all the participants (79 patients), the stool antigen test, the serum creatinine levels, and blood urea nitrogen (BUN) were recorded at baseline and 6 months after H. pylori eradication treatment. Stool antigen test was performed in a medical diagnostic laboratory according to immune assay methods. Creatinine and BUN were measured by using biochemical methods and kits (Pars Co., Iran). Measurement were performed according to the manufacturer’s instruction using an automatic autoanalyzer Hitachi 917 (Hitachi, Taiwan).
Intervention and data collection
The patients who had a positive stool antigen test received the triple eradication regimen of H pylori infection including a one-week course of omeprazole (20 mg twice a day, Abidi Pharma Co, Iran), amoxicillin (1 g twice a day, Daana Pharma Co, Iran), and azithromycin (500 mg, Rouzdarou Co, Iran) one gram daily for the first three days. Omeprazole was continued for three weeks at the dose of 20 mg daily [32]. The patients were given verbal instructions to take their medications regularly during the treatment course and not to stop their therapeutic regimen.
Stool antigen test, serum levels of creatinine and BUN were measured and recorded at baseline and six months after treatment. Furthermore, the GFR of patients whose H. pylori infection was successfully eradicated and those with therapeutic failure, after 6 months, were measured and compared with each other. The value of GFR was calculated to determine the effect of the H pylori eradication on renal function (Equation 1):
Equation 1:Abbreviated MDRD study equation
GFR=186×(serum creatinine)-1.154×(age)-0.203×(0.742 if female)×1.210(if African-American)
Statistical analysis
Qualitative parameters were reported by frequency and percent, and quantitative parameters were reported by Mean±SD. The chi-square test and Fisher’s Exact Test were used to compare the qualitative parameters in the two groups of the study. One sample Kolmogorov-Semenov test was used to evaluate the distribution of parameters. Independent t-test was used to compare the means of the studied groups. To compare between means before and after the intervention in the studied groups, we applied paired t-test. All statistical analysis was conducted by using SSPS software version 23, and differences with a value of p<0.05 were considered significant.
Findings
Participants
Overall, 270 patients with CKD were evaluated for H. pylori infection. In total, 79 patients with CKD and a positive stool antigen test for H. pylori entered in the study, and 49 patients completed the study. The trend of changes in GFR was evaluated and compared in CKD patients in whom H. pylori infection was successfully eradicated (15 patients, group A) to those whose infection had not eradicated (34 patients, group B).
Patient characteristics in the two study parts were similar with no significant difference between the two groups in demographic characteristics (age, gender ratio, and baseline GFR).
The minimum and maximum ages of the patients were 24 and 69 years, respectively. The mean age of the patients was 54.5±11.6 years in group A and 55.84±9.20 years in group B. Male participants represented 40% of the negative test group, compared to approximately 55.9% in the other group. Conversely, female participants made up 55.9% of the negative test group, while they constituted around 44.1% in the other group.
The patients who completed the study did not report serious adverse effects. The eradication rate of the course of the regimen was 30.6% when evaluated at month 6.
GFR in patients with negative Helicobacter pylori stool antigen group (49.40±15.54) was more than in positive Helicobacter pylori stool antigen group (44.90±13.70), however this difference was not significant (p=0.75).
The mean of GFR before the eradication of H. pylori in group A slightly increased from 48.54±8.66 mL/min to 49.5±15.4 mL/min after 6 months of receiving treatment with anti H. pylori drugs. However, this difference was not significant (p=0.18). In the group B, the trend of changes in GFR values did not change significantly in both groups (p=0.48).
Discussion
This study aimed to determine the effect of Helicobacter pylori infection eradication on glomerular filtration rate in patients with chronic kidney disease.
