**Core tip:** Hemodialysis (HD) patients have a poor prognosis related in part to protein-energy wasting (PEW), associated with low levels of ghrelin. The severity of gastric mucosal atrophy has been suggested as the major determinant of ghrelin levels. Eradication of *Helicobacter pylori* (*H. pylori*) improves nutritional status, with serum cholinesterase and cholesterol levels stimulated by rising ghrelin levels and appetite, especially in *H. pylori* infection-positive patients with severe gastric mucosal atrophy. Although infection rates of *H. pylori* have been decreasing in HD patients, it would be preferable to eradicate *H. pylori* promptly before progression of gastric atrophy for prevention of gastric cancer and PEW.

INTRODUCTION
============

With ongoing progress in medical and dialysis machine techniques, the number of chronic renal failure patients receiving hemodialysis (HD) is increasing at a rate of 7% per year. At least 2.9 million Asians require dialysis, including Japanese, who live in an aging society and experience changes in their living environment\[[@B1],[@B2]\]. HD patients often experience gastrointestinal symptoms (*e.g*., nausea, abdominal pain, and constipation) caused by elevated urea levels, decreased gastrointestinal motility, amyloid protein deposition, and sensory disturbances, and are at increased risk of developing gastrointestinal diseases (*e.g*., peptic ulcer disease, gastric antral vascular ectasia, gastroesophageal reflux disease, and gastric cancer)\[[@B3]-[@B7]\]. The risk of gastric mucosal damage is elevated in this population, in association with high ammonia levels\[[@B8]\], systemic and/or local chronic circulatory failure\[[@B9],[@B10]\], and hypergastrinemia\[[@B11]\]. Gastroduodenal diseases such as peptic ulcer and gastric cancer have been linked to chronic *Helicobacter pylori* (*H. pylori*) infection\[[@B12]-[@B15]\]. In HD patients, the role of chronic *H. pylori* infection in their prognosis and quality of life (QOL) has not been defined.

In general, QOL in HD patients is poor. This affects their nutritional status, and thereby contributes to the development of malnutrition, which is a potent predictor of morbidity and mortality\[[@B16],[@B17]\]. The state of metabolic and nutritional derangement called protein-energy wasting (PEW) has a major impact on mortality in HD patients\[[@B16],[@B17]\]. Improving the prognosis of HD patients with PEW requires determination of its etiology and the development of prophylactic strategies\[[@B18],[@B19]\].

The complex interactions of gastroduodenal disease, nutritional status, and *H. pylori* infection in HD patients (which tends to decrease with increasing time on dialysis\[[@B20]\]) remain to be elucidated. Here, we review the association between *H. pylori* infection and HD, and the relationship between *H. pylori* and nutritional status in this population. Finally, we review the effects of *H. pylori* eradication therapy in *H. pylori*-positive HD patients on nutritional status and plasma ghrelin levels.

*H. PYLORI* INFECTION IN HD PATIENTS
====================================

*H. pylori* is a spiral-shaped, microaerophilic Gram-negative flagellate bacterium isolated in 1983 from gastric biopsy specimens of patients with chronic atrophic gastritis\[[@B21]\]. The gastric mucosa of approximately 50% of the world's population is infected with *H. pylori*, and the infection levels exceed 70% in some developing areas\[[@B15],[@B22]-[@B24]\].

Previously, we reported that the prevalence of *H. pylori* infection in 539 Japanese HD patients with a mean treatment period of 8.4 ± 0.3 year in 1997 was 48.6% (95%CI: 44.3%-52.9%). This was significantly lower than that in dyspepsia patients with normal renal function \[78.5% (74.1%-82.4%), *P* \< 0.001\] and individuals receiving annual health checks \[69.4% (60.3%-77.5%), *P* \< 0.001\]\[[@B20]\]. In a meta-analysis of reports investigating the prevalence of *H. pylori* in dialysis patients before 2009, the prevalence in patients receiving HD and continuous ambulatory peritoneal dialysis (CAPD) was 43.9% \[(95%CI: 42.2%-45.6%), 1435/3272\] and 34.8% \[(29.6%-40.2%), 113/325\], respectively, which was again significantly lower than that in individuals with normal renal function \[49.8% (48.0%-51.7%), 1476/2961, *P* \< 0.001\]\[[@B25]\]. Although infection rates differ among different geographic populations, in East Asian countries where the prevalence of *H. pylori* infection and incidence of gastric cancer is relatively high, the latest statistics show the infection rate in HD patients to be 44.5% (41.55%-47.6%, 474/1065), which is significantly lower than that in individuals with normal renal function \[54.0% (50.9%-57.1%), 560/1038, *P* \< 0.001\]\[[@B25]\]. Importantly, the prevalence in individuals with normal renal function is similar in patients receiving HD treatment for \< 1 year\[[@B20]\]. HD treatment, but not uremia from chronic renal failure, may play an important role in the decreased prevalence of *H. pylori* infection.

