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\begin{document}

\title{Proton pump inhibitors use and the risk of chronic kidney disease: a
prospective cohort study}



\author[1]{Xingyu Zhang}%
\author[2]{Qiangsheng He}%
\author[3]{Zhong Jing}%
\author[2]{Jin-Qiu  Yuan}%
\author[1]{Xiaoyu Dai}%
\affil[1]{Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China}%
\affil[2]{The Seventh Affiliated Hospital Sun Yat-sen University}%
\affil[3]{Sichuan Mianyang 404 Hospital}%


\vspace{-1em}



  
  \date{May 18, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background: Proton pump inhibitors (PPIs) are widely used worldwide and
have been linked to kidney diseases. However, it remains unclear about
the role of PPI use in the development of chronic kidney disease (CKD).
Aims: To examine the association between PPI use and risk of CKD.
Methods: This is a prospective analysis of 472,373 participants free of
any renal failure diagnosis from the UK Biobank. Incident CKD was
identified based on medical history and linkage to data on primary care
and hospital admissions. Self-reported PPI use was firstly assessed
using a touchscreen questionnaire, and then confirmed by a trained
staff. We estimated the hazard ratios (HRs) and confidence interval
(CIs) with Cox regression models adjusting for potential confounders.
The number needed to harm (NNH) was calculated at one and five years of
follow-up. Results We documented 7,291 cases of CKD over a median of 8.1
years follow-up. After adjustment for potential confounders, regular PPI
users had a 24\% increased risk of CKD incident compared to non-regular
PPI users (HR1.24, 95\%CI1.16 -1.33). The NNH was 773.1 and 177.5 for
one and five years of follow-up, respectively. Directly compared with H2
receptor antagonist, a less potent acid suppressor, PPI use was
associated with 17\% higher risk of CKD (HR 1.17, 95\% CI 1.00 to 1.36).
Conclusions Regular use of PPI is associated with an increased risk of
CKD. Healthcare providers should carefully weigh up the potential
benefits against risk in prescribing PPIs, particularly for long-term
continuous use.%
\end{abstract}%



\sloppy


\textbf{Title: Proton pump inhibitors use and the risk of chronic kidney
disease: a prospective cohort study}

\textbf{Running title: Proton pump inhibitors use and risk of CKD}

Xing-Yu Zhang\textsuperscript{1*}, Qiang-Sheng He\textsuperscript{2*},
Zhong Jing\textsuperscript{3*}, Jin-Qiu Yuan\textsuperscript{2\#}and
Xiao-Yu Dai\textsuperscript{1\#}

1. Department of Nephrology, Mianyang Central Hospital, School of
Medicine, University of Electronic Science and Technology of China,
Mianyang, China 2.~Clinical Research Center, The Seventh Affiliated
Hospital, Sun Yat-sen University, Shenzhen, Guangdong; Scientific
Research Center, The Seventh Affiliated Hospital, Sun Yat-sen
University, Shenzhen, Guangdong, China

3. Department of Nephrology, Mianyang 404 Hospital, Mianyang, China

*These authors have contributed equally to this work

\textsuperscript{\#}Corresponding Authors:

Jin-Qiu Yuan, Clinical Research Center, The Seventh Affiliated Hospital,
Sun Yat-sen University, Shenzhen, Guangdong; Scientific Research Center,
The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen,
Guangdong, China;

e-mail: yuanjinqiu2006@163.com.

Xiao-Yu Dai, Department of Nephrology, Mianyang Central Hospital, School
of Medicine, University of Electronic Science and Technology of China,
Mianyang, China; e-mail:daixy001@163.com

\textbf{Summary}

\textbf{Background:}Proton pump inhibitors (PPIs) are widely used
worldwide and have been linked to kidney diseases. However, it remains
unclear about the role of PPI use in the development of chronic kidney
disease (CKD).

\textbf{Aims} : To examine the association between PPI use and risk of
CKD.

\textbf{Methods:} This is a prospective analysis of 472,373 participants
free of any renal failure diagnosis from the UK Biobank. Incident CKD
was identified based on medical history and linkage to data on primary
care and hospital admissions. Self-reported PPI use was firstly assessed
using a touchscreen questionnaire, and then confirmed by a trained
staff. We estimated the hazard ratios (HRs) and confidence interval
(CIs) with Cox regression models adjusting for potential confounders.
The number needed to harm (NNH) was calculated at one and five years of
follow-up.