In the current study, the frequency of a positive H. pylori stool antigen in patients with chronic kidney injury was 34 from total 49 patients after 6 months of treatment. In other words, H. pylori infection was eradicated in only 30.6% of the subjects after treatment. Normally, the eradication is effective in up to 70% of cases. In this study, the rate of eradication was lower than normal. This can be explained by the widespread prescription of various antibiotics in CKD patients, and the common resistance of H. pylori to the following antibiotics; Erythromycin and Amoxicillin. Furthermore, the extensive use of medications in these patients probably reduced the antibiotics concentration for eradication. Moreover, it has been demonstrated that the presence of uremic toxins could minimize the absorption of antibiotics in CKD population. This could also be justified by the fact that the subjects failed to stop the PPI (Proton Pump Inhibitors) medications before testing, the sensitivity of stool the H. pylori antigen test is low and the recurrence of the infection. Our results were consistent with the results obtained by Sugimoto & Yamaoka and Schoonjans et al. [33, 34].
Different studies have suggested various etiologies for H. pylori recurrence. For instance, the ongoing activation of the inflammatory cascade, has elevated release and diminished clearance of pro-inflammatory cytokines, endotoxemia following fluid overload, reduced amount of anti-toxins levels, the migration of activated inflammatory agents in the digestive tract, and the presence of comorbidities have been proposed to explain H. pylori recurrence [35]. Following the rise in the blood volume, the gastrointestinal permeability increases. Moreover, the accumulation of endotoxins such as lipopolysaccharides of gram-negative bacteria takes place in the gastrointestinal tract. This phenomenon recruits the monocytes to the site of inflammation and further increases the release of pro-inflammatory cytokines [35, 36]. All of these factors might be involved in complicating the clinical outcome of patients with CKD and H. pylori infection, simultaneously.
The results of this study demonstrated that eradication of H. pylori infection in CKD patients may increase the glomerular filtration rate slightly and not taking a therapeutic strategy for this infection could worsen the patient's clinical outcome, although these differences not significant. Similar to previous studies, the results of this study showed that the transfer of bacteria from the gastrointestinal tract into the bloodstream increases in patients with renal insufficiency. Thereby, the eradication of this chronic infection may slow down the progression of CKD [35, 36]. In a cross-sectional study conducted on kidney transplant patients, no significant difference was observed in estimated GFR (eGFR) of the patients whose H. pylori infection test was either positive or negative [37]. In a clinical trial on 132 patients with various ranges of kidney function (normal to ESRD), a relation between the rate of successful eradication of H. pylori infection and different levels of GFR was explored. The authors of this study found no association between H. pylori eradication and kidney function [38].
In the present study, the percentage of patients whose infection had successfully eradicated at the end of the study was low. This could explain the fact that the differences in GFR between the groups, although in favor of H. pylori eradication, were not significant. In the study conducted by Abdulrahman & Al-Quorain, the prevalence of H. pylori infection in ESRD patients was reported in 40% of the subjects. The prevalence of this infection was similar in ESRD patients and renal transplant recipients [39]. In a prospective cohort study comprised of 198 ESRD patients undergoing maintenance hemodialysis, the prevalence of H. pylori infection was reported in 41% of the patients (81 positive cases out of 198 studied subjects). The patients underwent 13C-urea breath test (13C-UBT) for determination of H. pylori infection. It is noteworthy that multivariate analysis of the results was suggestive of a protective role for H. pylori infection against gastric erosion in this particular population. Hence, H. pylori eradication may increase the risk of esophagogastric mucosal lesions in patients on hemodialysis [40]. Wang et al.'s study on among 3593, the positive rate of H. pylori infection was 37.3%. H. pylori-positive participants had a lower level of eGFR than H. pylori-negative participants. In univariate analysis, the positive rate of H. pylori infection and RR (relative risk) became larger with eGFR decreased, however, the association was not significant after adjustment for other factors. Further multiparameter analysis showed age and sex were the main confounders between eGFR and H. pylori infection [41]. Wijarnpreecha et al. showed H. pylori in patients with non-dialysis-dependent kidney diseases is 53%. This study consistent with our study does not support the association between H. pylori infection and non-dialysis-dependent kidney diseases nor CKD [9].
