Do PPIs Increase the Risk for Renal Damage or Mortality?

Proton pump inhibitors (PPIs) are ubiquitous in patient medication lists, whether prescribed alone or as part of a cocktail to treat many upper gastrointestinal disorders. A variety of adverse renal effects have been associated with chronic PPI use, and these drugs have been blamed for episodes of acute kidney injury and progression of chronic kidney disease. It is no surprise then that some researchers have pondered whether chronic PPI use can contribute to the ultimate adverse effect in medicine: death.

PPIs Versus H2RAs and Mortality

Using the Department of Veterans Affairs national healthcare database of military veterans, Al-Aly and colleagues analyzed the use of PPIs and their counterparts, H2-receptor antagonists (H2RAs), to see whether there was any association with increased mortality. Their retrospective database study, however, is different from most, in that they incorporated several adjustments articulated by Hernán and Robins by which large observational studies can emulate (not replace) a large randomized trial.

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Figure 1

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From 2002 to 2004, nearly 215,000 veterans were prescribed either a PPI or an H2RA in a ratio of about 3:1, respectively. Researchers followed their course for 10 years and identified their cause of death in one of nine organ-specific categories. Using a variety of statistical models, the researchers measured the association of PPI and H2RA use with each cause of death. Once a statistically significant finding was identified, they delved further to identify etiologies.

Their analyses show a slightly higher mortality rate of almost 38% in the group prescribed a PPI, compared with 37% for the entire cohort and just under 36% for H2RA users. Four causes of mortality were associated with PPI use: circulatory system, genitourinary system, and oncologic and infectious diseases. Further analyses revealed that three specific etiologies were associated with mortality in the setting of chronic PPI use: cardiovascular disease, upper gastrointestinal cancers, and…wait for it…chronic kidney disease.

Is the PPI to Blame?

How do we interpret these results? I would caution against any rash decision-making based on an observational study. Despite using sophisticated techniques to emulate a large clinical trial, database studies remain hypothesis-generating, in my opinion. We live in a time where big data sets are plentiful and ripe for a variety of analyses. Still, they cannot replace a slowly and rigorously conducted randomized trial.

For now, this study as well as others emphasize the need for continued re-evaluation of PPI use. Not all patients require chronic PPI therapy. As adverse renal effects continue to be reported, de-escalation measures should be implemented whenever possible.

Do you ask your patients about PPI use? Use the comments section below to tell us about any cases of AKI or CKD where you suspect chronic PPI use as the culprit.

Tejas P. Desai, MD, is a practicing nephrologist in Charlotte, North Carolina. His academic interests include the use of social media for physician, student, and patient education. He is the founder of NOD Analytics, a free social media analytics group that serves the medical education community. He has two wonderful children and enjoys spending time with them and his wife.

Follow Tejas P. Desai, MD, on Twitter: @nephondemand

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