Recently, infection rates of *H. pylori* have been decreasing. A large-scale Japanese epidemiological study showed that the infection rate in Japanese has declined to 30%-50%, especially in younger patients\[[@B26]\]. Supporting this phenomenon, an investigation of 500 Japanese HD patients with a mean treatment duration of 6.9 ± 6.6 years (2015) reported that the prevalence of infection had dramatically decreased, to 15.0% (95%CI: 12.0-18.4)\[[@B27]\]. Although it has not yet been proven, decreasing rates of *H. pylori* infection suggest that the incidence of peptic ulcer disease and gastric cancer is expected to be decreasing in HD patients and that QOL in HD patients has improved due to decreases in *H. pylori-*related gastrointestinal disease.

TREATMENT PERIODS OF HD AND *H. PYLORI* INFECTION
=================================================

There is an inverse relationship between *H. pylori* infection and dialysis treatment duration (Table [1](#T1){ref-type="table"})\[[@B20],[@B27]-[@B31]\]. We showed that the duration of HD treatment in *H. pylori-*positive patients was 4.6 ± 3.8 years, which is significantly shorter than that in *H. pylori-*negatives (7.3 ± 6.9 years, *P* = 0.001)\[[@B27]\]. Interestingly, the finding of decreased *H. pylori* infection is characteristic of the prevalence of infection decreasing when the treatment period is ≥ 2 year\[[@B28]\], and the infection rate gradually decreases up to four years after the initiation of HD and is followed by a plateau\[[@B20]\]. In a 4-year follow-up survey of *H. pylori-*positive patients, the prevalence of infection was 51.6% at 1 year, 42.9% at 2 year, and 38.3% at 4 year in the absence of eradication therapy. In other words, 26.7% of patients were naturally cured of *H. pylori* infection over four years\[[@B20]\].

###### 

Hemodialysis treatment duration and *Helicobacter pylori* infection status in hemodialysis patients\[[@B27]\], %

                                  **\< 1 yr**    **1-3 yr**      **3-10 yr**      **\> 10 yr**    ***P* value**
  ------------------------------- -------------- --------------- ---------------- --------------- ---------------
  *H. pylori* infection rate      23.8 (15/63)   16.7 (18/108)   15.0 (34/226)    7.8 (8/13)      0.043
  Rate of *H. pylori* negatives   55.5 (35/63)   62.0 (67/108)   68.1 (154/226)   68.9 (71/103)   \> 0.05

It is unknown why HD patients have a lower prevalence of *H. pylori* infection. One hypothesis is that HD patients have higher levels of pro-inflammatory cytokines\[[@B32]\]. As a result, gastric atrophy progresses, and finally *H. pylori* are not able to live in the gastric mucosa\[[@B33]-[@B35]\]. Another hypothesis is that elevated blood urea and urea nitrogen levels may inhibit *H. pylori* growth\[[@B36]\]. A third hypothesis is that *H. pylori* may be cured with incidental antibiotic treatment, because most HD patients suffer from an increased incidence of bacterial infections, and because plasma levels of antimicrobial agents may be higher in HD patients than in individuals with normal renal function\[[@B37]\].