Thereby, the difference between groups in GFR is important in clinical management, although the GFR difference between and within two groups was not significant. It is recommended that all patients who are candidates for renal transplant should be screened for H. pylori infection, and the patient should undergo an eradication regimen for a favorable outcome. This is suggested since the risk of progressing to severe disease is increased while the patients are taking immunosuppression medications.
The major limitation of the investigation was the small percentage of H. pylori eradicated patients. Although the results of this interventional study were promising, these findings need to be confirmed in prospective and interventional studies with larger groups of patients to evaluate the exact role of H. pylori eradication in clinical outcomes of CKD patients. In future studies, it is suggested to apply more accurate procedures for the diagnosis of H. pylori infection, such as UBT and increase the number of follow-up visits to confirm the eradication. Moreover, a second diagnostic procedure should be applied simultaneously to correctly estimate the prevalence of infection and achieve an acceptable level of eradication for this infection.
Conclusion
H. pylori eradication in CKD patients slightly increases the GFR and concurrent H. pylori infection and chronic renal failure may complicate the patient’s underlying disease.
Acknowledgments: The results of this trial are a part of a post-graduate thesis (Saeede Jahanbani). We gratefully acknowledge the Vice Chancellor for Research, Yasuj University of Medical Sciences for the support.
Ethical Permissions: This research has been approved by the Research Ethics Committee of Yasuj University of Medical Sciences (with ethics code: I.YUMS.REC.1396.99).
Patients completed a written informed consent form. Patients were allowed to withdraw from the study at any stage of the study, also, with the occurrence of any unwanted side effects. The treatment process was carried out under the supervision of internal specialists. To perform laboratory tests, the same samples that are routinely prescribed to the patient in periodical evaluations were used. Declaration of Helsinki was considered in this research.
Conflicts of Interests: The authors of the present study declare that they have no conflict of interest.
Authors' Contribution: Abbasi Larki R (First Author), Original Researcher/Methodologist/Introduction Writer/Discussion Writer (30%); Azad A (Second Author), Original Researcher/Methodologist/Introduction Writer/Discussion Writer (30%); Jannesar R (Third Author), Methodologist/Assistant Researcher/Introduction Writer (10%); Manzouri L (Fourth Author), Assistant Researcher/Introduction Writer/Statistical Analyst/Discussion Writer (15%); Jahanbani S (Fifth Author), Assistant Researcher/Introduction Writer/Methodologist/Discussion Writer (15%)
Funding/Support: This paper is extracted from an Internal Medicine resident thesis at Yasuj University of Medical Sciences.
Chronic kidney disease is a progressive disease with no cure and high morbidity and mortality that usually occurs in the adult population. Preservation of kidney function can improve outcomes and be achieved through non-pharmacological strategies (dietary and lifestyle modification) and chronic kidney disease-targeted and kidney disease-specific pharmacological interventions [1]. Patients require monitoring for complications of CKD such as hyperkalemia, metabolic acidosis, hyperphosphatemia, vitamin D deficiency, secondary hyperparathyroidism, and anemia [2]. In addition to physical, mental and emotional dimensions, quality of life, depression [3], sleep disorders [4], and reduced life expectancy affect both patients and caregivers [5]. A patient with CKD for a period equal to or longer than three months, a glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2 or a GFR greater than 60 mL/min/1.73 m2 and with evidence of structural damage He showed the kidney [6]. Some studies show that the prevalence of chronic kidney failure in Iran is increasing [3]. The final stage of this disease ESRD (End Stage Renal) is irreversible kidney loss and patients permanently need alternative treatments such as kidney transplants or dialysis [3]. Reduction in the glomerular filtration rate and progressing to the dialysis stage impose on patients many emotional and financial burdens as well as loss of quality life [7]. The following risk factors play a role in the development and progression of CKD: Female gender, high BMI, race with high prevalence in people of Black and South Asian origin, old age, increased waist circumference, arterial hypertension, and some comorbidities such as diabetes [8]. Unfortunately, the current global increase in type-II diabetes also contributes to the rising prevalence of CKD. The previous studies reported the prevalence of H. pylori infection among patients with CKD range between 20 and 60% [9].
