Determining the frequency of Helicobacter pylori in children with chronic kidney failure and its relationship to gastrointestinal symptoms

Key Clinical Message As there is no significant mutual relationship between Helicobacter pylori infection and chronic kidney disease in children, its routine study is not justified and is recommended only in symptomatic cases. Abstract Children suffering from chronic kidney disease (CKD) often complain of indigestion but, if it is accompanied by abdominal pain, it is necessary to investigate and rule out Helicobacter pylori infection to confirm functional dyspepsia. Epidemiological studies in adults have conflicting results regarding the association between Helicobacter pylori infection and CKD. In this study, we determined the prevalence of H. pylori in children with kidney failure and its relationship to their gastrointestinal symptoms. In this retrospective study, 54 children with chronic kidney failure admitted to the hemodialysis ward of the Children's Medical Center, Tehran, Iran between 2012 and 2020 were studied. The mean age of our patients was 11.89 ± 3.99 years and their sex distribution was equal. H. pylori infection was reported in only three patients with 5.6%. Based on our findings, epigastric pain in children was the most common gastrointestinal symptom (70.4%). Among all patients, three patients (5.6%) died, all of them were male (P = 0.075). The most prevalent underlying cause of kidney failure in our patients was neurogenic bladder. We did not find any significant relationship between the increased risk of chronic kidney failure and co‐infection with H. pylori. Investigating the cause of epigastric pain and looking for H. pylori is very important in CKD children under hemodialysis because if they receive a transplant the possibility of gastrointestinal complications will be increased with the use of steroid and immunosuppressive drugs.

Epidemiological studies in adults have conflicting results regarding the association between Helicobacter pylori infection and CKD.In this study, we determined the prevalence of H. pylori in children with kidney failure and its relationship to their gastrointestinal symptoms.In this retrospective study, 54 children with chronic kidney failure admitted to the hemodialysis ward of the Children's Medical Center, Tehran, Iran between 2012 and 2020 were studied.The mean age of our patients was 11.89 ± 3.99 years and their sex distribution was equal.H. pylori infection was reported in only three patients with 5.6%.Based on our findings, epigastric pain in children was the most common gastrointestinal symptom (70.4%).Among all patients, three patients (5.6%) died, all of them were male (P = 0.075).The most prevalent underlying cause of kidney failure in our patients was neurogenic bladder.We did not find any significant relationship between the increased risk of chronic kidney failure and co-infection with H. pylori.
Investigating the cause of epigastric pain and looking for H. pylori is very important in CKD children under hemodialysis because if they receive a transplant the possibility of gastrointestinal complications will be increased with the use of steroid and immunosuppressive drugs.

| INTRODUCTION
Chronic kidney disease (CKD) is defined as an irreversible reduction in kidney function, which can be fatal in the absence of dialysis or transplantation.This condition is associated with diverse clinicopathological conditions of the digestive, cardiac, vascular, pulmonary, and immune systems. 1,2There have been discussions about the mutual relation between Helicobacter pylori infection and CKD. 3,4Yet, the pathogenesis of H. pylori infection in CKD patients is not clearly defined. 5,6Patients with CKD often complain of dyspepsia due to various causes, and H. pylori infection should be excluded from the diagnosis of functional dyspepsia. 7. pylori is the most prevalent chronic bacterial infection in humans and is associated with several other gastrointestinal disorders including gastritis, peptic ulcer, gastric cancer, and extra-nodal marginal zone lymphoma of mucosa-associated lymphoid tissue. 6,8Although H. pylori is observed in 20%-40% of the general population, it has been accepted as an etiological factor in peptic ulcers, chronic gastritis, indigestion, gastric, and mucosa-related cancers. 9Overall, the risk of gastrointestinal complications and cancer is higher in CKD patients than in the general population. 10It is known that H. pylori can play an important role in the gastrointestinal symptoms of patients with chronic kidney failure.Also, early diagnosis and treatment for H. pylori infection might prevent its impact on renal function. 11This study is designed to investigate the prevalence of H. pylori in pediatric CKD and its relation to gastrointestinal symptoms.