PEPSINOGEN IN HD PATIENTS
=========================

Human pepsinogens (PGs) are proenzymes that act on pepsin. Serum PG levels reflect the status of the gastric mucosa, and decreased PG secretion is a marker of gastric mucosal atrophy. In patients without renal dysfunction, measurements of serum PG levels are used in screening for gastric cancer and gastric mucosal atrophy\[[@B38]\]. In addition, serum PG levels and the PG I/PG II ratio are useful in determining the level of gastric acid secretion\[[@B39]\]. Recently in Japan, a combination of the serum PG level and *H. pylori*-IgG level, namely the ABC method, has been commonly used at health screenings as a useful marker for gastric cancer\[[@B40]\]. Because PG is eliminated *via* the kidney, serum PG levels are elevated in patients with renal dysfunction\[[@B41]\]. The value of serum PG levels as a biomarker of gastric atrophy and the capacity of gastric acid secretion in HD patients was heretofore unknown.

A recent report has demonstrated that PG I and II levels and PG I/PG II ratios in *H. pylori*-negative HD patients are significantly higher than those in *H. pylori*-positives and that PG I levels positively correlate with PG II levels and PG I/PG II ratio in *H. pylori-*negative HD patients (\|R\| = 0.849 and \|R\| = 0.569), past-infection patients (\|R\| = 0.870 and \|R\|=0.575) and current-infection patients (\|R\| = 0.784 and \|R\| = 0.517)\[[@B26],[@B42]\]. In addition, a receiver operating characteristic curve using a cut-off value of 7.75 demonstrated that the sensitivity and specificity of PG I/PG II ratio in predicting the absence of *H. pylori* were 88.7% and 84.0%, respectively\[[@B26]\]. Therefore, serum PG I/PG II ratio may be a valid marker for *H. pylori* infection status and gastric mucosal atrophy in HD patients. Further large-scale studies are needed to verify this.

NECESSITY OF *H. PYLORI* ERADICATION THERAPY FOR HD PATIENTS
============================================================

The incidence rates of peptic ulcer and gastric cancer in HD patients are higher than those in individuals with normal renal function\[[@B7],[@B43]\]. In addition, because most HD patients receive anti-thrombotic therapy and/or non-steroidal anti-inflammatory drugs (NSAIDs), the development of drug-induced ulcers and hemorrhage from gastroduodenal lesions easily occurs and often causes fatal blood loss. Therefore, prompt *H. pylori* eradication therapy is necessary for *H. pylori*-infected HD patients\[[@B12],[@B13]\], especially in HD patients with a higher risk of disease development, such as those with a past history of peptic ulcer, gastroduodenal hemorrhage, or use of anticoagulants and/or NSAIDs.

To reduce the risk of gastric cancer, the Japanese health insurance system in 2012 began covering *H. pylori* eradication therapy for all patients with endoscopic gastritis as well for peptic ulcers, gastric mucosa-associated-lymphoid tissue (MALT) lymphoma, post-endoscopic resection of early gastric cancer, and idiopathic thrombocytopenic purpura (ITP)\[[@B44]-[@B49]\]. In Japan, first-line eradication therapy is limited to a regimen that employs a standard dose of vonoprazan or proton pump inhibitor (PPI) administered twice daily, amoxicillin (AMPC) 750 mg twice daily, and clarithromycin (CAM) 200 mg or 400 mg twice daily for 1 wk. Unfortunately, because the prevalence of CAM-resistant *H. pylori* strains in Japan is increasing (\> 30%), the eradication rate is gradually decreasing\[[@B14],[@B50]-[@B53]\]. Eradication therapy is more challenging in HD patients since they have many exposures to antimicrobial agents due to immune system impairment\[[@B54],[@B55]\]. In fact, 36.4% of patients with chronic renal failure are reported to be infected with CAM-resistant strains, which is significantly higher than in patients with normal renal function (15.2%)\[[@B54]\]. Our recent data published in 2017 shows that rate of CAM-resistant strains in HD patients is 40.5% of infected patients\[[@B55]\]. Alternative regimens may be designed to use *H. pylori-*susceptible antimicrobial agents, increased dosages of antimicrobial agents and PPIs, increased dosing frequency, and longer treatment periods, according to international treatment guidelines\[[@B13],[@B52],[@B56]-[@B60]\].

