Proton pump inhibitor use increases the risk of peritonitis in peritoneal dialysis patients.

Peritonitis is a major and the most significant complication of peritoneal dialysis (PD). Although some predictors of peritonitis in PD patients are known, the association between proton pump inhibitor (PPI) use and peritonitis has not been characterized. Here, we examined whether PPI use is a risk factor for the development of peritonitis, based on a single-center retrospective analysis of 230 consecutive Japanese PD patients at Narita Memorial Hospital. We assessed the association between PPI use and subsequent first episode of peritonitis using multivariate Cox proportional hazards models, following adjustment for clinically relevant factors. The median follow-up period was 36 months (interquartile range, 19-57 months). In total, 86 patients (37.4%) developed peritonitis. Analysis with multivariate Cox proportional hazards models revealed the following significant predictors of peritonitis: PPI use (adjusted hazard ratio [HR] = 1.72, 95% confidence interval [CI]: 1.11-2.66; P = 0.016) and low serum albumin level (per g/dl adjusted HR = 0.59, 95% CI: 0.39-0.90; P = 0.014). Thus, PPI use was independently associated with PD-related peritonitis. The results suggest that nephrology physicians should exercise caution when prescribing PPIs for PD patients.

Introduction

Peritonitis is a major and the most significant complication of peritoneal dialysis (PD), which is associated with significant morbidity, catheter loss, transfer to hemodialysis, and permanent membrane damage, and occasionally death [1]. Therefore, it is important to prevent and reduce the risk for developing peritonitis in patients on PD. Important modifiable risk factors, such as recent invasive procedures (colonoscopy, sigmoidoscopy, cystoscopy, hysteroscopy), nasal Staphylococcus aureus carriage, and exit-site and/or tunnel infections [2-5] have been identified; in addition to these risk factors, constipation, smoking, domestic pets, obesity, depression, hypokalemia, and hypoalbuminemia have been shown as predictors of peritonitis [6-9].

Although proton pump inhibitors (PPIs) are among the top 10 most widely used drugs in the world, PPI use has been associated with increased risk of enteric infections, such as Clostridium difficile infection and spontaneous bacterial peritonitis (SBP) in cirrhosis patients [10-14]. This is probably due to bacterial overgrowth within the gastrointestinal tract and translocation across the epithelial barrier by usage of acid-suppressive therapy [11,12].

Regarding PD patients, the relationship between PPIs and peritonitis has not been extensively studied. Zhong et al. reported a meta-analysis showing a significant association between H2-receptor antagonist (H2RA) use and “enteric peritonitis”; peritonitis was caused by enteric bacteria, but PPI use was not identified as a risk factor [15]. However, the study sample size was small, which might have led to the underestimation of the influence of PPIs. Therefore, the result remains to be elucidated and should be validated. The aim of the present study was to examine whether PPI use might be a risk factor for peritonitis using a large retrospective PD cohort in Japan.

Materials and methods

Study population and data source

The present study included patients aged >20 years undergoing PD as renal replacement therapy between January 1997 and December 2017 at Narita Memorial Hospital. Among the total of 252 consecutive patients, 22 (8.7%) were excluded because of missing data. Finally, 230 PD patients (91.2%) were included (Fig 1).

Fig 1

Flow diagram of the patient selection.

All data were fully anonymized and that the ethics committee of Narita Memorial Hospital (approval number: 29-12-01) waived the requirement for obtaining informed consent from the patient because of the retrospective nature of this study.

Data collection

Baseline characteristics at the start of PD, including age, sex, body mass index, laboratory data (hemoglobin, serum albumin, serum potassium, C-reactive protein, estimated glomerular filtration rate [eGFR]; estimated using the equation recently generated by the Japanese Society of Nephrology: eGFR [mL/min/1.73 m2] = 194 × Scr-1.094 × Age-0.287 × 0.739 [if female] [16]), urine output per day, and peritoneal transport characteristics (D/P creatinine at 240 minutes during peritoneal equilibration test), hypertension, diabetes mellitus, previous atherothrombotic events (coronary heart disease, thromboembolic stroke, aortic aneurism and/or peripheral vascular disease requiring intervention or hospital admission), cause of kidney disease (diabetic nephropathy, glomerulonephritis, and renal sclerosis), domestic pet, smoking, constipation (defined as a state of using laxative), and the usage of any immunosuppression (previous and ongoing) were collected retrospectively from the medical records.

Tenckhoff catheters (Hayashidera Co. Ltd., Ishikawa, Japan) were placed using a sterile surgical technique and conventional PD solutions (Dianeal-N. 1.5% or 2.5% dextrose, and icodextrin; Baxter Healthcare, Tokyo, Japan), and Y-sets and twin-bag systems were utilized in all PD patients. Patients and their caregivers underwent a standard training program after catheterization.