| METHOD AND MATERIALS
In this retrospective study, 54 patients with chronic kidney failure admitted to the hemodialysis ward of the Children's Medical Center, Tehran, Iran between 2012 and 2020 were studied.The sampling method was based on patients aged (1-18 years) with chronic kidney failure who were undergoing hemodialysis permanently at least once a week.Patients with the use of non-steroidal anti-inflammatory drugs (NSAIDs), patients with a history of H. pylori eradication treatment, and subjects with incomplete medical records were excluded from the study.Patients with clinical symptoms and gastrointestinal complications with a positive test were subjected to a serology test with 5 cc of blood to check IgG and IgM for H. pylori.Then the patients were subjected to endoscopic and serological gastrointestinal examinations.All patients underwent endoscopic study and if there were positive findings stool examinations were done to ascertain the presence of H. pylori antigen.
Detailed clinical data were retrospectively collected from the patient's medical records.This information included demographic characteristics, gastrointestinal symptoms such as heartburn, abdominal pain, type of drug used, method of checking H. pylori infection, kind of underlying disease, type of dialysis, life status, endoscopy, and pathology results.This study was approved by the Ethics Committee of Tehran University of Medical Sciences (Ethics number: IR.TUMS.CHMC.REC.1401.091).

| Statistical analysis
Statistical analysis was done by SPSS software version 26.The qualitative variables were indicated as numbers and percentages.Analytical analysis was performed using chisquared test.A p < 0.05 was considered significant.

| RESULTS
In this study, 54 patients with chronic kidney failure undergoing hemodialysis with gastrointestinal complaints were studied.The sex difference was equal (27 boys and 27 girls).The age range of patients was 1-18 years old, and the mean age was 11.89 ± 3.99 years.Considering the distribution of the age categories; most of the patients were in the range of 10-14 years old (n: 22; 40.7%).
The most common gastrointestinal symptoms in these children were epigastric pain (70.4%) and nausea (16.7%).Four (7.4%) had no signs and symptoms at all.The most commonly used drug was Famotidine (57.4%), followed by Protein Pump Inhibitor (13%), and the most combination treatments were Famotidine and PPI (n: 13, 24.1%).The average duration of treatment was 6.17 ± 5.03 months (range; 1-24 months).Of the entire cohort, a total of three patients (5.6%) died and all of them were male (P = 0.075).More details of findings are provided in Table 1.
All patients underwent the endoscopic study, and in case of positive findings stool examinations were conducted alongside to ascertain the presence of Helicobacter antigen.According to the endoscopic research, 47 (87%) children, chronic kidney disease, functional dyspepsia, gastritis, Helicobacter pylori, peptic ulcer had symptoms of gastritis, 4 (7.4%)patients presented with both gastritis and esophagitis, and only three patients were reported positive for H. pylori infection, all were female and the other 24 females had negative H. pylori results.All 27 males had negative Helicobacter study results (P = 0.075).It is noticeable that none of our patients had positive stool antigens.Additionally, those who died did not have severe gastrointestinal symptoms.
The primary etiology of CKD and ultimately end-stage renal disease (ESRD) was neurogenic bladder (18.5%) and nephronophthisis was identified as an additional etiological factor, observed in 13.06% of cases.
Based on the findings derived from endoscopy, gastritis had been diagnosed in 47 patients (87%) while simultaneous gastritis and esophagitis were identified in 4 cases (7.4%).Generally, famotidine is the most frequently administered drug in dyspepsia 57.4% and the Protein Pump Inhibitors have a market score of 13%.Also, according to medical prescriptions, the pairing of Famotidine and PPI is the most prevalent combination therapy (24.1%) (Table 2).The distribution of GI symptoms and causes of disease according to the Helicobacter status showed no significant difference between the groups (Tables 3 and 4).