There is no optimal *H. pylori* eradication regimen in HD patients yet (Table [2](#T2){ref-type="table"}). Some antimicrobial agents, especially AMPC, are known to exacerbate renal dysfunction. The maximum drug concentration of AMPC in patients with renal failure is 2-4 times higher than in patients with normal renal function, and the half-life is 5-20 times as long as that in healthy individuals\[[@B37]\]. Although several previous reports showed no severe adverse effects of AMPC in HD patients receiving eradication therapy\[[@B4],[@B11],[@B30],[@B61]-[@B65]\], the Japanese guidelines for *H. pylori* eradication therapy in the Japanese Society of Helicobacter Research recommends a reduction in AMPC dosage for HD patients\[[@B12]\] and the Japanese drug prescribing guidelines accordingly recommend that the dosage of AMPC for patients with renal failure should be reduced by 70%. In fact, the toxic effects of AMPC in HD patients have been reported in various studies\[[@B66]-[@B68]\]; for example, Sheu et al\[[@B68]\] reported that patients with a lansoprazole-CAM-metronidazole regimen had a lower risk of acute renal failure than those with a lansoprazole-CAM-AMPC regimen (2% *vs* 18%; relative risk, 0.128, 95%CI: 0.016-0.979) for chronic renal failure non-dialysis patients. Overdose of drugs has to be carefully prevented. Although an optimal regimen for dosage and periods of AMPC in HD patients is not described in the Japanese guidelines for eradication\[[@B12]\], an AMPC-reduced regimen may be appropriate in HD patients.

###### 

*Helicobacter pylori* eradication therapy for chronic renal failure patients

  **Year**                       **Author**                                                                                                    **Country**   ***n***    **Regimen**                                                                             **Treatment period**   **Eradication rate (%)**   **Analytic methods**
  ------------------------------ ------------------------------------------------------------------------------------------------------------- ------------- ---------- --------------------------------------------------------------------------------------- ---------------------- -------------------------- -------------------------
  1997                           Tamura et al\[[@B61]\]                                                                                        Japan         14         LPZ (30) oid/ 8 wk, AMPC (500) oid/ 3 wk, plaunotol (80) tid/ 24 wk                     21 d                   78.6                       RUT, Culture, Histology
  1998                           Munos de Bustillo E et al\[[@B30]\]                                                                           Spain         23         OPZ (20) bid, AMPC (500) tid                                                            14 d                   60.8                       UBT
  23                             plus OPZ (20) bid, CAM (500) bid                                                                              14 d          82.6                                                                                                                                                 
  1998                           Tokushima et al\[[@B62]\]                                                                                     Japan         17         LPZ (30) oid/ 8 wk, AMPC (500)                                                          21 d                   76.5                       RUT, Culture, Histology
  10                             LPZ (30) oid, AMPC (250), MNZ (250) bid/                                                                      7 d           90                                                                                                                                                   
  1999                           Araki et al\[[@B63]\]                                                                                         Japan         17         OPZ (20) oid/ 8 wk, AMPC (250) oid, CAM (200) oid/ 3 wk, polaprizinc (0.5) bid/ 24 wk   21 d                   88.2                       IgG, Histology
  1999                           Gur et al\[[@B11]\]                                                                                           Turkey        25         FAM (40) oid, CAM (500) bid, MNZ (250) bid                                              15 d                   80                         Histology, RUT
  2001                           Wang et al\[[@B64]\]                                                                                          China         38         OPZ (20), AMPC (1000), CAM (500) bid                                                    7 d                    86.8                       Stool
  2002                           Mak et al\[[@B91]\]                                                                                           China         21 (CRF)   OPZ (20), AMPC (1000), CAM (500) bid                                                    7 d                    90.5                       RUT
  2002                           Tsukada et al\[[@B65]\]                                                                                       Japan         39         OPZ (30) bid, AMPC (500) tid, CAM (400) bid                                             7 d                    82.1                       UBT
  2003                           Mak et al\[[@B92]\]                                                                                           China         25 (CRF)   OPZ (20) or LPZ (30), AMPC (1000), CAM (500) bid                                        7 d                    96                         Histology
  2003                           Sheu et al\[[@B67]\]                                                                                          China         38 (CRF)   LPZ (30), AMPC (750), CAM (500) bid                                                     7 d                    76.3                       
  40 (CRF)                       LPZ (30), CAM (500), MNZ (500) bid                                                                            7 d           92.5       Stool                                                                                                                                     
  2004                           Sezer et al\[[@B4]\]                                                                                          Turkey        17         OPZ (20), AMPC (1000), CAM (500) bid/                                                   14 d                   94.1                       Endoscopy
  2007                           Tseng et al\[[@B93]\]                                                                                         China         34 (CRF)   ESO (40) or OPZ (20) bid, AMPC (1000) bid, CAM (500) bid                                7 d                    94.1                       UBT
  2007                           Itatsu et al\[[@B69]\]                                                                                        Japan         11         LPZ (60), AMPC (750), CAM (400)                                                         7 d                    72.7                       RUT
                                                                                                                                                             9          LPZ (60), CAM (400)                                                                     7 d                    33.3                       
  2010                           Change et al\[[@B70]\]                                                                                        Korea         12         OPZ (20), AMPC (250), CAM (250), bid                                                    7 d                    83.4                       RUT, Histology
  2010                           Jalalzadeh et al\[[@B94]\], Falaknazi et al\[[@B95]\]                                                         Iran          37         OPZ (20), AMPC (1000), CAM (250), bid                                                   14 d                   81.1                       IgG, UBT, Stool
  2012                           Seyyedmajidi et al\[[@B96]\], Jalalzadeh et al\[[@B97],[@B98]\]                                               Iran          17         OPZ (20), AMPC (500), CAM (250), bid                                                    14 d                   82.4                       UBT, Stool
  Vafaeimanesh et al\[[@B99]\]                                                                                                                                                                                                                                                                                    
  20                             OPZ (40), AMPC (500), azithromycin (250), bid                                                                 14 d          80                                                                                                                                                   
  2014                           Makhlough et al\[[@B100]\]                                                                                    Iran          21         PPZ (40), AMPC (500), CAM (250), bid                                                    14 d                   66.7                       RUT, Histology
  24                             Sequential therapy (PPT \[40\] 10 d, AMPC (500) bid, 5 d and CAM (250), tinidazole (500), bid, 5 d            10 d          84                                                                                                                                                   
  2016                           Makhlough et al\[[@B101]\]                                                                                    Iran          20         PPZ (40), AMPC (500), CAM (500), bid                                                    14 d                   70                         RUT, Stool
  20                             Hybrid regimen PPZ (40), AMPC (500), bid, 7 d + PPZ (40), AMPC (500), CAM (500), tinidazole (500), bid, 7 d   14 d          100                                                                                                                                                  
  2018                           Sahara et al\[[@B55]\]                                                                                        Japan         18         ESO (20), AMPC (750), CAM (200) bid                                                     7 d                    77.8                       IgG
  19                             ESO (20), AMPC (250), CAM (200) bid                                                                           7 d           84.2                                                                                                                                                 