The characteristics of peritonitis were evaluated in terms of the organisms isolated from the PD effluent. PD effluent was obtained aseptically and inoculated into blood culture bottles. Identification of isolates was performed.

PD-related peritonitis was diagnosed if at least 2 of the following diagnostic criteria were met: (1) abdominal pain or cloudy PD effluent; (2) leukocytosis in the peritoneal fluid effluent (white blood cells >100/mm3, with at least 50% polymorphonuclear neutrophils); or (3) a positive Gram stain or positive culture from PD effluent [17].

The anonymous data set is shown in S1 Table.

Exposure and outcomes

The main exposure of interest was the PPI during the follow-up period. The primary outcome was the first episode of peritonitis caused by any organism (Gram-positive and -negative organisms and fungi), including culture-negative peritonitis.

Patients who took any PPI for at least 1 week continuously were included in the PPI group, whereas the remaining patients were categorized into the non-PPI group, as previously reported [14]. In those who developed peritonitis in the PPI group, only the patients who took PPI before developing peritonitis were included in the PPI group. We also obtained information regarding the use of H2RA, which was defined as at least 1 week continuously of prescribed H2RA. PPIs included the following drugs: omeprazole, esomeprazole, lansoprazole, rabeprazole, or vonoprazan. H2RA included the following drugs: cimetidine, ranitidine, or famotidine.

Patients were followed up until the first episode of peritonitis or other censoring events, including loss to follow-up, death (cardiovascular disease, malignancy, infection, and others), end of PD, or end of the follow-up for this study, whichever happened to be earlier. We also obtained other outcomes, including recurrence of peritonitis (≧2 episodes of peritonitis), PD withdrawal and its cause (peritonitis, peritoneal dysfunction, impairment of activities of daily living (ADLs), and kidney transplantation), and encapsulating peritoneal sclerosis (EPS).

Statistical analysis

Differences in clinical characteristics and outcomes between the PPI and non-PPI groups were compared by using the Wilcoxon rank-sum test or Fisher’s exact test. To evaluate predictors of the first episode of peritonitis, univariate and multivariate Cox proportional hazards (CPH) models were constructed, including clinically relevant factors as previously reported [2-8].

The proportional hazards assumption for covariates was tested using scaled Schoenfeld residuals. For continuous variables, the Wilcoxon rank-sum test was performed to assess the significance of intergroup differences. Categorical variables were expressed as percentages and compared using Fisher’s exact test. The cumulative probability of the development of the first episode of peritonitis was calculated using the Kaplan-Meier method and log-rank test. The level of statistical significance was set at P<0.05. All statistical analyses were performed using JMP version 14.0.0 (SAS Institute, Cary, NC, USA).

Results

Study participants and clinical characteristics

The present study included 230 PD patients, with 73 (31.7%) patients in the PPI group and 157 (68.3%) patients in the non-PPI group. The baseline characteristics of the two groups are summarized in Table 1. The PPI group had a higher proportion of previous atherothrombotic events (32.9% vs. 19.8%, P = 0.030) than the non-PPI group. The other factors at baseline were not significantly different between the two groups.

Table 1

Comparison of baseline characteristics between the proton pump inhibitor (PPI) (n = 73) and non-PPI (n = 157) groups.

	PPI group(n = 73)	Non-PPI group(n = 157)	P value
Age (year)	64 (54–72)	64 (56–77)	0.649
Male (N (%))	53 (72.6)	112 (71.3)	0.823
Body mass index (kg/m2)	22.2 (19.7–24.1)	22.3 (20.0–24.7)	0.587
Hemoglobin (g/dL)	9.9 (9.0–11.3)	9.9 (9.0–11.0)	0.985
Serum albumin (g/L)	3.4 (2.9–3.8)	3.5 (3.1–3.9)	0.193
Serum potassium (mEq/L)	4.1 (3.5–4.8)	4.2 (3.6–4.7)	0.257
CRP (mg/dL)	0.3 (0.1–2.6)	0.2 (0.1–0.7)	0.374
eGFR (mL/m/1.73 m2)	7.6 (5.7–9.7)	6.9 (5.7–8.7)	0.129
Urine output (ml/day)	1040 (700–1400)	1000 (800–1315)	0.726
D/P creatinine	0.70 (0.58–0.79)	0.67 (0.58–0.77)	0.889
Hypertension	64 (87.7)	125 (79.6)	0.137
Diabetes mellitus	42 (57.5)	71 (45.2)	0.082
Previous atherothrombotic event	24 (32.9)	31 (19.8)	0.030
Usage of immunosuppression	3 (4.1)	15 (9.6)	0.152
Use of H2RA	10 (13.7)	26 (16.6)	0.698
Cause of kidney disease			0.442
Diabetic nephropathy	43 (58.9)	78 (49.7)
Glomerulonephritis	20 (27.4)	43 (27.4)
Renal sclerosis	2 (2.7)	13 (8.3)
Others	8 (11.0)	23 (14.6)
Domestic pet	16 (21.9)	32 (20.8)	0.844
Smokers (current/ex-)	16 (21.9)	26 (16.6)	0.683
Constipation (use of laxative)	51 (69.9)	114 (72.6)	0.667

Median (interquartile range), categorical values are expressed as number (proportion).

