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 (systolic blood pressure,hyperlipidemia, diabetes,
CVD, overall health rating, longstanding illness ), and concomitant
medication use (including 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 ‘do not know ’ and ‘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.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).