\textbf{Results} We documented 7,291 cases of CKD over a median of 8.1
years follow-up. After adjustment for potential confounders, regular PPI
users had a 24\% increased risk of CKD incident compared to non-regular
PPI users (HR1.24, 95\%CI1.16 -1.33). The NNH was 773.1 and 177.5 for
one and five years of follow-up, respectively. Directly compared with H2
receptor antagonist, a less potent acid suppressor, PPI use was
associated with 17\% higher risk of CKD (HR 1.17, 95\% CI 1.00 to 1.36).

\textbf{Conclusions} Regular use of PPI is associated with an increased
risk of CKD. Healthcare providers should carefully weigh up the
potential benefits against risk in prescribing PPIs, particularly for
long-term continuous use.

\textbf{Keywords:} Proton pump inhibitors, chronic kidney disease, UK
Biobank

\textbf{INTRODUCTION}

Proton pump inhibitors (PPIs) are primarily indicated for both the
treatment and prevention of acid-related disorders, such as
gastroesophageal reflux disease{[}GERD{]}, peptic ulcers and
non-steroidal anti-inflammatory drugs {[}NSAIDs{]} bleeding
prophylaxis.\textsuperscript{1} Given the combination of high efficacy
with low toxicity and safety of short-term use, PPIs widely prescribed
and are among the top 10 most frequently used classes of drugs
worldwide.\textsuperscript{2,3} However, the overutilization of PPIs
became health concern, and 40\% to 60\% were taking a PPI with no
appropriate indication.\textsuperscript{4} Overutilization of PPIs not
only increased heathcare cost expenditure but have also been linked to
various adverse effects.\textsuperscript{4} Observational studies have
shown that long-term use of PPIs was associated with \emph{Clostridium
difficile} infection, community-acquired pneumonia, hypomagnesemia, bone
fractures, rheumatoid arthritis and type 2
diabetes\textsuperscript{5-9}. Concerns have been raised about increased
risk of kidney disease in PPIs users.

Chronic Kidney Disease (CKD) is a condition where kidneys fail to
function optimally. It is characterized by progressive loss of kidney
function that can eventually result in end-stage renal disease
(ESRD).\textsuperscript{10} CKD is an important contributor to morbidity
and mortality worldwide with a global prevalence of CKD 9.1\% in 2017,
resulting in 35.8 million disability-adjusted life years and 1.2 million
deaths.\textsuperscript{11}Risk factors influencing CKD are complex,
including the unhealthy lifestyles, obesity, cardiovascular disease,
diabetes mellitus (DM), hypertension and inappropriate drugs
use.\textsuperscript{11-13} The growing drugs use, like NSAIDs, may also
be a contributor to the higher prevalence of CKD.\textsuperscript{13,14}
There is a growing evidence that PPI use might affect kidney function
and thus result in CKD.\textsuperscript{15-18} A meta-analysis of three
observational studies found that PPI use was associated with increased
risk of CKD (risk ratios {[}RR{]} 1.29, 95\% Confidence Interval
{[}CI{]}, 1.22--1.36).\textsuperscript{16} These observational studies
are thought-provoking but have important limitations to the evidence
base, such as either inadequate assessment of exposures through
retrospective recall or administrative claims data, or insufficient
adjustment of important confounders such as lifestyle
habits.\textsuperscript{1,16}A recent randomized controlled trial
including over 17 000 participants found that Pantoprazole seemed to
have a modest, although not statistically significant, greater risk of
CKD compared with placebo (OR 1.17; 95\% CI 0.94 to
1.15).\textsuperscript{19} However, this trial was questioned with a
short follow-up time and insufficient statistical
power.\textsuperscript{20,21}

Given the high prevalence of both PPIs use and CKD incident,
understanding their association may have important influence on the
clinical practice. We therefore performed this prospective cohort study
to examine the association between PPI use and incident CKD in the
general population using the UK biobank dataset.

