PPIs causing CKD? Really? Let’s take a look at that
Proton pump inhibitors (PPIs) have made their way to the lead story of the national news. This time it’s not because they do a great job at relieving GI distress, but instead it’s about two recently reported association studies linking PPIs to chronic kidney disease (CKD). Let’s face it, the mere mention of the word kidney in the national news is rarity. However, it’s not the first time PPIs have been linked to the kidney. PPIs have been a rare but well-recognized cause of acute interstitial nephritis and hypomagnesemia. So, what’s the fuss all about? Because this is the first time they have been linked to CKD.
Everything started back in January of 2016 when JAMA Internal Medicine published findings from Lazarus et al demonstrating the association between PPI usage and chronic kidney disease in two cohorts (ARIC and the the Geisinger Health System). Let’s dive a little deeper into the study. This article got the NephJC treatment earlier this year as well. Got there for a more detailed analysis.
What was the study design?
This was an observational, prospective cohort study. The used the Atherosclerosis Risk in Communities (ARIC) study of 10,482 patients and validated these findings in the Geisinger Health System Replication (GHSR) cohort of 248,751 patients.
What did they measure?
ARIC- annual telephone survey, CKD and AKI through diagnostic codes, baseline medications were obtained, in 2006 on details re new PPI or ongoing PPI was obtained.
GHSR- baseline medications were obtained, CKD was defined on basis of new eGFR of <60.
What did they assume?
They assumed after PPI was started they were a permanent user (henceforth referred to as PPI users).
What did they find?
- PPI users in both cohorts had higher BMI, hypertension, cardiovascular disease, and exhibit more polypharmacy (with antihypertensives, aspirin, diuretics and statins).
- More incident CKD in PPI users versus no PPI use (see table below) and importantly no difference in CKD was seen in H2 receptor antagonist use (negative control).
3. In the GHSR group BID PPI was associated with an even greater association of CKD.
What does all of this mean?
First, these are association studies. That means a huge amount of residual bias exists even after the best corrections for confounding variables. The issue is this- are PPIs given to sicker patients with more commodities? Is this a direct link? We know that PPIs have been reported to cause acute interstitial nephritis and hypomagnesemia (as above). But, it is plausible that they also cause CKD? The strength of this study- two cohorts with large numbers of patients showing a clear safety signal in a very commonly used drug. We need to remain diligent in deprescribing all meds without good indication and it appears that the risk-benefit profile for PPIs is shifting even further to the left.
Then, in April PPIs were again in the news this time in JASN with another association study, this time with the hard endpoint of ESRD (remember the JAMA Internal Medicine paper was on eGFR of <60 or CKD coding).
What is added by the new JASN paper?
This was another association study. It was performed in a large number of VA patients (~170,000) who recently started PPIs and compared these patients to a group (~20,000) who recently started H2 blockers. The groups were followed for 5 years. They found the PPI group have more incident CKD defined as an eGFR <60 but they also found more ESRD! This study provides even more evidence associating PPIs with CKD. Again, the same caveats hold true about association studies. This tweet sums it up.