Helicobacter pylori (H. pylori) is a gram-negative spiral rod and its infection is common, that is commonly found in the stomach [10]. The prevalence of this disease is related to age, ethnicity, related diseases, geographical areas, socio-economic status, and health conditions [11].
The transmission of this bacterium occurs via the fecal-oral, and oral-oral routes [12]. There is a direct relationship between Helicobacter pylori infection and its transmission with water pollution, low-quality lifestyle, poor diet, smoking and lack of physical activity [13]. The global prevalence of Helicobacter pylori infection in adults has decreased from 50 to 55% to 43% [14, 15] which is mostly attributed to the improvement of socio-economic status, living standards and health conditions, increasing the use of antibiotics including eradication treatment [11].
Recent evidence has proposed the implication of H. pylori in a variety of extra gastric diseases, such as neurological diseases [16], coronary heart disease [17], and glaucoma [18]. Furthermore, a concurrence between H. pylori infection and a number of diseases such as biliary, pancreatic and colon diseases has been reported [19-21]. The suggested mechanism for these diseases is that chronic infection by H. pylori causes chronic inflammation with a low degree as a biological response. Inflammatory factors produced by the gastric mucosa such as tumor necrosis (TNF) and cytokines (IL) are induced in gastritis, diabetes, metabolic syndrome, atherosclerosis and obesity, which are secreted into blood circulation and metabolic profiles [13, 22].
Some evidence emphasizes the association between H. pylori infection and the upcoming development of end-stage renal disease (ESRD). A large nation-based study indicated that concomitant H. pylori infection with CKD puts patients at increased risk of progression to ESRD [23, 24]. The common feature of all the indicated pathological diseases is the presence of a low-grade systemic inflammation [16].
Despite the well-studied effects of H. pylori infection on other organs of the body, no conclusive evidence was shown to indicate that this pathogen may secondarily lead to diminished renal function. The results of some studies indicated a lower prevalence rate of H. pylori infection in CKD or ESRD patients [25, 26]. Increased inflammatory cytokines in patients with CKD leads to gastric mucosal damage, which in turn makes it difficult for H. pylori to survive [25]. Furthermore, a recent meta-analysis estimated the prevalence on H. pylori infection in 44% of the ESRD and 53% in non-dialysis-dependent CKD patients. They concluded that H. pylori infection has a protective role in ESRD [27]. In peptic ulcer disease (PUD) patients with CKD and ESRD, a lower rate of infection with this pathogen has been reported [26]. A possible explanation for this report is the severe inflammation and progressive gastric atrophy due to uremic milieu and dialysis which restrain the pathogen from surviving in the gastric environment [28]. The prevalence of ESRD in H. pylori positive cases has been described 3.72 times higher than in non-infected cases in some other studies. They concluded that H. pylori could be a predisposing factor in the progression of renal failure [23]. In Turkey, the prevalence was reported even higher, around 66% [27], while in Iran, the concurrence of H. pylori infection and ESRD was estimated between 28% to 67% [24, 29, 30].
Moreover, an association between H. pylori infection and a series of inflammatory and immunological events has been described. Hence, H. pylori trigger a cascade of local and systemic immunological and inflammatory responses believed to be the source of extra-gastric complications of this infection [31]. The release of inflammatory cytokines could be independently associate with the weakness and lack of energy experienced by CKD patients. Thus, it is assumed that H. pylori eradication further enhances the quality of life in this group of patients [22]. Recent studies have shown the importance of studying gastrointestinal diseases and outside gastrointestinal diseases associated with H. pylori infections [16]. Knowing the factors affecting this disease helps us take effective measures to prevent, treat and reduce complications and reduce costs because effective treatment for advanced kidney disease includes dialysis and kidney transplantation both of which are costly. On the other hand, due to the conflicting results of different studies on the exact effect of H. pylori infection on CKD patients, this study aimed to determine the effect of Helicobacter pylori infection eradication on glomerular filtration rate in patients with chronic kidney disease.