Conversion factors for units: SCr in mg/dL to μmol/L, × 88.4; eGFR (mL/min/1.73 m2) = 194 × Scr-1.094 × Age-0.287 × 0.739 (if female)

Abbreviations: eGFR, estimated glomerular filtration rate; H2RA, H2-receptor antagonist; CRP, C-reactive protein; D/P, dialysate/plasma ratio

Outcome data

PD retrieval

Peritonitis incidence

During the follow-up period (median, 36 months; interquartile range, 19–57 months), 86 patients (37.4%) developed at least one episode of peritonitis. Forty-one (56.2%) and 45 (28.7%) patients in the PPI and non-PPI groups, respectively, developed peritonitis at least once (P<0.001; Table 2). Among the total of 41 patients who developed peritonitis in the PPI group, 36 (87.8%) developed peritonitis during the period of PPI use. The remaining 5 (12.2%) patients developed peritonitis after discontinuation of PPI, but these patients had taken H2RA instead of PPI. The proportion of recurrent episodes of peritonitis (≥2 episodes) was higher in the PPI group than in the non-PPI group (19 [26.0%] patients vs 24 [15.3%] patients, P = 0.041). The incidence of peritonitis was 0.30 and 0.18 person-year in the PPI and non-PPI groups, respectively. The cumulative probabilities of the first episode of peritonitis at 1, 3, and 5 years were 0.22, 0.43, and 0.63, respectively, in the PPI group and 0.14, 0.22, and 0.39, respectively, in the non-PPI group, indicating that the PPI group had a higher risk for developing peritonitis than did the non-PPI group (log-rank test: P = 0.003; Fig 2). Furthermore, the cumulative probabilities of the first episode of peritonitis in those who took PPI at the onset of peritonitis are shown in S1 Fig. The cumulative probabilities of peritonitis at 1, 3, and 5 years were 0.19, 0.69, and 0.94, respectively.

Table 2

Comparison of outcome between the proton pump inhibitor (PPI) (n = 73) and non-PPI (n = 157) groups.

	PPI group(n = 73)	Non-PPI group(n = 157)	P value
Outcomes
PD retrieval
Peritonitis incidence
Peritonitis (at least one episode)	41 (56.2)	45 (28.7)	<0.001
Peritonitis (≥2 episode)	19 (26.0)	24 (15.3)	0.041
PD withdrawal	57 (78.1)	122 (77.7)	0.664
Peritonitis	11 (19.3)	17 (13.9)
Peritoneal dysfunction	15 (26.3)	40 (32.8)
ADL impairment	3 (5.3)	12 (9.8)
Renal transplantation	3 (5.3)	2 (1.6)
Others	10 (17.5)	20 (16.3)
EPS	2 (2.7)	1 (0.6)	0.190
Other outcomes
Death	10 (13.7)	19 (12.1)	0.434
Cardiovascular disease	5 (50.0)	10 (52.6)
Malignancy	0 (0)	2 (10.5)
Infection	5 (50.0)	3 (15.8)
Others	0 (0)	4 (21.1)
Observation period (months)	44 (22–60)	34 (18–56)	0.147

Median (interquartile range), categorical values are expressed as number (proportion).

Abbreviations: EPS, encapsulating peritoneal sclerosis; CVD, cardiovascular disease, PD, peritoneal dialysis; ADL, activity of daily living

Fig 2

Cumulative probability of the first episode of peritonitis.

In the univariate models, low serum albumin level and PPI use were significantly associated with overall peritonitis. Multivariate adjustment for clinically relevant factors attenuated the association between low serum albumin (per 1 g/dl adjusted HR = 0.59, 95% CI): 0.39–0.90; P = 0.014), PPI use (HR, 1.73; 95% CI, 1.12–2.68; P = 0.013), and peritonitis (Table 3). H2RA use was not identified as a risk factor for peritonitis in the univariate and multivariate models.

Table 3

Predictors of peritonitis.