\textbf{Methods}

\textbf{Study and participants}

UK Biobank is a well-characterized prospective cohort study of 500,000
individuals aged 40--69 years who were recruited from 21 assessment
centers across U.K.. In 2006-2010, eligible participants were invited to
visit the closest assessment center to complete the baseline assessment,
including a touchscreen questionnaire, physical measures and biological
samples collection. Further details about the UK Biobank cohort have
been published elsewhere.\textsuperscript{22}The UK Biobank study have
been approved by the North West Multi-centre Research Ethics Committee,
the England and Wales Patient Information Advisory Group, and the
Scottish Community Health Index Advisory Group. All participants
provided written informed consent prior to data collection. In the
present study, we excluded participants who subsequently withdrew from
the study (n=1298), those with cancers diagnosis (n=26 820) and renal
failure diagnosis (n=2036) prior to baseline, leaving a total of 472,373
participants included in final analysis.

\textbf{Assessment of PPIs use}

At baseline, self-reported PPI use was firstly assessed from
participants using a touchscreen questionnaire, and then confirmed
during verbal interview with a trained staff. The recorded type of PPIs
included omeprazole, lansoprazole pantoprazole, rabeprazole and
esomeprazole. In this study, regular use of PPIs was defined as taking
PPIs in most days of week for the last 4 weeks.

\textbf{Assessment of Outcome}

Incident CKD was identified based on medical history and linkage to data
on primary care and hospital admissions. We used the chronic renal
failure (synonym of CKD) variables provided by UK Biobank, which
integrated information from these different data sources (including
primary care, hospital admissions, self-report and death register).
Details of the algorithms used to identify CKD could be found on the UK
Biobank website (\emph{www.ukbiobank.ac.uk} ). Participants with
prevalent of any type of renal failure were excluded at baseline. At the
time of analysis, complete follow-up was available up to 31 October 2017
for England and Wales and 31 October 2016 for Scotland.

\textbf{Covariates}

Covariate information were obtained from touchscreen questionnaire and
verbal interview at baseline. Sociodemographic factors (age, sex,
ethnicity), lifestyle habits (smoking status, alcohol consumption, sleep
time, and dietary intake), multivitamin and mineral supplements intake,
and general health (overall health rating and longstanding illness) were
self-reported. Index of multiple deprivation based on postcode of
residence was determined as a composite measure of socioeconomic status.
Blood pressure was measured by research staff. Current concomitant
comorbidities (hyperlipidemia, diabetes, cardiovascular disease,
esophagitis/Barrettsesophagus, GERD, peptic ulcer, upper
gastrointestinal bleeding) were assessed using the same way to assess
CKD. Other medication use, including aspirin, non-NSAIDs, acetaminophen,
angiotensin-converting enzyme inhibitors{[}ACEIs{]}, angiotensin II
receptor blockers {[}ARBs{]}, beta-blockers, calcium channel blockers,
thiazide diuretics, statin, metformin, histamine-2 receptor antagonists
{[}H2RAs{]}, and anticoagulants/ antiplatelets~drugs, were assessed
using the same way to assess PPI use. Height and weight were measured by
trained research staff and used to calculate body mass index (BMI).

\textbf{Data Analysis}

We calculated person-years from the recruitment date to the date of
first diagnosis of CKD, death, or the last date of follow-up, whichever
happened first. We fitted Cox regression models with age as the
timescale to estimate hazard ratios (HR) and 95\% confidence intervals
(CI) of PPI use on CKD incidence. First, we stratified the analyses by
sex and age at baseline (in years, 37-55, 55-65, [?]65 years). We then
fitted multivariable-adjusted models with additional adjustment for
ethnicity, socioeconomic status, smoking status, alcohol consumption,
physical activity, fruit and vegetable intake, red and process meat
intake, BMI, sleep time, multivitamin use, mineral supplements intake,
current medical status \emph{(systolic blood pressure,hyperlipidemia,
diabetes, CVD, overall health rating, longstanding illness} ), and
concomitant medication use (including \emph{aspirin, non-aspirin NSAIDs,
acetaminophen, ACEIs, ARBs, beta-blockers, calcium channel blockers,
thiazide diuretics, statin, metformin} )(model1). To address the
possible confounding effect of clinical indications for PPI use, we
additionally adjusted for esophagitis/Barretts esophagus, GERD, peptic
ulcer, and upper gastrointestinal bleeding, H2RA use and
anticoagulants/antiplatelets~drugs use. Proportional hazards assumption
was checked using Schoenfeld's tests and no violation was shown. For
covariates with selections of `\emph{do not know} ' and `\emph{prefer
not to answer} ', or with missing data, we included an
``unknown/missing'' value indicator. Given that PPIs and H2RAs have
similar clinical indications, we investigated the association between
regular H2RA use and CKD risk and performed a head-to-head comparison
between PPIs andH2RAs.To present possible association in a clinically
translatable way, we calculated the number needed to harm (NNH) based on
the method described by Altman D.G and Andersen P.K.\textsuperscript{23}