AMPC: Amoxicillin; CAM: Clarithromycin; ESO: Esomeprazole; FAM: Famotidine; LPZ: Lansoprazole; MNZ: Metronidazole; NA: Not available; OPZ: Omeprazole; PPZ: Pantoprazole; RUT: Rapid urease test; UBT: Urea breath test; bid: Twice-daily dosing; tid: Three-times-daily dosing.

Recently, we have adopted a regimen composed of PPI and CAM, both at conventional dosage, and a dose of AMPC that is one-third of the conventional dosage (250 mg twice daily), and investigated the efficacy and safety of this regimen\[[@B55]\]. This regimen in HD patients provided equivalent efficacy as the standard dose in conventional therapy for non-dialysis patients in Japan (82.4% and 82.4%, respectively)\[[@B55]\]. Although this suggests that AMPC-reduced triple therapy is effective and safe for HD patients\[[@B55],[@B69],[@B70]\], the sample number of these reports is small, and it is necessary to set an optimal regimen in HD using a larger number of subjects.

Although the eradication rate with the Japanese standard triple therapy was first reported as approximately 85%-91%, it has gradually decreased year by year because of increased prevalence of CAM-resistant strains of *H. pylori*. Because the eradication rates with tailored treatments based only on CAM susceptibility are not very high (71.9%-94.3%), more advanced tailored treatment considering other factors (*e.g*., different doses of antibiotics and PPIs, different dosages and treatment period) are required to achieve high eradication rates. A tailored *H. pylori* eradication regimen based on CAM susceptibility and maintaining acid secretion (rabeprazole, 10 mg, q.i.d.) is useful because it can achieve an eradication rate exceeding 95%, irrespective of eradication history, thus overcoming differences among CYP2C19 genotypes\[[@B52]\]. However, there was no report to investigate efficacy of tailored regimen in HD patients.