	Univariate model		Multivariate model
	HR (95% CI)	P value	HR (95% CI)	P value
Age (per 10 years)	1.14 (0.95–1.37)	0.141	1.03 (0.85–1.26)	0.758
Male (vs. female)	1.34 (0.83–2.17)	0.227	1.24 (0.76–2.02)	0.388
Diabetes	1.80 (1.17–2.77)	0.007	1.44 (0.92–2.28)	0.114
Previous atherothrombotic event	1.30 (0.80–2.12)	0.296	0.98 (0.59–1.64)	0.948
Usage of immunosuppression	0.88 (0.40–1.90)	0.739	0.87 (0.38–1.98)	0.738
Serum albumin (per 1.0 g/dL)	0.51 (0.35–0.75)	<0.001	0.59 (0.39–0.90)	0.014
PPI use	1.90 (1.24–2.90)	0.003	1.72 (1.11–2.66)	0.016
H2RA use	1.11 (0.65–1.92)	0.699	1.13 (0.63–2.01)	0.682

HR, hazard ratio; CI, confidence interval

PPI, proton pump inhibitor; H2RA, H2-receptor antagonist

Data are the HR, 95% CI, and P value from Cox proportional hazard regression analyses.

Adjusted for clinical characteristics including age, sex, diabetes, previous atherothrombotic event, usage of immunosuppression, serum albumin level, PPI use, and H2RA use.

PD withdrawal

PD withdrawal occurred in 57 (78.1%) and 122 (77.7%) patients in the PPI and non-PPI groups, respectively. Among the causes of PD withdrawal, peritonitis occurred in 11 (19.3%) and 17 (13.9%) patients, peritoneal dysfunction in 15 (26.3%) and 40 (32.8%), impairment in ADLs in 3 (5.3%) and 12 (9.8%), and renal transplantation in 3 (5.3%) and 2 (1.6%) patients of the PPI and non-PPI groups, respectively (P = 0.664).

Other outcomes

During the observation period, 10 (13.7%) and 19 (12.1%) patients in the PPI and non-PPI groups, respectively, had mortality events of all causes, indicating that the cause of death was not different between the two groups (P = 0.434; Table 2).

Organisms that caused peritonitis in the two groups

Table 4 shows the distributions of the causative pathogens of PD-related peritonitis in both the PPI and non-PPI groups. Among the 86 patients with the first episode of peritonitis, 41 (47.7%) patients were in the PPI group and 45 (52.3%) patients were in the non-PPI group. The organisms isolated from the PD effluent were not different between the PPI and non-PPI groups (P = 0.808).

Table 4

Comparison of isolated organism of peritonitis between the proton pump inhibitor (PPI) (n = 41) and non-PPI (n = 45) groups.

	PPI group(n = 41)	Non-PPI group(n = 45)	P value
Organisms			0.808
Gram-positive	15 (36.6)	14 (31.1)
Coagulase-negative Staphylococcus	4	4
Staphylococcus aureus	5	6
Streptococcus species	5	3
Enterococcus species	1	1
Gram-negative	7 (17.1)	5 (11.1)
Pseudomonas species	2	0
Klebsiella pneumoniae	0	2
Acinetobacter baumannii	0	1
Others	5	2
Fungi	1 (2.4)	1 (2.2)
Culture-negative	14 (34.2)	15 (33.3)
Others	4 (9.8)	10 (22.2)

Median (interquartile range), categorical values are expressed as number (proportion).

Gram-positive bacteria were the most common pathogens, accounting for 33.7% of the bacteriologic cultures (n = 29; 15 [36.6%] in the PPI group and 14 [31.1%] in the non-PPI group). Gram-negative bacteria accounted for 14.0% of the bacteriologic cultures (n = 12; 7 [17.1%] in the PPI group and 5 [11.1%] in the non-PPI group). Culture-negative peritonitis was observed in 29 (33.7%) patients, including 14 (34.2%) patients from the PPI group and 15 (33.3%) from the non-PPI group.

Discussion

In this retrospective single center cohort of 230 consecutive Japanese PD patients, we evaluated the association of PPI use and peritonitis. We found that PPI use was associated with increased risk of peritonitis.

PPIs are used worldwide, and the ratio of PPI usage was higher in PD patients because of various gastrointestinal conditions, such as gastroesophageal reflux disease, peptic ulcer, and ulcer prophylaxis for anti-platelet therapy [2].

In cirrhosis patients, the clinical risk of PPI use in developing SBP was reported in several meta-analyses, including well-designed large cohort studies [10-14]. The potential mechanisms for PPIs to increase the risk of SBP have been reported in several previous studies [17-21]. Some in vitro studies showed that PPIs affect the inflammatory cells, including lymphocytes, neutrophils, or natural killer cells, directly. Other studies have indicated that PPIs inhibit the oxidative burst in human neutrophils and disturb the response by dendritic cells to microbial ligands [18,19]. These impaired functions of the immune cells might promote the translocation of intestinal bacteria, thereby leading to peritonitis. All of these effects may cause changes in the natural gut microbial environment, which subsequently leads to increased bacterial colonization in the gastrointestinal tract [20,21]. Overall, PPIs may predispose patients to bacterial overgrowth within the gastrointestinal tract and translocation across the impaired epithelial barrier [21], which increases the risk for peritonitis development.