To evaluate potential effect modifiers, we conducted additional
stratified analyses according to sex, age, BMI, smoking status, alcohol
consumption, hypertension, diabetes, GERD and clinical indication for
PPI use. We performed a number of sensitivity analyses to check the
robustness of the primary results. First, we excluded CKD incidents and
death cases during the first two years of follow-up to minimize reverse
causality. Second, we excluded participants with cardiovascular disease
to minimize potential influence of the medical condition. Third, we
restricted the analyses to participants with no missing data on any
covariates. Lastly, we also performed propensity score matching and
inverse treatment probability weights analyses to control for the
influence of confounding variables. All analyses were conducted using
the R software (version 3.5.0, R Foundation for Statistical Computing,
Vienna, Austria).

\textbf{Results}

This study included 472,373 participants in the final analyses. Table 1
showed the baseline characteristics of participants by regular PPI use.
At baseline, 46 530 (9.85\%) participants reported regular use of PPIs.
PPI users tended to be deprived, consumed less alcohol, less physically
active, with a higher rate of comorbidities (hyperlipidemia, diabetes,
and CVD), and were more likely to use other medications (like aspirin,
NSAID sandstatin). As expected, PPI users had higher rate of
esophagitis/Barretts esophagus, GERD, peptic ulcer, and upper
gastrointestinal bleeding. Regular PPI users also had a poorer
self-reported overall health rating, and higher rate of longstanding
illness.

During a median follow-up of 8.1 years, we documented 1661 incident CKD
events among the 46,530 PPI users (4.53 per 1000 person-years), and 5630
events among 425,843 nonusers (1.65 per 1000 person-years). In the
initial age and sex-stratified model, regular PPI users had 2.15 times
higher risk of incident CKD as compared to non-users (HR 2.15, 95CI
2.03-2.27) (Table 2).The association was attenuated somewhat, but
remained significant after adjustment for potential confounders,
including sociodemographic factors, lifestyle habits, presence of
comorbidities, and use of other medications (HR1.24, 95\%CI 1.17
-1.31).The estimated risk was unchanged after further adjustment for
clinical indications for PPI use (HR1.24, 95\%CI 1.16-1.33).For easy
interpretation, NNHs were calculated based on based on the fully
adjusted HR and the CKD incidence among non-PPI users. Every 773.1 (95\%
CI, 690.3 to 946.5), 406.7 (95\% CI, 357.8 to 506.5), and 177.5 (95\%
CI, 152.8 to 226.5) regular PPI users may result in one CKD case over
one, two and five years, respectively (\textbf{Figure 1} ). Regarding
different types of PPIs, we found the increased risk of CKD was
associated with Omeprazole and Lansoprazole (HR 1.24, 95\%CI 1.14 --
1.34 and 1.26, 1.14 -- 1.38, respectively), but not with other PPIs,
mainly due to the relative low number of cases (Table 3).

We also found that a slightly stronger association between PPI use and
acute kidney injury (AKI). In the fully adjusted model, regular PPI
users had a 30\% higher risk of AKI incident (HR 1.30, 95\%CI 1.22 --
1.38) (\textbf{Table S1} ). Given the similar clinical indications for
PPIs and H2RAs, we also evaluated the association between regular use of
H2RAs use and CKD risk. In the basic model, regular use of H2RAs was
associated with a 69\% greater risk of CKD (HR 1.69, 95\%CI 1.49 --
1.91). However, this association disappeared after adjustment for
potential confounders and clinical indications for H2RAs use (HR 1.03,
95\%CI 0.91-- 1.16) (\textbf{Table S2} ). Direct comparison showed that
PPI use was associated with 17\% higher risk of CKD compared with H2RAs
use (HR 1.17, 95\% CI 1.00 to 1.36) (\textbf{Table S3} ).