*H. PYLORI* INFECTION AND NUTRITION STATUS IN HD PATIENTS
=========================================================

HD patients have many risk factors that affect mortality, such as chronic inflammation and metabolic and nutritional derangement\[[@B16],[@B17],[@B71]\]. PEW is defined as a state of decreased body stores of protein and energy fuels (body protein and fat mass) and is diagnosed if three features are present: (1) Abnormal nutrition markers (*i.e*., low serum levels of albumin, transthyretin or cholesterol); (2) reduced body mass (*i.e*., low or reduced body or fat mass or weight loss with reduced intake of protein and energy); and (3) reduced muscle mass (*i.e*., muscle wasting or sarcopenia, and reduced mid-arm muscle circumference)\[[@B72]\].

Ghrelin, an orexigenic peptide released primarily from endocrine cells in the stomach, is important in the pathogenesis of PEW in HD patients\[[@B71],[@B73],[@B74]\]. Ghrelin has multiple functions, including enhancement of the orexigenic effect, protein anabolism, anti-inflammatory action, and cardiovascular protection\[[@B74],[@B75],[@B76]\]. Plasma ghrelin levels increase after fasting and decrease after eating. Ghrelin levels are elevated in patients with a lean body\[[@B77]\]. Plasma ghrelin levels have been found to be associated with malnutrition in patients with advanced-stage cancer and anorexia nervosa\[[@B76]\]. In HD patients, a low ghrelin level increases the risk of cardiovascular mortality and morbidity\[[@B78]\], and the utility of monitoring plasma ghrelin at fixed intervals has been proven as a biomarker for mortality in HD patients\[[@B71]\].

*H. pylori* infections affect ghrelin levels. *H. pylori*-positive patients have lower gastric mucosal and plasma ghrelin levels and a smaller population of ghrelin-positive cells in the gastric mucosa\[[@B79]\]. Although subjects with normal renal function show a correlation between plasma ghrelin level and the severity of gastric mucosal atrophy\[[@B79]\], the association between ghrelin and *H. pylori* infection and between ghrelin and gastric mucosal atrophy in HD patients is less well understood. In an analysis using 78 HD patients and 51 non-dialysis patients with chronic renal disease, des-acyl ghrelin levels in HD patients were significantly higher than those in non-dialysis patients, and ghrelin levels decreased with the progress of endoscopic gastric mucosal atrophy in HD patients (Table [3](#T3){ref-type="table"})\[[@B19]\]. Importantly, acyl-ghrelin levels in the non-*H. pylori* infection HD group (39.4 ± 23.0 fmol/mL) were significantly higher than in patients with current (24.6 ± 17.5 fmol/mL, *P* = 0.022) and past *H. pylori* infection (23.4 ± 19.9 fmol/mL, *P* = 0.007) (Table [4](#T4){ref-type="table"})\[[@B18]\], suggesting that the severity of serological and endoscopic gastric mucosal atrophy is a major determinant of ghrelin levels (Table [3](#T3){ref-type="table"}). In fact, multiple regression analysis shows a significant positive correlation between acyl ghrelin and PG I levels (β = 0.738, *P* \< 0.001) and significant negative correlations between ghrelin and age, albumin, and creatinine levels\[[@B19]\]. Therefore, PG level is the most influential determinant of plasma acyl and des-acyl ghrelin levels in HD patients. This suggests that plasma and gastric mucosal ghrelin levels are influenced by not only long-standing enhanced gastric mucosal inflammation induced by *H. pylori* infection but also by gastric mucosal atrophy\[[@B79]\]. Because plasma and gastric ghrelin levels depend on the number of ghrelin immunoreactive cells in the gastric mucosa\[[@B79]-[@B81]\], plasma ghrelin levels may be influenced more by the severity of atrophy than current *H. pylori* infection in HD patients. Therefore, it is important to consider methods to prevent progression of gastric mucosal atrophy in HD patients.