Meanwhile, in PD patients, few studies have reported the association between PPIs and PD-related peritonitis [15,22-24], and no previous studies have shown the significant association between PPIs and PD-related peritonitis. Thus far, only one recent meta-analysis consisting of 6 observational studies involving 378 PD patients has evaluated the relationship between PPI, H2RA, and enteric peritonitis [15]. Although the results showed that H2RA use in PD patients was associated with an increased risk of enteric peritonitis (odds ratio [OR] = 1.27; 95% CI: 1.02‐1.57), PPI use was not identified as a risk factor (OR = 1.13; 95% CI: 0.72‐1.77); the results should be interpreted cautiously in the following points.

As for the methodological point, the meta-analysis included a small number of patients, which may have underestimated the influence of PPI on peritonitis development. Furthermore, although Pérez [22], included in the meta-analysis, showed that H2RA use, at the time of starting PD, was associated with peritonitis, PPIs did not show a significant association with peritonitis in their Cox proportional hazard model. However, when taking into account the data on H2RA use during the follow-up period in the time-dependent Cox proportional hazard models, a significant association between H2RA and peritonitis was not found; therefore, the result should be interpreted cautiously.

As for the point on the pathological mechanism of the drug for peritonitis, in the abovementioned meta-analysis, the difference in the influence for peritonitis between PPI and H2RA was considered to be the difference in the pharmacokinetics between PPI and H2RA. Namely, the clearance of PPI showed no significant pharmacokinetics between patients with renal failure and healthy volunteers [25]. Meanwhile, the metabolism of ranitidine, a H2RA drug, was reduced in PD patients [26], resulting in more lasting effects of H2RA in these patients, which may increase the risk of developing peritonitis. However, the dose of ranitidine examined in the study [26] was higher than the current recommended dose for PD patients; therefore, the result could not be applied. In a different point of view, most of the previous studies in PD patients had evaluated the association between PPI or H2RA and “enteric” peritonitis, which was caused by the enteric organisms [15,22,23,26]. However, the definition of “enteric” organisms was different in each study, namely, enteric bacteria included in each study was different. Furthermore, generally, previous studies did not include peritonitis caused by Streptococcus or Staphylococcus for “enteric” organisms. However, some studies showed that Streptococcus and Staphylococcus increased significantly in the gut of PPI users [21,27-29]. Therefore, the peritonitis caused by Streptococcus and Staphylococcus should be evaluated in addition to previously defined enteric organisms to examine the relationship between PPI and peritonitis.

Contrary to the previous studies, the present study showed that H2RA was not a risk factor for peritonitis development. The reason was unclear, but it might be that bacterial colonization of the small intestine and bacterial overgrowth might occur more easily in subjects using PPIs, because PPIs are associated with stronger acid suppression than H2RA even in PD patients with kidney dysfunction, as previously reported in patients with normal kidney function [28, 29]. Given that the effect of both PPI and H2RA for gut microbial environment was not directly compared, it is unknown which drug has a stronger influence on the intestinal environment in PD patients. Therefore, further studies should be undertaken in the future to clarify the mechanism.

Interestingly, as for the pathophysiological mechanism of PD-related peritonitis, the environment of gut microbiomes was different among races, which might be due to the differences in genes, eating habits, living environments, and metabolic levels [23,30]. The difference in gut microbiome might have a different influence on PPIs, resulting in different risks for peritonitis development in each race. Therefore, in the future, results should be validated in various populations through well-designed studies.

This study also showed that a lower serum albumin level was a significant risk factor for peritonitis, as previously reported [8]. Hypoalbuminemia in patients with renal failure is multifactorial and may result from malnutrition or inflammation, and it is possible that the increased risk for peritonitis in hypoalbuminemic patients relates to an underlying inflammatory state [8]. In the future, it should be assessed whether hypoalbuminemia is a true predictor or simply the effect of inflammation, by analysis of another cohort involving patients with various clinical characteristics; however, the present study suggests that patients with hypoalbuminemia should be carefully managed for peritonitis.

This study has several limitations. First, the retrospective nature of this design, confounded by indication of PPI, was not fully adjusted. Furthermore, we did not obtain information regarding the reason behind the administration of PPI or H2RA. Second, medication compliance with PPI was unadjusted, which may have resulted in a potential bias. Third, information on the dosage of PPI and H2RA treatment was lacking; hence, the intensity of anti-gastric acid effect could not be precisely assessed. Fourth, there was a lack of information regarding exit-site infection, which was identified as a risk factor for peritonitis [31]; therefore, these factors should be assessed in future studies. Fifth, because of the retrospective nature of the present study, we could not determine the basis for starting PPI treatment, and therefore could not establish a causal link between PPI treatment and peritonitis.

Our study has 2 advantages. First, our research is among the largest retrospective cohort studies with a long follow-up period. Second, we were able to assess the relationship between intensive exposure to PPI and peritonitis, which suggested a significant relationship between PPI treatment and peritonitis.