Materials and Methods
Study design
The present study was an interventional study involving a group of patients with H. pylori infection. After 6 months of follow-up, H. pylori infection was eradicated in some patients (group A), while it persisted in others (group B). Therefore, we compared GFR within and between the two groups at baseline and 6 months after.
Participants, eligibility criteria, and settings
The study population consisted of patients referred to an outpatient nephrology clinic in Yasuj, Iran from August to January 2016. Inclusion criteria included patients aged between 18 to 70 years, diagnosed with CKD with a GFR between 30 to 60 mL/min, a positive stool antigen test for H. pylori infection, and a negative pregnancy test at the time of the study, without renal malignancy, or a history of transplantation. However, those who had undergone surgery for any reason or had a history of hospitalization, myocardial infarction, stroke, acute kidney injury (AKI), and hypertension crisis in the past 6 months were excluded. Furthermore, enrolled patients had not taken any of the following medications during the past two months: Anti-Helicobacter pylori antibiotics, anti-acids, proton pump inhibitors (PPIs), and non-steroidal anti-inflammatory drugs (NSAIDs).
Sample size
The sampling method in this study was convenience sampling. A total of 270 eligible patients with CKD and GFR between 30 to 60 mL/min who were referred to the Nephrology Clinic affiliated to Yasuj University of Medical Sciences, Yasuj, Iran, (from August 2016 to January 2017) were recruited for the present study. They were referred to the laboratory for fecal antigen testing, however, only 79 patients with a positive fecal antigen test were included in the study.
Laboratory measurements
For all the participants (79 patients), the stool antigen test, the serum creatinine levels, and blood urea nitrogen (BUN) were recorded at baseline and 6 months after H. pylori eradication treatment. Stool antigen test was performed in a medical diagnostic laboratory according to immune assay methods. Creatinine and BUN were measured by using biochemical methods and kits (Pars Co., Iran). Measurement were performed according to the manufacturer’s instruction using an automatic autoanalyzer Hitachi 917 (Hitachi, Taiwan).
Intervention and data collection
The patients who had a positive stool antigen test received the triple eradication regimen of H pylori infection including a one-week course of omeprazole (20 mg twice a day, Abidi Pharma Co, Iran), amoxicillin (1 g twice a day, Daana Pharma Co, Iran), and azithromycin (500 mg, Rouzdarou Co, Iran) one gram daily for the first three days. Omeprazole was continued for three weeks at the dose of 20 mg daily [32]. The patients were given verbal instructions to take their medications regularly during the treatment course and not to stop their therapeutic regimen.
Stool antigen test, serum levels of creatinine and BUN were measured and recorded at baseline and six months after treatment. Furthermore, the GFR of patients whose H. pylori infection was successfully eradicated and those with therapeutic failure, after 6 months, were measured and compared with each other. The value of GFR was calculated to determine the effect of the H pylori eradication on renal function (Equation 1):
Equation 1:Abbreviated MDRD study equation
GFR=186×(serum creatinine)-1.154×(age)-0.203×(0.742 if female)×1.210(if African-American)
Statistical analysis
Qualitative parameters were reported by frequency and percent, and quantitative parameters were reported by Mean±SD. The chi-square test and Fisher’s Exact Test were used to compare the qualitative parameters in the two groups of the study. One sample Kolmogorov-Semenov test was used to evaluate the distribution of parameters. Independent t-test was used to compare the means of the studied groups. To compare between means before and after the intervention in the studied groups, we applied paired t-test. All statistical analysis was conducted by using SSPS software version 23, and differences with a value of p<0.05 were considered significant.
Findings
Participants
Overall, 270 patients with CKD were evaluated for H. pylori infection. In total, 79 patients with CKD and a positive stool antigen test for H. pylori entered in the study, and 49 patients completed the study. The trend of changes in GFR was evaluated and compared in CKD patients in whom H. pylori infection was successfully eradicated (15 patients, group A) to those whose infection had not eradicated (34 patients, group B).