###### 

Clinical characteristics in hemodialysis patients between patients with and without gastric mucosal atrophy\[[@B19]\]

                              **Atrophy (-)**       **Atrophy (+)**      ***P*-value**
  --------------------------- --------------------- -------------------- ---------------
  N (Male/Female)             28 (17/11)            50 (33/17)           \-
  Age                         67.7 ± 12.3           71.6 ± 11.0          0.155
  Dialysis periods (yr)       7.5 (2.4-16.8)        7.7 (3.1-12.7)       0.681
  Acyl-ghrelin                38.0 (23.5-57.0)      18.0 (12.0-26.3)     \< 0.001
  Desacyl-ghrelin             303 (248-533)         200 (137-277)        \< 0.001
  BMI (kg/m^2^)               19.8 ± 3.2            19.6 ± 2.8           0.773
  Albumin (g/dL)              3.5 ± 0.3             3.4 ± 0.4            0.273
  Total cholesterol (mg/dL)   166 ± 37              154 ± 36             0.165
  Cholinesterase (U/L)        245 ± 111             219 ± 68.7           0.205
  Intact PTH (pg/mL)          351 ± 294             247 ± 192            0.062
  Ferritin (ng/mL)            128 ± 118             128 ± 221            0.989
  PG I (ng/mL)                416.2 (314.2-783.7)   196.0 (73.8-358.8)   \< 0.001
  PG II (ng/mL)               42.3 (31.6-60.0)      28.4 (16.8-45.7)     0.003
  PG I/II ratio               10.89 (9.11-13.38)    7.31 (4.17-11.08)    0.001
  nPCR (g/kg/d)               0.94 ± 0.14           0.85 ± 0.16          0.022

BMI: Body mass index; BUN: Blood urea nitrogen; PTH: Parathyroid hormone; CRP: C-reactive protein; PG: Pepsinogen; ABI: Ankle-brachial pressure index; nPCR: Normalized protein catabolic rate.

###### 

Plasma acyl-ghrelin and desacyl-ghrelin levels according to *Helicobacter pylori* status in hemodialysis patients\[[@B18]\]

                                     **Non-infection (*n* = 29)**   **Past-infection (*n* = 27)**                   **Present infection (*n* = 17)**
  ---------------------------------- ------------------------------ ----------------------------------------------- -----------------------------------------------
  Plasma acyl-ghrelin (fmol/mL)      39.4 ± 23.0                    23.4 ± 19.9[a](#T4FN1){ref-type="table-fn"}     24.6 ± 17.5[a](#T4FN1){ref-type="table-fn"}
  Plasma desacyl-ghrelin (fmol/mL)   353.2 ± 190.2                  242.1 ± 139.6[a](#T4FN1){ref-type="table-fn"}   236.3 ± 143.6[a](#T4FN1){ref-type="table-fn"}

*P* \< 0.05 *vs* Non-infection group.

HD patients with gastric mucosal atrophy have a lower normalized protein catabolic rate (nPCR) than non-atrophy patients\[[@B19]\]. Chronic persistent damage to the gastric mucosa and gastric mucosal atrophy in *H. pylori*-positive HD patients may contribute to decreased protein intake, PEW, and decreased body weight *via* decreased ghrelin production. Because ghrelin level is associated with mortality related to cardiovascular disease and PEW in HD patients, alternative management, such as *H. pylori* eradication therapy, before the progression of gastric mucosal atrophy might be necessary to prevent the decrease in ghrelin level in HD patients\[[@B74],[@B78]\].

*H. PYLORI* ERADICATION THERAPY AND NUTRITION STATUS IN HD PATIENTS
===================================================================

*H. pylori* infection affects the incident rate of gastroduodenal disease and nutritional status\[[@B20],[@B25]\]. *H. pylori* eradication therapy often causes individuals with normal renal function to develop hyperlipidemia and hyperproteinaemia, along with an increase of body weight and BMI\[[@B80]\]. This phenomenon is considered to be due to increases in plasma ghrelin level followed by increased appetite and food intake after *H. pylori* eradication therapy\[[@B82],[@B83]\] In CAPD patients, *H. pylori* eradication therapy significantly improves anorexia, inflammation, and malnutrition\[[@B84]\]. After *H. pylori* eradication, CAPD patients with anorexia showed a significant increase in markers of nutrition and in VAS scores for almost all questions. Significant differences were also found in lymphocyte count, nPCR, prealbumin, albumin, CRP, before-lunch desire to eat, after-lunch desire to eat, hunger before lunch, hunger after lunch, fullness before lunch, consumption after lunch, and palatability\[[@B85]\]. However, it is unclear whether nutritional disorders in HD patients improve after eradication therapy. It is important to answer this clinical question to improve the poor prognosis in HD patients.