Conclusion

PPI use was independently associated with PD-related peritonitis. The results suggest that nephrologists should pay attention when prescribing PPI in PD patients.

Cumulative probability of the first episode of peritonitis in those who took PPI at the onset of peritonitis.

(TIF)

Click here for additional data file.

Anonymous dataset of PD patients.

(XLSX)

Click here for additional data file.

9 Sep 2019

PONE-D-19-22245

Proton pump inhibitor use increases the risk of peritonitis in peritoneal dialysis patients

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Reviewer #1: Maeda S et al explored the association between proton pump inhibitor use and peritonitis using single-center retrospective cohort in their hospital. As a total of 230 peritoneal dialysis patients in the past 20 years have been enrolled, this study is well designed as retrospective cohort study. However I think this work is suitable for being published in PLOS ONE, it cannot be accepted in its original form. I have a several queries such as unclear causal association between PPI use and the occurrence of peritonitis.

1) The authors define PPI group as ` The patients who took PPI at least 1 week. '. I think it does not include the information about the timing when PPI was taken.

2) Furthermore, this definition does not clarify whether peritonitis was developed within the period the patients took PPI.

3) The authors assume intestinal flora change and bacterial translocation due to oral PPI as the mechanism of peritonitis development. However, logical consistency is insufficient if peritonitis had not occurred within the period when PPI had been prescribed.

The authors should clarify whether the patients were suffered from peritonitis during the period of taking PPI.

Reviewer #2: Dr. Maeda S et al. reported the association between proton pump inhibitor (PPI) use and the risk of peritonitis in peritoneal dialysis patients in the retrospective single center cohort. In general, the work is interesting, although there are several deficiencies that need to be addressed before it would be suitable for publication, including:

1. The authors had defined patients who took any PPI for at least 1 week as the PPI group. How many patients had taken any PPI at onset of peritonitis? The authors should show the Kaplan-Meier curve of patients who took any PPI at onset of peritonitis.

2. The authors should describe the usage of previous/ongoing immunosuppression in Table 1.

3. The observational, nonrandomized design does not permit to establish a causality link between treatment with PPI and outcomes. The authors should well describe the possibility that PPI use may just be a confounding factor for other, unknown variables.in limitation.

Reviewer #3: In this manuscript, the authors evaluated the association of PPI use and peritonitis, and they found that PPI use was associated with increased risk of peritonitis. This paper must be the first one showing the risk of PPI for peritonitis as the authors say and might be very important information in clinical practice for the PD patients, however there seems to be several points should be revised.

1. The authors defined the PPI group as the patients who took any PPI for at least 1 week and did not define the timing of taking the medicine. Please explain why the authors defined the period of prescription as 1 week and if you have some articles you used as reference, please specify them.

2. Patients taking steroid or immunosuppressant are vulnerable to infection. Please describe the number of patients taking steroid or immunosuppressant, if you have data.

3. The reason why the association between H2-receptor antagonist (H2RA) use and peritonitis was not significant might be due to the small sample size. Please clarify the number of the patients taking H2RA in Table 1.

Reviewer #4: In the manuscript entitled “Proton pump inhibitor use increases the risk of peritonitis in peritoneal dialysis patients”, authors conducted a retrospective PD patient study to assess the risk of using PPI against peritonitis. The study is well designed and provides good recommendation for the nephrologists. There are some issues that need to be addressed before publishing.

1) It is not clear where the H2RA patient cohort is coming from? Please make it clear and include the data in Figure 1

2) In the table 2 make it clear that Peritonitis, peritoneal disfunction etc are the reasons for PD retrieval. Because of the way the table is structured, it took some effort to understand. Make some font changes, or tab difference to make it easy to follow

3) In this study, baseline data from the patients show that serum albumin from PPI and non-PPI groups are comparable. It is known that inflammation can cause hypoalbuminemia. In other studies where they predicted serum albumin as risk factor, the base serum level at admission was lower. In the current study, it is not clear the low serum albumin is really a predictor or the effect of inflammation, please comment and clarify.

4) A minimum treatment of 1 week with PPI was included in the PPI group. Was the treatment continuous, or intermittent?

5) Authors often compared with another meta analysis and commented that the current work has more sample number. It is not true. Please correct the facts contextually.

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

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3 Oct 2019

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Maeda S et al explored the association between proton pump inhibitor use and peritonitis using single-center retrospective cohort in their hospital. As a total of 230 peritoneal dialysis patients in the past 20 years have been enrolled, this study is well designed as retrospective cohort study. However I think this work is suitable for being published in PLOS ONE, it cannot be accepted in its original form. I have a several queries such as unclear causal association between PPI use and the occurrence of peritonitis.

1) The authors define PPI group as ` The patients who took PPI at least 1 week. '. I think it does not include the information about the timing when PPI was taken.