Patient characteristics in the two study parts were similar with no significant difference between the two groups in demographic characteristics (age, gender ratio, and baseline GFR).
The minimum and maximum ages of the patients were 24 and 69 years, respectively. The mean age of the patients was 54.5±11.6 years in group A and 55.84±9.20 years in group B. Male participants represented 40% of the negative test group, compared to approximately 55.9% in the other group. Conversely, female participants made up 55.9% of the negative test group, while they constituted around 44.1% in the other group.
The patients who completed the study did not report serious adverse effects. The eradication rate of the course of the regimen was 30.6% when evaluated at month 6.
GFR in patients with negative Helicobacter pylori stool antigen group (49.40±15.54) was more than in positive Helicobacter pylori stool antigen group (44.90±13.70), however this difference was not significant (p=0.75).
The mean of GFR before the eradication of H. pylori in group A slightly increased from 48.54±8.66 mL/min to 49.5±15.4 mL/min after 6 months of receiving treatment with anti H. pylori drugs. However, this difference was not significant (p=0.18). In the group B, the trend of changes in GFR values did not change significantly in both groups (p=0.48).
Discussion
This study aimed to determine the effect of Helicobacter pylori infection eradication on glomerular filtration rate in patients with chronic kidney disease.
In the current study, the frequency of a positive H. pylori stool antigen in patients with chronic kidney injury was 34 from total 49 patients after 6 months of treatment. In other words, H. pylori infection was eradicated in only 30.6% of the subjects after treatment. Normally, the eradication is effective in up to 70% of cases. In this study, the rate of eradication was lower than normal. This can be explained by the widespread prescription of various antibiotics in CKD patients, and the common resistance of H. pylori to the following antibiotics; Erythromycin and Amoxicillin. Furthermore, the extensive use of medications in these patients probably reduced the antibiotics concentration for eradication. Moreover, it has been demonstrated that the presence of uremic toxins could minimize the absorption of antibiotics in CKD population. This could also be justified by the fact that the subjects failed to stop the PPI (Proton Pump Inhibitors) medications before testing, the sensitivity of stool the H. pylori antigen test is low and the recurrence of the infection. Our results were consistent with the results obtained by Sugimoto & Yamaoka and Schoonjans et al. [33, 34].
Different studies have suggested various etiologies for H. pylori recurrence. For instance, the ongoing activation of the inflammatory cascade, has elevated release and diminished clearance of pro-inflammatory cytokines, endotoxemia following fluid overload, reduced amount of anti-toxins levels, the migration of activated inflammatory agents in the digestive tract, and the presence of comorbidities have been proposed to explain H. pylori recurrence [35]. Following the rise in the blood volume, the gastrointestinal permeability increases. Moreover, the accumulation of endotoxins such as lipopolysaccharides of gram-negative bacteria takes place in the gastrointestinal tract. This phenomenon recruits the monocytes to the site of inflammation and further increases the release of pro-inflammatory cytokines [35, 36]. All of these factors might be involved in complicating the clinical outcome of patients with CKD and H. pylori infection, simultaneously.
The results of this study demonstrated that eradication of H. pylori infection in CKD patients may increase the glomerular filtration rate slightly and not taking a therapeutic strategy for this infection could worsen the patient's clinical outcome, although these differences not significant. Similar to previous studies, the results of this study showed that the transfer of bacteria from the gastrointestinal tract into the bloodstream increases in patients with renal insufficiency. Thereby, the eradication of this chronic infection may slow down the progression of CKD [35, 36]. In a cross-sectional study conducted on kidney transplant patients, no significant difference was observed in estimated GFR (eGFR) of the patients whose H. pylori infection test was either positive or negative [37]. In a clinical trial on 132 patients with various ranges of kidney function (normal to ESRD), a relation between the rate of successful eradication of H. pylori infection and different levels of GFR was explored. The authors of this study found no association between H. pylori eradication and kidney function [38].
