Eradication of Helicobacter pylori in Hemodialysis Patients

Abstract

Background. Helicobacter pylori (H. pylori) are a causative agent of digestive disease. Although a proton pump inhibitor combined with amoxicillin-clarithromycin is the accepted drug treatment for H. pylori eradication in Japan, there is no consensus treatment for hemodialysis patients. Study. Seventy-seven hemodialysis patients underwent upper digestive tract endoscopy. Biopsy specimens were taken, and histological findings, culture, and rapid urease tests were performed to confirm the presence of H. pylori. H. pylori-positive patients were then administered at random either a seven-day lansoprazole (60 mg a day)-amoxicillin (750 mg a day)-clarithromycin (400 mg a day) (LAC) regimen or a seven-day lansoprazole (60 mg a day)-clarithromycin (400 mg a day) (LC) regimen. The success of H. pylori eradication was determined from histological findings, culture, and rapid urease tests. Results. In 13 of 77 patients (13.6%), ulcers and/or ulcer scars were seen by endoscopy. Thirty-one patients (40.3%) were positive for H. pylori, and 20 patients among them were randomized to one of two regimens: one is seven-day LAC regimen (eleven patients) and the other is seven-day LC regimen (nine patients). Eradication was successful in nine of the eleven patients (72.7%) receiving the LAC regimen, but in only three of the nine patients (33.3%) who underwent the LC regimen. No serious adverse effects were observed with either regimen, and 95% of the patients reported complete compliance. Conclusion. A seven-day low dose LAC regimen is safe and effective and recommended for treatment of H. pylori infection in hemodialysis patients.

Keywords:

• hemodialysis
• LAC regimen
• LC regimen

INTRODUCTION

There is an increasing number of patients undergoing dialysis in Japan, and it is reported that in excess of 220,000 patients will receive dialysis therapy by the end of 2002. The life expectancy of hemodialysis patients has been extending with the progression of dialysis technology. Presently in hemodialysis patients, the incidence of ulcer is similar to that of patients who have not received hemodialysis.[1–3] However, as the frequency of upper gastrointestinal tract bleeding is significantly higher in hemodialysis patients,[4] the prevention of gastro-duodenal ulcers is important.

Because Helicobacter pylori (H. pylori) eradication therapy effectively prevents recurrent bleeding from peptic ulcers,[5],[6] the same therapy may also be effective for the treatment of upper digestive diseases in hemodialysis patients, as well as the general population. Among the many studies investigating H. pylori eradication treatments, few have examined H. pylori infection specifically in patients with hemodialysis,[7] making detection and eradication of H. pylori in hemodialysis patients an important clinical issue.

The treatment regimen for H. pylori eradication that is approved in Japan includes a combination of clarithromycin (CAM), amoxicillin (AMOX), and a proton pump inhibitor for seven days.[8] This treatment regimen is known to be effective for eradication in 80–90% of cases, with few adverse effects.[9–11] However, there have been few reports about the efficacy and safety of eradication therapy for H. pylori in hemodialysis patients.[12],[13] CAM is metabolized both in the liver and kidney,[14] while AMOX is metabolized mainly in the kidney.[15] Therefore, the optimization of AMOX dosage is necessary in hemodialysis patients. To establish a safe and efficacious regimen for the eradication of H. pylori in hemodialysis patients, the outcome of a seven-day dual regimen consisting of lansoprazole and CAM was compared to a seven-day triple therapy regimen consisting of lansoprazole and half of a dosage AMOX and CAM.

PATIENTS AND METHODS

From August 1999 to May 2004, 77 chronic hemodialysis patients (51 males and 26 females) who underwent endoscopy for medical check participated in this study. All patients received regular hemodialysis therapy in Oji hospital. They were between 28 and 89 years of age (62.9 ± 12.1 years, mean ± SD). The duration of dialysis averaged 53.3 ± 52.6 months. The underlying disease in the majority of these patients was diabetic nephropathy.

The study is outlined in Figure 1. Written informed consent was obtained from all patients before endoscopy. All endoscopies were performed under local anesthesia (Xylocaine) using an Olympus XQ-200, XQ210, XQ230, XQ240, or XP260 endoscope. Six biopsy specimens were taken from the greater curvature of the antrum and the gastric body. Paired biopsy specimens from the antrum and gastric body were used for culture, histological analysis, and rapid urease testing. To culture bacteria, biopsy specimens were placed in transport medium immediately after the biopsy procedure and cultured in isolation for five to seven days. For histological identification of bacteria, specimens were stained with Giemsa. The PYLORITEK TEST KIT^R (Serim Research Corp., Elkhart, Indiana, USA) was used for rapid urease testing. The presence of H. pylori was confirmed by positive results in at least two of these tests or by a positive result in culture.

Figure 1. Demographic schema of study design. Seventy-seven hemodialysis patients underwent upper gastrointestinal endoscopy. The presence of Helicobacter pylori (H. pylori) was assessed by histology, rapid urease test and cultivation. Positive H. pylori status was assigned based upon at least two positive results. Patients who were diagnosed as being H. pylori-positive and wished to receive therapy were enrolled into this study. Patients were randomly assigned into two groups.