Patients who took any PPI for at least 1 week were included in the PPI group, whereas the remaining patients were categorized into the non-PPI group, as previously reported [14]. In those who developed peritonitis in the PPI group, only the patients who took PPI before developing peritonitis were included in the PPI group.

We modified the sentence of the 2nd paragraph in the “Exposure and outcomes” section as follows.

“Patients who took any PPI for at least 1 week continuously were included in the PPI group, whereas the remaining patients were categorized into the non-PPI group, as previously reported [14]. In those who developed peritonitis in the PPI group, only the patients who took PPI before developing peritonitis were included in the PPI group. Patients who took any H2RA for at least 1 week continuously constituted the H2RA group, similar to the definition of the “PPI group”. PPIs included the following drugs: omeprazole, esomeprazole, lansoprazole, rabeprazole, or vonoprazan. H2RA included the following drugs: cimetidine, ranitidine, or famotidine.”

2) Furthermore, this definition does not clarify whether peritonitis was developed within the period the patients took PPI.

Among the total of 41 patients who developed peritonitis in the PPI group, 36 (87.8%) patients developed peritonitis within the period of PPI use. The remaining 5 (12.2%) patients developed peritonitis after stopping PPI, but these patients took H2RA instead of PPI. This suggests that the continued anti-acid effect might predispose the patients to develop peritonitis.

3) The authors assume intestinal flora change and bacterial translocation due to oral PPI as the mechanism of peritonitis development. However, logical consistency is insufficient if peritonitis had not occurred within the period when PPI had been prescribed.

The authors should clarify whether the patients were suffered from peritonitis during the period of taking PPI.

Among the total of 41 patients who developed peritonitis in the PPI group, only 5 (12.2%) patients developed peritonitis after stopping PPI. However, these patients took H2RA after PPI stopping; therefore, it might be the continued effect of anti-gastric acid suppression by H2RA, which led to intestinal flora changes and bacterial translocation after stopping PPI.

We inserted the following sentence in the first paragraph of the “Peritonitis incidence” subsection under the “Outcome data” section

“Among the total of 41 patients who developed peritonitis in the PPI group, 36 (87.8%) patients developed peritonitis within the period of PPI use. The remaining 5 (12.2%) patients developed peritonitis after stopping PPI, but these patients had taken H2RA instead of PPI.“

Reviewer #2: Dr. Maeda S et al. reported the association between proton pump inhibitor (PPI) use and the risk of peritonitis in peritoneal dialysis patients in the retrospective single center cohort. In general, the work is interesting, although there are several deficiencies that need to be addressed before it would be suitable for publication, including:

1. The authors had defined patients who took any PPI for at least 1 week as the PPI group. How many patients had taken any PPI at onset of peritonitis? The authors should show the Kaplan-Meier curve of patients who took any PPI at onset of peritonitis.

Among the total of 41 patients who developed peritonitis in the PPI group, 36 (87.8%) patients developed peritonitis within the period of PPI use. The remaining 5 (12.2%) patients developed peritonitis after stopping PPI, but these patients took H2RA instead of PPI. As your comments, we showed the Kaplan-Meier curve of patients who took any PPI at onset of peritonitis in the supplemental figure.

We inserted the following sentence in the first paragraph of the “Peritonitis incidence” subsection under the “Outcome data” section

“Furthermore, the cumulative probabilities of the first episode of peritonitis in those who took PPI at onset of peritonitis were also shown (Supplemental Figure 1).”

2. The authors should describe the usage of previous/ongoing immunosuppression in Table 1.

We have no information about the usage of previous/ongoing immunosuppression. Thus, we inserted the following sentence in the limitation paragraph.

“Fourth, information about exit-site infection and the use of previous/ongoing immunosuppressive treatment, which were identified as risk factors for peritonitis, was lacking; therefore, these factors should be assessed in future studies.”

3. The observational, nonrandomized design does not permit to establish a causality link between treatment with PPI and outcomes. The authors should well describe the possibility that PPI use may just be a confounding factor for other, unknown variables.in limitation.

We inserted the following sentence in the limitation.

“Fifth, because of the retrospective nature of the present study, we could not determine the basis for starting PPI and establish a causality link between PPI and peritonitis.”

Furthermore, we modified the sentence of last paragraph under the “Discussion” section, as follows.

“Second, we were able to assess the relationship between the intensive exposure of PPI and peritonitis, which suggested a significant relationship between PPI and peritonitis.”

Reviewer #3: In this manuscript, the authors evaluated the association of PPI use and peritonitis, and they found that PPI use was associated with increased risk of peritonitis. This paper must be the first one showing the risk of PPI for peritonitis as the authors say and might be very important information in clinical practice for the PD patients, however there seems to be several points should be revised.