At 1 year after eradication therapy, serum cholinesterase levels significantly increase compared with the level before eradication (303.2 ± 76.0 *vs* 287.3 ± 68.1 IU/L, *P* = 0.029). In particular, cholesterol (before, 196.6 ± 23.2 mg/dL; after, 206.1 ± 25.9 mg/dL, *P* = 0.042) and cholinesterase levels (before, 296.9 ± 70.8 IU/L; after, 316.4 ± 73.8 IU/L, *P* = 0.049) increase more in patients with mild-moderate gastric mucosal atrophy than in those with severe atrophy. This observation suggests that eradication therapy has contributed to improvement of PEW in HD patients. We therefore recommend that HD patients be checked for *H. pylori* infection and that eradication therapy should be initiated before the progression of gastric atrophy.

It is possible that the improvement in nutritional status and increase in BMI after eradication therapy depends not only on an increase in ghrelin levels but also on another biological mechanism(s), such as an improvement in gastrointestinal motility\[[@B86]\], change in gut microbiome profile\[[@B87]\], and/or increase in absorption ability\[[@B88]\]. Betrapally et al\[[@B87]\] reported that alterations to the intestinal microbiota affect the development of nonalcoholic steatohepatitis by influencing digestion, development of obesity, immune response, and production of gut hormones. *H. pylori* eradication therapy changes the gastrointestinal microbiota\[[@B89]\]. A study to examine whether the long-term prognosis of HD patients is improved by the effect of eradication therapy on the microbiota will be required to investigate this hypothesis further.

*H. PYLORI* AND ANEMIA IN HEMODIALYSIS PATIENTS
===============================================

*H pylori* has been identified as a possible cause of vitamin B12 and iron deficiency in the general population. Trimarchi et al\[[@B90]\] reported that *H. pylori*-positive HD patients may present with lower vitamin B12 blood levels and that *H. pylori* should be suspected in HD patients when low or low-normal vitamin B12 levels or macrocytosis exist.

CONCLUSION
==========

Chronic renal failure patients receiving HD have a low prevalence of *H. pylori* infection. More than one-third of patients receiving \< 4 year of dialysis had naturally cured *H. pylori* infection within the 4 year observation period. However, because chronic renal failure patients have a higher risk of gastroduodenal disorders, all HD patients are recommended to receive endoscopic check-ups to reduce the chance of developing peptic ulcer disease. Moreover, patients with *H. pylori* infection should also receive eradication therapy including AMPC 250 mg twice daily to prevent peptic ulcer, gastric cancer, and hemorrhage from gastroduodenal lesions. QOL in HD patients is usually poor and affects their nutritional status. Severity of gastric atrophy is shown to be the major determinant of ghrelin levels in HD patients and eradication treatment of *H. pylori* improves nutrition status by increasing serum cholinesterase and cholesterol levels. *H. pylori* eradication before progress of gastric atrophy may be required to prevent a decrease in ghrelin levels and improve prognosis of HD patients in relation to poor nutritional status.

Manuscript source: Invited manuscript

Specialty type: Gastroenterology and hepatology

Country of origin: Japan

Peer-review report classification

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Conflict-of-interest statement: No potential conflicts of interest.

Peer-review started: February 23, 2018

First decision: March 15, 2018

Article in press: March 25, 2018

P- Reviewer: Papamichail K, Paoluzi OA, Pellicano R, Slomiany BL S- Editor: Wang XJ L- Editor: A E- Editor: Huang Y

[^1]: Author contributions: Sugimoto M, Yasuda H and Andoh A wrote the paper.

    Correspondence to: Mitsushige Sugimoto MD, PhD, Associate Professor, Division of Digestive Endoscopy, Shiga University of Medical Science Hospital, Seta Tsukinowa-cho, Shiga 520-2192, Japan. <sugimo@belle.shiga-med.ac.jp>

    Telephone: +81-77-5482618 Fax: +81-77-5482618