In subgroup analyses, the estimates for risk of CKD associated with PPI
use did not differ by age, BMI, smoking status, alcohol consumption,
hypertension, diabetes, GERD and clinical indication for PPI use
(\textbf{Figure 2} ). However, the estimated risk of CKD with PPI use
seemed to be higher among women than men (p-interactions =0.003). Our
primary results remained unchanged in several sensitivity analyses by
excluding CKD incidents and death cases identified during the first 2
years of follow-up, excluding the participants with cardiovascular
disease, and limiting our analysis to participants with no missing
covariate data (\textbf{Table S4} ). When we applied inverse treatment
probability weights based on the propensity scores, the estimated HR for
CKD was 1.40 (95 \% CI 1.25--1.57). The results of propensity
score--matching analysis were similar.

\textbf{Discussion}

In this prospective population-based cohort study of over 0.47 million
participants, we found that regular use of PPI was associated with a
24\% increased risk of CKD adjusting for several potential confounding
variables. The association was likely to be more marked in men than
women. Additional analysis showed that H2RA, a less potent
acid-suppressor, was not associated with CKD. Similar findings were
demonstrated for the outcome of AKI. The association between PPI use and
CKD persists across several sensitivity analyses and did not show clear
evidence of variance among the major types of PPIs.

There are increasing evidence from observational studies suggesting that
long-term use of PPIs is associated with risk of kidney disease, such as
interstitial nephritis, acute kidney injury, and chronic kidney disease
(CKD)\textsuperscript{15,17,24}.Lazarus and colleagues using data of 10
482 participants in the Atherosclerosis Risk in Communities study found
that PPI users had a 50\% higher risk of CKD (HR, 1.50, 95\%CI 1.14
-1.96) and validated this findings in a second large cohort of248 751
patients\textsuperscript{25}. In addition, Arora et
al\textsuperscript{18} and Xie et al\textsuperscript{15} also found that
the risk of kidney disease was 10 -28\% higher in patients who used PPIs
than in non-usersor H2RAs use. Some systematic review and meta-analysis
summarized aforementioned three studies and concluded that PPI use was
significantly associated with increased the risks of
CKD\textsuperscript{17,24,26}. However, lack of adjustment for several
important confounders, such as diet, alcohol intake and physical
activity, might introduce bias of the findings\textsuperscript{27}.
Furthermore, PPIs users might have poor health status, which may were
considered as key confounder factors,\textsuperscript{28,29} but not
been controlled in most previous observational studies. In our study, we
controlled for these confounders and confirmed that PPI use could
increase the risk of CKD.

In addition to aforementioned observational studies, a large randomized
controlled trial was conducted to evaluate the safety of PPI
pantoprazole among 17 598 participants with a median follow-up of 3
years. The researchers found that pantoprazole was likely to have a
modest, although not statistically significant, higher risk of CKD
compared with placebo (OR 1.17; 95\% CI 0.94 to
1.15).\textsuperscript{19} However, the trail had also some limitations,
such as insufficient power, a short follow-up time frame, potential
selection bias and possible conflicts
ofinterests\textsuperscript{20,21}. The estimated effect of this trial
was smaller than our estimates (HR 1.24). Possible explanations included
different population characteristics and follow-up time, the presence of
residual confounders, and other biases.

Our results also indicated that women were more likely to a higher risk
for CKD associated with PPI use. Similar result was reported that
PPI-associated AKI was more frequently among women than men (55.42\%vs
44.58\%)\textsuperscript{30}. Anothercohort study including over 120 000
individuals indicated that the increased of AKI with statin use was more
marked in women than men\textsuperscript{31}. A similar phenomenon was
observed that PPI induced hypomagnesemia occurs more commonly among
women than men\textsuperscript{32}. Since previous studies have shown
that hypomagnesemia was associated with incidence and mortality of
kidney disease\textsuperscript{18,33,34}, this phenomenon might explain
this gender disparity. Another possible explanation for this gender
disparity was that drug-induced nephrotoxicity was associated with
immune hypersensitivity reaction\textsuperscript{35,36}, which occurs
more commonly in women than men.