Patients with H. pylori infection were randomly assigned to seven-day regimens of either LAC or LC, consisting of 30 mg b.d lansoprazole, 375 mg b.d amoxicillin and 200 mg b.d. clarithromycin, or 30mg b.d lansoprazole and 200 mg b.d clarithromycin, respectively (see Figure 2). Blood exams (WBC, RBC, Hb, Hct, PLT, GOT, GPT, γ-GTP) were performed on all patients before and after therapy. At the completion of therapy, patients were interviewed to report adverse effects and compliance.

Figure 2. Eradication therapy.

Three months after completion of the H. pylori eradication therapies, all patients underwent endoscopy to measure the success of eradication. Biopsies were taken from the six points examined in the previous endoscopy. Positive results for H. pylori in any of the tests described above were scored as evidence of a failure to eradicate.

For statistical analysis, univariate associations were first investigated using the Fisher's exact test. A p value less than 0.05 was regarded as statistically significant.

RESULTS

Prevalence of H. pylori in Hemodialysis Patients

Thirty-one of 77 (40.3 %) of hemodialysis patients had H. pylori infection. The mean age of H. pylori positive patients was 64.1 ± 10.3 years old. H. pylori infection was first seen in patients forty years old or above (see Figure 3). The percent of H. pylori-infected patients increased in those over age, and 71.4% of patients seventy or older were positive.

Figure 3. Percentage of Helicobacter pylori-positive patients relative to age. Cases of Helicobacter pylori infection were not observed until age forty years or above.

Gastric ulcers and/or ulcer scars were detected in 14.3% of patients, overall, and duodenal ulcer and/or ulcer scars were detected in 2.2% of patients. However, the percentage of patients infected with H. pylori was 53.8% among those with gastric ulcers and/or ulcer scars, and 66.7% among those with duodenal ulcers and/or ulcer scars. The percentage of H. pylori-positive patients was relatively constant regardless of the duration of hemodialysis (see Figure 4).

Figure 4. Percentage of patients infected with Helicobacter pylori relative to the number of elapsed years since beginning dialysis. There was no correlation between the duration of patients’ hemodialysis and the prevalence of H. pylori infection. In patients with prolonged duration of hemodialysis, the proportion of H. pylori-positive patients did not change.

Eradication of H. pylori When Following the LAC or LC Regimen

Twenty of 31 (64.5%) H. pylori-positive patients received eradication therapy (18 males, 13 females; mean age 65.8 ± 10.4 years, range 42–89 years). These patients were randomly assigned to one of two therapeutic regimens. Eradication was successful in nine of 11 patients (72.7%) receiving the LAC regimen and in three of the nine patients (33.3%) receiving the LC regimen (p = 0.064; see Figure 5).

Figure 5. Success of treatment in eradicating Helicobacter pylori. Of the eleven patients selected to receive the LAC regimen, eradication was successful in nine (72.7%). H. pylori were eradicated in three of the nine patients (33.3%) who received the LC regimen.

Among the 20 patients interviewed, 19 (95%) reported complete compliance, while one patient in the LC regimen took only three of the seven days of medication (42.9%). No adverse effects were reported in 95% (19 out of 20) of all patients following either regimen; one patient in the LC group reported taste disturbance (11%, 1 out of 9). Based on blood test findings, liver function disorder was recognized in one patient receiving the LC regimen. Prior to eradication therapy, his aminotransferase (AST) level was 34 IU/L and alanine aminotransferase (ALT) level was 20 IU/L, whereas after the treatment, AST was 42 IU/L and ALT was 31 IU/L. Enzyme levels indicative of liver function returned to the normal range in two weeks.

DISCUSSION

Nausea, abdominal discomfort and pain are frequent symptoms in uremic patients, and many patients undergoing hemodialysis experience complications of the upper gastrointestinal tract.[16] Because patient reports of peptic ulcer incidence are generally controversial,[17] it is not easy to predict whether the incidence of peptic ulcers would be higher in hemodialysis patients than in patients without hemodialysis. It has been reported that in western countries, the incidence of ulcer in patients who undergo hemodialysis is similar to the general population.[1],[2] However, there are no reports of the incidence of peptic ulcer in hemodialysis patients in Japan. In this study, gastric/duodenal ulcer and ulcer scarring were observed in 14.3% of patients.

Also regarding the prevalence of H. pylori infection in patients with hemodialysis, there are various reports available. The current authors surveyed and summarized the previous studies that studied the prevalence of H. pylori infection in patients receiving hemodialysis (see Table 1).[12], [18–28] In the present study, 40.3% of hemodialysis patients were infected with H. pylori. Considering that the prevalence of H. pylori infection has been reported to be higher than 70% among Japanese adults over 50 years of age,[29] these results indicate the relative percentage of H. pylori-positive hemodialysis patients could be lower than the general patient population. It has been reported that urea concentrations of six mmol/L or higher can inhibit the growth of H. pylori.[30] Thus, the high levels of urea nitrogen and gastric juice urea reported in patients receiving dialysis[31] may possibly inhibit the growth of H. pylori. However, the period of time on hemodialysis did not show any positive correlation with the incidence of H. pylori infection in the current study. Previously, it has been reported that there was no difference in the prevalence of H. pylori infection in dialysis patients in regard to age, dialysis period, or the timing of symptom appearance.[32]

