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)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
patients25. In addition, Arora et
al18 and Xie et al15 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
CKD17,24,26. However, lack of adjustment for several
important confounders, such as diet, alcohol intake and physical
activity, might introduce bias of the findings27.
Furthermore, PPIs users might have poor health status, which may were
considered as key confounder factors,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).19 However, the trail had also some limitations,
such as insufficient power, a short follow-up time frame, potential
selection bias and possible conflicts
ofinterests20,21. 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%)30.
Anothercohort study including over 120 000 individuals indicated that
the increased of AKI with statin use was more marked in women than
men31. A similar phenomenon was observed that PPI
induced hypomagnesemia occurs more commonly among women than
men32. Since previous studies have shown that
hypomagnesemia was associated with incidence and mortality of kidney
disease18,33,34, this phenomenon might explain this
gender disparity. Another possible explanation for this gender disparity
was that drug-induced nephrotoxicity
was associated with
immune hypersensitivity
reaction35,36, 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)37,38, which
may transition to chronic
interstitial nephritis, and
subsequently result in the development of CKD39.
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 treatment15,39.
Therefore, CKD might be a long-term complication and consequence of
PPI-induced AIN due to incomplete recovery of renal function and chronic
interstitial nephritis39. In addition, PPI use has
been linked to hypomagnesemia, which could cause endothelial dysfunction
by promoting atherosclerosis, inducing inflammation and inhibiting
endothelial proliferation33,40, consequently result in
the development of CKD33. In addition, previous
studies found that PPI use was associated with the gut microbiota
alterations41, and diabetes42, which
in turn may increase the risk of CKD33,43. 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.