The underlying mechanism of the association between PPI use and CKD
remain unclear. One possible explanation is that PPIs could increase the
risk of acute interstitial nephritis (AIN)\textsuperscript{37,38}, which
may transition to chronic interstitial nephritis, and subsequently
result in the development of CKD\textsuperscript{39}. Previous study
revealed that a significant proportion of patients that suffered
PPI-induced AIN did not recover to baseline, having either partial or no
renal recovery, possibly because of rapid progression AIN from
inflammatory interstitial cellular infiltrates to interstitial fibrosis
and chronic interstitial nephritis, especially in those patients with
delayed diagnosis or treatment\textsuperscript{15,39}. Therefore, CKD
might be a long-term complication and consequence of PPI-induced AIN due
to incomplete recovery of renal function and chronic interstitial
nephritis\textsuperscript{39}. In addition, PPI use has been linked to
hypomagnesemia, which could cause endothelial dysfunction by promoting
atherosclerosis, inducing inflammation and inhibiting endothelial
proliferation\textsuperscript{33,40}, consequently result in the
development of CKD\textsuperscript{33}. In addition, previous studies
found that PPI use was associated with the gut microbiota
alterations\textsuperscript{41}, and diabetes\textsuperscript{42}, which
in turn may increase the risk of CKD\textsuperscript{33,43}. More
research is required to investigate the underlying mechanisms.

A notable strength of our study is that this study was based on a
well-established prospective cohort, which collected detailed
information on lifestyle factors, medications use, and health
conditions. We were able to fully investigate potential confounding
factors that were often not available in administrative medical
databases. In addition, the large sample size and event number enabled
us to get precisely estimated effects for individual class of PPIs and
subgroups. Lastly, a wide of robust sensitivity analyses enhanced the
validity of our findings.

This study had several limitations. First, as an observational study, we
cannot fully exclude potential confounding effect. PPI users might have
poor health status and be more concerned about their personal health, so
they may be more likely to receive CKD related tests. However, the
residual confounding effect might be small as our analyses were based on
model with comprehensive adjustment for clinical indication PPI use,
comorbidities and overall health status. Second, because information
about PPI use was collected only once in the baseline, we were unable to
investigate the effects of time varying covariates and exposures on CKD.
Third, we could not investigate the possible dose-response relationship
due to insufficient information on dose and duration of PPI use. Lastly,
despite the large sample size, this study may not be able to examine the
effect of specific types of PPIs such as esomeprazole, rabeprazole and
pantoprazole on CKD due to the relative low number of cases.

In conclusion, this large cohort study found that regular use of PPIs
was associated with increased risk of CKD. Although the causal
relationship cannot be determined with an observational study, given
that the large number of PPI users as well as the potential risk of CKD
and other adverse effects such as enteric infections, healthcare
providers should carefully weigh up the potential benefits against risk
in prescribing PPIs, particularly for long-term continuous use. Further
researches are needed to confirm our findings and to explore the
possible mechanisms.

\textbf{ACKNOWLEDGEMENTS}

This research has been conducted using the UK Biobank Resource under
Application (no. 51671). We thank all participants and study staff of UK
Biobank.

\textbf{STATEMENT OF INTERESTS:} None

\textbf{FUNDING:} This work was supported by the National Natural
Science Foundation of China (82003408, 82003524, 82060511 and 82103913),
the Startup Fund for the 100 Top Talents Program, SYSU (392012). The
funders had no role in the design and conduct of the study; collection,
management, analysis, and interpretation of the data; preparation,
review, or approval of the manuscript; and decision to submit the
manuscript for publication.

\textbf{AUTHORSHIP}

Guarantor of the article: Xiaoyu Dai.

XD and JY conceived of the research. XZ, QH and ZJ analyzed the dataset
and wrote the first draft of the manuscript. XD, QH and JY interpreted
the results, revised the draft paper, and read and approved the final
manuscript.