| DISCUSSION
CKD is defined as the presence of kidney damage and the loss of kidney function. 12One of the symptoms of chronic kidney failure is digestive symptoms, and these patients often complain of indigestion for various reasons.It is considered that uremic toxins and uremic neuropathy, gastrointestinal hypomotility, visceral hypersensitivity to gastric distension, amyloid protein deposition, and H. pylori infection have important roles in the development of dyspeptic symptoms in CKD patients.These symptoms are similar to H. pylori infection and H. pylori infection is also seen in CKD patients as in normal people.Helicobacter infection should be excluded to diagnose the final cause of digestive symptoms as functional indigestion. 5he present study is conducted to investigate the prevalence of H. pylori in pediatric kidney failure and relationship with gastrointestinal symptoms.Our results showed there is no significant relationship between the increased risk of chronic kidney failure and H. pylori infection and vice versa.Based on our findings the most common gastrointestinal symptom in pediatric CKD is epigastric pain (70.4%).
Increasing interest in assessing the association between H. pylori infection and CKD is due to the presence of extraintestinal associations with H. pylori infection such as insulin resistance or metabolic syndrome also seen in CKD patients.It is suggested there is a significant relationship between H. pylori infection and chronic kidney patients because this infection is more common in those with diabetes and high blood pressure which are the most common causes of CKS. 13 Based on our findings, there was no notable relationship between H. pylori and chronic kidney failure.Similar to our findings, Gu et al.'s study showed no significant association between dialysis-related chronic renal failure and H. pylori infection. 4Contrary to our results, Wijarnpreecha et al. stated a significant relationship between chronic renal failure not related to dialysis and H. pylori infection. 8The difference in sample size may be the cause of this discrepancy.Alhoufie et al. reported the prevalence of acute H. pylori infections in 33.1% of kidney failure patients. 14In a study by Wijarnpreecha et al., the estimated prevalence of H. pylori in ESRD patients is 44%. 8In our study, H. pylori infection was reported in only three patients with 5.6%.In our study, most of the patients were in the range of 10-14 years old, and the sex distribution was equal.The study by Alhoufie et al. showed no remarkable distribution of H. pylori infection among different age groups of renal failure patients. 14Matini et al. reported patients' complaints of epigastric pain, nausea, vomiting, then abdominal bloating. 15In a study by Ardalan et al. a. majority of renal failure patients usually suffer from gastrointestinal complications such as gastric erosions. 16The findings of this study are consistent with the current study.The most prevalent underlying cause of kidney failure in our patients was neurogenic bladder.While Xiong et al. noted 32.9% of H. pylori-seropositivity in renal failure patients suffering from hypertension as an underlying disease which concurs with recent observations. 17Also, Alhoufie et al. reported 32.9% of H. pyloriseropositivity in renal failure patients suffering from hypertension as an underlying cause of CKD. 14 Similar to the current study, in the study by Hooman et al. there was no correlation between H. pylori infection and gender. 18s CKD patients often complain of dyspepsia, H. pylori is a probable cause, but the underlying mechanism is not fully understood.The present study can help in better understanding of this pathology in CKD patients This study has several limitations.First, the sample size was small, and second, there was no control group.Another limitation of the study is its retrospective nature and singlecentric base.

| CONCLUSION
Our study shows no significant relationship between H. pylori and chronic kidney failure in children.Due to the low prevalence of H. pylori in patients with chronic kidney failure and the association of H. pylori with gastrointestinal symptoms, it is suggested that endoscopy and examination should be performed only in symptomatic patients.However, since the number of patients studied in this research was small, we suggest conducting more T A B L E 3 The pathology results according to GI Symptoms.

Total
Demographic and baseline characteristics of patients.Clinical characteristics of patients.
T A B L E 1 The pathology results according to the cause of the disease.NEZHAD et studies with a sample size in several dialysis centers on a larger number of patients.There are concerns that H. pylori eradication therapy may worsen kidney function in patients with decreased renal function.