1. The authors defined the PPI group as the patients who took any PPI for at least 1 week and did not define the timing of taking the medicine. Please explain why the authors defined the period of prescription as 1 week and if you have some articles you used as reference, please specify them.

In the present study, PPI use was defined as patients who took any PPI for at least 1 week, as previously reported [14], showing that the steady maximum mean percentage time of gastric pH >4 was seen after taking PPI for 1week.

2. Patients taking steroid or immunosuppressant are vulnerable to infection. Please describe the number of patients taking steroid or immunosuppressant, if you have data.

We have no data about the usage of previous/ongoing immunosuppression. Thus, we inserted the following sentence in the limitation paragraph.

“Fourth, information about exit-site infection and the use of previous/ongoing immunosuppressive treatment, which were identified as risk factors for peritonitis, was lacking; therefore, these factors should be assessed in future studies.”

3. The reason why the association between H2-receptor antagonist (H2RA) use and peritonitis was not significant might be due to the small sample size. Please clarify the number of the patients taking H2RA in Table 1.

We clarified the number of the patients taking H2RA in Table 1.

Reviewer #4: In the manuscript entitled “Proton pump inhibitor use increases the risk of peritonitis in peritoneal dialysis patients”, authors conducted a retrospective PD patient study to assess the risk of using PPI against peritonitis. The study is well designed and provides good recommendation for the nephrologists. There are some issues that need to be addressed before publishing.

1) It is not clear where the H2RA patient cohort is coming from? Please make it clear and include the data in Figure 1

In the present study, we focused on the relationship between PPI use and peritonitis. Therefore, if the information about H2RA was included in Figure 1, it might be confusing. Then, we presented the data of H2RA in Table 1. Please check and advise whether the modifications made are correct or not.

2) In the table 2 make it clear that Peritonitis, peritoneal disfunction etc are the reasons for PD retrieval. Because of the way the table is structured, it took some effort to understand. Make some font changes, or tab difference to make it easy to follow

We modified the structure of Table 2 as per your recommendation.

3) In this study, baseline data from the patients show that serum albumin from PPI and non-PPI groups are comparable. It is known that inflammation can cause hypoalbuminemia. In other studies where they predicted serum albumin as risk factor, the base serum level at admission was lower. In the current study, it is not clear the low serum albumin is really a predictor or the effect of inflammation, please comment and clarify.

Various factors such as inflammation or malnutrition might lead to hypoalbuminemia. The difference of albumin level between the present and other previous studies suggests that the conditions or underlying diseases of the kidney failure might be different among the studied patients.

Therefore, our results should be validated in other cohorts.

We modified the following sentence in the Discussion.

“Although in the future, it should be assessed whether hypoalbuminemia is really a predictor or the effect of inflammation in another cohort including patients with various clinical characteristics, the present study suggests that patients with hypoalbuminemia should be carefully managed for peritonitis.”

4) A minimum treatment of 1 week with PPI was included in the PPI group. Was the treatment continuous, or intermittent?

Patients who took any PPI for at least 1 week continuously were included in the PPI group.

We modified the sentence in the 2nd paragraph of the “Exposure and outcomes” section as follows.

“Patients who took any PPI for at least 1 week continuously were included in the PPI group, whereas the remaining patients were categorized into the non-PPI group, as previously reported [14].”

5) Authors often compared with another meta analysis and commented that the current work has more sample number. It is not true. Please correct the facts contextually.

We consider that it might be possible that the abovementioned meta-analysis including 378 patients might be too small to evaluate the effect the PPI. Therefore, it should be validated in other larger studies.

Submitted filename: 20191002_plosone_revise_comments.docx

Click here for additional data file.

24 Oct 2019

Proton pump inhibitor use increases the risk of peritonitis in peritoneal dialysis patients

PONE-D-19-22245R1

Dear Dr. Ito,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

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With kind regards,

Hideharu Abe, M.D., Ph. D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

Reviewer #4: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: (No Response)

Reviewer #3: Yes

Reviewer #4: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: (No Response)

Reviewer #3: Yes

Reviewer #4: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: (No Response)

Reviewer #3: Yes

Reviewer #4: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: (No Response)

Reviewer #3: Yes

Reviewer #4: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I believe that the authors have completely revised their manuscript R1. I have no more queries or comments about it.

Reviewer #2: (No Response)

Reviewer #3: The issues I pointed out were addressed appropriately. The reason why H2RA use was not identified as a risk factor of peritonitis might be due to the small number of patients using H2RA (n=36). I think this manuscript is acceptable in this form.

Reviewer #4: The Authors have satisfactorily addressed all the comments and made necessary changes in the manuscript.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Reviewer #4: No

28 Oct 2019

PONE-D-19-22245R1

Proton pump inhibitor use increases the risk of peritonitis in peritoneal dialysis patients

Dear Dr. Ito:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Hideharu Abe

Academic Editor

PLOS ONE