\textbf{SUPPORTING INFORMATION}

Additional Supporting Information is available online. STROBE Checklist
was in the end of Supporting Information

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Table 1. Baseline Characteristics of the Study Populations by PPI use\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
& Regular PPI use & Regular PPI use\tabularnewline
& No & Yes\tabularnewline
Number of participants\textsuperscript{*} & \textbf{425843} &
\textbf{46530}\tabularnewline
Mean (SD) Age, years & 56.5 (8.11) & 59.9 (7.29)\tabularnewline
Male & 196435 (46.1\%) & 21058 (45.3\%)\tabularnewline
N (\%) White & 402225 (94.5\%) & 44250 (95.1\%)\tabularnewline
Mean (SD) Index of multiple deprivation & 17.1 (13.9) & 20.0
(15.8)\tabularnewline
Smoking status & &\tabularnewline
Current & 44839 (10.5\%) & 5328 (11.5\%)\tabularnewline
Previous & 141956 (33.3\%) & 19281 (41.4\%)\tabularnewline
Never & 239048 (56.1\%) & 21921 (47.1\%)\tabularnewline
Alcohol consumption & &\tabularnewline
Daily or almost daily & 87605 (20.6\%) & 8213 (17.7\%)\tabularnewline
One to four times a week & 210968 (49.5\%) & 19949
(42.9\%)\tabularnewline
One to three times a month & 48492 (11.4\%) & 5471
(11.8\%)\tabularnewline
Special occasions only or never & 78778 (18.5\%) & 12897
(27.7\%)\tabularnewline
Physical activity & &\tabularnewline
Low & 62645 (14.7\%) & 8625 (18.5\%)\tabularnewline
Moderate & 140208 (32.9\%) & 13913 (29.9\%)\tabularnewline
High & 140908 (33.1\%) & 12585 (27.0\%)\tabularnewline
Mean (SD) fruit and vegetable intake & 4.62 (3.09) & 4.61
(3.21)\tabularnewline
Mean (SD) red and process meat intake (times/week) & 2.81 (1.13) & 2.88
(1.11)\tabularnewline
Mean (SD) sleep time (hour) & 8.13 (1.12) & 8.09 (1.37)\tabularnewline
BMI & 27.2 (4.69) & 29.2 (5.13)\tabularnewline
Multivitamin use & 62113 (14.6\%) & 8166 (17.5\%)\tabularnewline
Intake of mineral supplements & 91120 (21.4\%) & 9561
(20.5\%)\tabularnewline
Mean (SD) systolic blood pressure (mm hg) & 139 (19.7) & 142
(19.1)\tabularnewline
Hyperlipidemia & 212875 (50.0\%) & 32352 (69.5\%)\tabularnewline
Diabetes & 23088 (5.4\%) & 5404 (11.6\%)\tabularnewline
CVD & 24027 (5.6\%) & 8832 (19.0\%)\tabularnewline
Esophagitis/barretts esophagus & 2356 (0.6\%) & 4092
(8.8\%)\tabularnewline
Gastroesophageal reflux disease & 8938 (2.1\%) & 18720
(40.2\%)\tabularnewline
Peptic ulcer & 4358 (1.0\%) & 5774 (12.4\%)\tabularnewline
Upper gastrointestinal bleeding & 2217 (0.5\%) & 1397
(3.0\%)\tabularnewline
Overall health rating & &\tabularnewline
Poor & 13688 (3.2\%) & 6259 (13.5\%)\tabularnewline
Fair & 80121 (18.8\%) & 16714 (35.9\%)\tabularnewline
Good & 255332 (60.0\%) & 21292 (45.8\%)\tabularnewline
Excellent & 76702 (18.0\%) & 2265 (4.9\%)\tabularnewline
Longstanding illness & 117678 (27.6\%) & 27350 (58.8\%)\tabularnewline
Aspirin use & 55564 (13.0\%) & 11398 (24.5\%)\tabularnewline
Non-aspirin NSAIDs use & 69163 (16.2\%) & 8039 (17.3\%)\tabularnewline
Paracetamol use & 89671 (21.1\%) & 15323 (32.9\%)\tabularnewline
ACEIs use & 37531 (8.8\%) & 8250 (17.7\%)\tabularnewline
ARBs use & 9872 (2.3\%) & 2712 (5.8\%)\tabularnewline
Beta-blockers use & 23290 (5.5\%) & 6452 (13.9\%)\tabularnewline
Calcium channel blockers use & 23416 (5.5\%) & 5406
(11.6\%)\tabularnewline
Thiazide diuretics use & 23949 (5.6\%) & 4870 (10.5\%)\tabularnewline
Metformin use & 10747 (2.5\%) & 2711 (5.8\%)\tabularnewline
Statin use & 60405 (14.2\%) & 15226 (32.7\%)\tabularnewline
H2RAs use & 7669 (1.8\%) & 2098 (4.5\%)\tabularnewline
Anticoagulants/antiplatelets~use & 6063 (1.4\%) & 2412
(5.2\%)\tabularnewline
\bottomrule
\end{longtable}

*Values within parenthesis are expressed as percentage.