In the present study, the percentage of patients whose infection had successfully eradicated at the end of the study was low. This could explain the fact that the differences in GFR between the groups, although in favor of H. pylori eradication, were not significant. In the study conducted by Abdulrahman & Al-Quorain, the prevalence of H. pylori infection in ESRD patients was reported in 40% of the subjects. The prevalence of this infection was similar in ESRD patients and renal transplant recipients [39]. In a prospective cohort study comprised of 198 ESRD patients undergoing maintenance hemodialysis, the prevalence of H. pylori infection was reported in 41% of the patients (81 positive cases out of 198 studied subjects). The patients underwent 13C-urea breath test (13C-UBT) for determination of H. pylori infection. It is noteworthy that multivariate analysis of the results was suggestive of a protective role for H. pylori infection against gastric erosion in this particular population. Hence, H. pylori eradication may increase the risk of esophagogastric mucosal lesions in patients on hemodialysis [40]. Wang et al.'s study on among 3593, the positive rate of H. pylori infection was 37.3%. H. pylori-positive participants had a lower level of eGFR than H. pylori-negative participants. In univariate analysis, the positive rate of H. pylori infection and RR (relative risk) became larger with eGFR decreased, however, the association was not significant after adjustment for other factors. Further multiparameter analysis showed age and sex were the main confounders between eGFR and H. pylori infection [41]. Wijarnpreecha et al. showed H. pylori in patients with non-dialysis-dependent kidney diseases is 53%. This study consistent with our study does not support the association between H. pylori infection and non-dialysis-dependent kidney diseases nor CKD [9].
Thereby, the difference between groups in GFR is important in clinical management, although the GFR difference between and within two groups was not significant. It is recommended that all patients who are candidates for renal transplant should be screened for H. pylori infection, and the patient should undergo an eradication regimen for a favorable outcome. This is suggested since the risk of progressing to severe disease is increased while the patients are taking immunosuppression medications.
The major limitation of the investigation was the small percentage of H. pylori eradicated patients. Although the results of this interventional study were promising, these findings need to be confirmed in prospective and interventional studies with larger groups of patients to evaluate the exact role of H. pylori eradication in clinical outcomes of CKD patients. In future studies, it is suggested to apply more accurate procedures for the diagnosis of H. pylori infection, such as UBT and increase the number of follow-up visits to confirm the eradication. Moreover, a second diagnostic procedure should be applied simultaneously to correctly estimate the prevalence of infection and achieve an acceptable level of eradication for this infection.
Conclusion
H. pylori eradication in CKD patients slightly increases the GFR and concurrent H. pylori infection and chronic renal failure may complicate the patient’s underlying disease.
Acknowledgments: The results of this trial are a part of a post-graduate thesis (Saeede Jahanbani). We gratefully acknowledge the Vice Chancellor for Research, Yasuj University of Medical Sciences for the support.
Ethical Permissions: This research has been approved by the Research Ethics Committee of Yasuj University of Medical Sciences (with ethics code: I.YUMS.REC.1396.99).
Patients completed a written informed consent form. Patients were allowed to withdraw from the study at any stage of the study, also, with the occurrence of any unwanted side effects. The treatment process was carried out under the supervision of internal specialists. To perform laboratory tests, the same samples that are routinely prescribed to the patient in periodical evaluations were used. Declaration of Helsinki was considered in this research.
Conflicts of Interests: The authors of the present study declare that they have no conflict of interest.
Authors' Contribution: Abbasi Larki R (First Author), Original Researcher/Methodologist/Introduction Writer/Discussion Writer (30%); Azad A (Second Author), Original Researcher/Methodologist/Introduction Writer/Discussion Writer (30%); Jannesar R (Third Author), Methodologist/Assistant Researcher/Introduction Writer (10%); Manzouri L (Fourth Author), Assistant Researcher/Introduction Writer/Statistical Analyst/Discussion Writer (15%); Jahanbani S (Fifth Author), Assistant Researcher/Introduction Writer/Methodologist/Discussion Writer (15%)
Funding/Support: This paper is extracted from an Internal Medicine resident thesis at Yasuj University of Medical Sciences.
Keywords:
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