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
(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) (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) (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) (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
(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 (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.