ACEIs, angiotensin-converting enzyme inhibitors; ARBs, angiotensin II
receptor blockers; H2RAs, histamine-2 receptor antagonists;CVD,
cardiovascular disease; NSAIDs, non-steroidal anti-inflammatory drugs.

Table 2. Associations of regular use of PPI with the risk of chronic
kidney disease\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
& Cases/ Person-years & Hazard Ratio {[}95\% Confidence Interval{]} &
Hazard Ratio {[}95\% Confidence Interval{]} & Hazard Ratio {[}95\%
Confidence Interval{]}\tabularnewline
& & Age and gender stratified model & Multivariable adjusted model
1\textsuperscript{+} & Multivariable adjusted model
2\textsuperscript{++}\tabularnewline
\textbf{PPI use} & & & &\tabularnewline
Non-regular PPI user & 5630/3417548 & 1.00{[}Reference{]} &
1.00{[}Reference{]} & 1.00{[}Reference{]}\tabularnewline
Regular PPI user & 1661/366674 & 2.15{[}2.03, 2.27{]} & 1.24{[}1.17,
1.31{]} & 1.24{[}1.16, 1.33{]}\tabularnewline
\bottomrule
\end{longtable}

+ Multivariable adjusted model 1: additionally adjusted for ethnicity
(white, or other), socioeconomic status (index of multiple deprivation,
fifth),smoking status (never smoker, previous smoker, or current
smoker), alcohol consumption (daily or almost daily, one to four times a
week, one to three times a month, special occasions only or never),
physical activity (low, moderate, or high), fruit and vegetable intake
([?]5 portions or \textless{}5 portions), red and process meat intake
(\textless{}twice/week, 2.0-2.9 twice/week, 3.0-3.9 twice/week,
\textgreater{}4.0 twice/week ), BMI, sleep time (\textless{}8 hours, 8
hours, 8 to 9 hours,\textgreater{}9 hours),~ multivitamin use (yes or
no), mineral supplements intake (yes or no),~~ overall health rating
(poor, fair, good, excellent) and longstanding illness (yes, no),
hyperlipidemia (yes or no), systolic blood pressure, diabetes (yes or
no), CVD (yes or no), and medications use, including aspirin,
non-aspirin NSAIDs, acetaminophen, angiotensin-converting enzyme
inhibitors, angiotensin receptor blocker, beta-blockers, calcium channel
blockers, thiazide diuretics, statin, metformin.

++Multivariable adjusted model 3: additionally adjusted for clinical PPI
use indication, including esophagitis/Barretts esophagus, GERD, peptic
ulcer, and upper gastrointestinal bleeding, H2RA use and
Anticoagulants/antiplatelets~use.

Table 3. Associations of type of PPIs with chronic kidney disease\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
& Cases/ Person-years & HR {[}95\% Cl{]}\tabularnewline
\textbf{Type of PPIs} & &\tabularnewline
No PPI use & 5630/3417548 & 1.00\tabularnewline
Omeprazole & 1023/237523 & 1.24{[}1.14, 1.34{]}\tabularnewline
Lansoprazole & 635/127975 & 1.26{[}1.14, 1.38{]}\tabularnewline
Esomeprazole & 73/18161 & 1.08{[}0.85, 1.39{]}\tabularnewline
Rabeprazole & 41/8745 & 1.16{[}0.85, 1.59{]}\tabularnewline
Pantoprazole & 33/7347 & 1.15{[}0.81, 1.63{]}\tabularnewline
\bottomrule
\end{longtable}

Estimated effects were based on the fully adjusted model (see footnote
in table 2).

Abbreviation: PPI, proton pump inhibitor; HR, Hazard Ratio; CI,
Confidence Interval

\textbf{Hosted file}

\verb`GRAPHICAL SUMMARY - new.docx`  available at \url{https://authorea.com/users/736928/articles/712250-proton-pump-inhibitors-use-and-the-risk-of-chronic-kidney-disease-a-prospective-cohort-study}

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