Are proton pump inhibitors (PPIs) putting millions of Americans at increased risk of chronic kidney disease?

A new observational study, published online recently by JAMA Internal Medicine, identified an association. The investigators, led by Johns Hopkins University researchers, are calling for more research to determine whether PPI use causes kidney damage.

The issue is critical, according to background information in the article, because PPIs are one of the most commonly prescribed medications in the United States. Overall, an estimated 100 million people a year use the drugs, most of them purchasing OTC products.

The study also points out that 70% of the PPI prescriptions are without indication, and that 25% of long-term PPI users could discontinue therapy without developing symptoms.

Yet, the authors say they could find no population-based studies looking at the association between PPI use and the risk of chronic kidney disease (CKD). Other observational studies have linked PPIs to serious adverse health outcomes such as greater risk of hospital-acquired pneumonia and C. difficile infection.

For the study, the researchers used data on self-reported PPI use in the Atherosclerosis Risk in Communities (ARIC) study (10,482 participants followed up for a median of nearly 14 years) or an outpatient PPI prescription (248,751 participants followed up for a median of 6 years) in the Geisinger Health System in Pennsylvania, where the results were replicated.  

At baseline, PPI users in both groups were more likely to have a higher body mass index and take antihypertensives, aspirin or statins, according to the report.

Results indicate that 56 incident CKD events occurred among 322 baseline PPI users (14.2 per 1,000-person years) and 1,382 events among 10,160 baseline nonusers (10.7 per 1,000 person-years) in the ARIC group. The 10-year estimated absolute risk of CKD among the 322 baseline PPI users was calculated at 11.8%, compared to the expected risk had they not used PPIs of 8.5%.

In the replication group at Geisinger, 1,921 incident CKD events were documented among 16,900 baseline PPI users (20.1 per 1,000 person-years) and 28,226 events among 231,851 baseline nonusers (18.3 per 1,000 person-years). The 10-year absolute risk of CKD among the 16,900 baseline PPI users was 15.6%, while the expected risk had they not used PPIs was 13.9%, study authors report.

The authors note several study limitations, including that participants who are prescribed PPIs may be at higher risk of CKD for reasons unrelated to their PPI use.

“We note that our study is observational and does not provide evidence of causality. However, a causal relationship between PPI use and CKD could have a considerable public health effect given the widespread extent of use,” the study concludes. “More than 15 million Americans used prescription PPIs in 2013, costing more than $10 billion.”

The researchers, who note calls for the reduction of unnecessary use of PPIs, concede several limitations of their study, including the possibility that participants prescribed PPIs might be a higher risk for CKD unrelated to their use of the medications.

An accompanying editorial by Adam Jacob Schoenfeld, MD and Deborah Grady, MD MPH, of the University of California, San Francisco, discusses recent data on adverse effects of PPIs as well as overuse of the drug class.

“A large number of patients are taking PPIs for no clear reason—often remote symptoms of dyspepsia or ‘heartburn’ that have since resolved,” Schoenfeld and Grady write. “In these patients, PPIs should be stopped to determine if symptomatic treatment is needed."

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