Table 1 Reported frequency of H.pylori infection in haemodialysis patients in 1991∼2005

Reference	Country	Number of healthy controls	Frequency of H.pylori infection in healthy controls (%)	Number of HD patients	Frequency ofH.pylori infectionin HD patients(%)	Measuring method
Loffeld RJ (1991)[18]	Netherland	No description	No description	30	43	Serology
Jaspersen D (1995)[19]	Germany	127	37	34	20.6	UBT, histology
Luzza F (1996)[20]	Italy	103	78	103	73	Serology
Abu Farsakh NA (1996)[21]	Jordan	100	73	92	48.9	Histology
Ozgur O (1997)[22]	Turkey	100	64	47	60	UBT, histology
Munoz de Bustillo E (1998)[23]	Spain	No description	No description	52	63.5	UBT
Yildiz A (1999)[24]	Turkey	55	72.5	47	65.9	Serology
Huang JJ (2000)[25]	Taiwan	42	60	33	47.1	Culture, stain
Wang YL (2001)[26]	Taiwan	80	60	80	50	HpSA, serology
Nakajima F (2002)[27]	Japan	No description	No description	51	27.5	UBT, culture, histology
Tsukada K (2002)[12]	Japan	55	56	47	30	UBT, histology
Nakajima F (2004)[28]	Japan	138	53.3	138	36.9	Serology
Itatsu T (unpublished data)	Japan	No description	No description	77	40.3	UBT, culture, histology

It has been shown that H. pylori eradication regimens with higher antibiotic dosages provide a higher incidence of cure.[33] However, because amoxicillin (AMOX) is mainly excreted from the kidney, especially high plasma concentrations of AMOX in patients on hemodialysis can be harmful,[34],[35] and it is necessary to adjust AMOX dosage for hemodialysis patients. In contrast, clarithromycin (CAM), which is primarily metabolized in the liver, is frequently used in eradication regimens because of its high toxicity to H. pylori. In Japanese patients without hemodialysis, it has been reported that the frequencies of cure when lansoprazole-AMOX-CAM regimens were applied using 800 versus 400 mg of CAM daily[36] were similar although adverse effects were significantly more frequent in the LAC regimen with 800 mg CAM.

Based on these findings, a daily dosage of CAM 400 mg daily was adopted, and a regimen was established that contained no AMOX. Accordingly, the two treatment regimens were compared. In one, the dosage of AMOX was reduced from 1500 to 750 mg daily (half of the usual dosage), and the other did not include any AMOX. It has been shown that a seven-day LAC regimen with 200 mg CAM b.d. is sufficient for cure among the general population of Japan.[36] The present study showed that the eradication rate using the LAC regimen (with reduced dosage of AMOX) was far higher than the LC regimen in hemodialysis patients. The success of eradication of H. pylori using the LAC regimen was comparable to previous reports, though on the other hand, the regimen without AMOX provided only a 42.9% cure rate, which was far lower than the previous ones (see Table 2).[12],[25],[28] Unfortunately, this study failed to yield the statistically significant difference, perhaps due to the small number of the studied patients. However, the cure rate of LC regimen seems apparently insufficient.

Table 2 Reported percentages of cured H.pylori-infected haemodialysis patients treated from 1991–2005

Reference	Regimen	Medicine dosage (mg)	Duration of medicine (days)	Percentage cured (%)
Munoz de Bustillo E (1998)[23]	1: Omeprazole	40	14	60.8 (14/23)
	amoxycillin	1500
	2 : omeprazole	40	14	82.6 (19/23)
	clarithromycin	1000
Wang YL (2001)[26]	Omeprazole	40	7
	amoxycillin	2000
	clarithromycin	1000
Tsukada K (2002)[12]	Omeprazole	60	7	91 (10/11)
	amoxycillin	1500
	clarithromycin	800
Itatsu T (unpublished data)	1: Lansoprazole	60	7	72.7 (9/11)
	amoxycillin	750
	clarithromycin	800
	2 : Lansoprazole	60		33.3 (3/9)
	clarithromycin	400

*Regimen 2 was performed subsequent to Regimen 1.

Regarding compliance of the study drugs, complete compliance was reported in all interviewed patients in the LAC group, and only one patient in the LC group discontinued medication because of taste disturbance. In addition, as to adverse events, one patient in the LC group showed apparent mild liver dysfunction that did not affect diagnosis, and no adverse effects were noted among interviewed LAC group patients.

As shown in Table 2, there are few reports describing how to perform H. pylori eradication treatment to hemodialysis patients, which makes one hesitate to tailor the combination and dosage of the treatment drugs. In this study, it was clearly shown that LAC regimen, including lansoprazole proton-pump inhibitor, 400 mg CAM, and 750 mg AMOX, provides a high chance of H. pylori eradication with no adverse effects, and that such a regimen is recommended for H. pylori eradication treatment in hemodialysis patients.