The use of proton pump inhibitors increased the risk of chronic kidney disease by 20%-50%, said the authors of two large population-based cohort analyses published online Jan. 11 in JAMA Internal Medicine.

These are the first such studies to link PPI use to chronic kidney disease (CKD), and the association held up after controlling for multiple potential confounders, said Dr. Benjamin Lazarus of Johns Hopkins University, Baltimore, and his associates. “Further research is required to investigate whether PPI use itself causes kidney damage and, if so, the underlying mechanisms of this association,” they wrote.

Proton pump inhibitors have been linked to other adverse health effects but remain among the most frequently prescribed medications in the United States. To further explore the risk of PPI use, the researchers analyzed data for 10,482 adults from the Atherosclerosis Risk in Communities (ARIC) study who were followed for a median of 13.9 years, and a replication cohort of 248,751 patients from a large rural health care system who were followed for a median of 6.2 years.

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Incident CKD was defined based on hospital discharge diagnosis codes, reports of end-stage renal disease from the United States Renal Data System Registry, or a glomerular filtration rate of less than 60 mL/min per 1.73 m2 that persisted at follow-up visits (JAMA Intern Med. 2016 Jan 11. doi: 0.1001/jamainternmed.2015.7193).

In the ARIC study, there were 56 cases of CKD among 322 self-reported baseline PPI users, for an incidence of 14.2 cases per 1,000 person-years – significantly higher than the rate of 10.7 cases per 1,000 person-years among self-reported baseline nonusers. The 10-year estimated absolute risk of CKD among baseline users was 11.8% – 3.3% higher than the expected risk had they not used PPIs. Furthermore, PPI users were at significantly higher risk of CKD after demographic, socioeconomic, and clinical variables were accounted for (hazard ratio, 1.50; 95% confidence interval, 1.1-2.0), after modeling varying use of PPIs over time (adjusted HR, 1.3; 95% CI, 1.2-1.5), after directly comparing PPI users with H2 receptor antagonist users (adjusted HR, 1.4; 95% CI, 1.01-1.9), and after comparing baseline PPI users with propensity score–matched nonusers (HR, 1.8; 95% CI, 1.1-2.7).

In the replication cohort, there were 1,921 new cases of CKD among 16,900 patients with an outpatient PPI prescription (incidence of 20.1 cases per 1,000 person-years). The incidence of CKD among the other patients was lower: 18.3 cases per 1,000 person-years. The use of PPIs was significantly associated with incident CKD in all analyses, and the 10-year absolute risk of CKD among baseline PPI users was 15.6% – 1.7% higher than the expected risk had they not used PPIs.

These observational analyses cannot show causality, but a causal relationship between PPIs and CKD “could have a considerable public health impact, give the widespread extent of use,” the researchers emphasized. “More than 15 million Americans used prescription PPIs in 2013, costing more than $10 billion. Study findings suggest that up to 70% of these prescriptions are without indication and that 25% of long-term PPI users could discontinue therapy without developing symptoms. Indeed, there are already calls for the reduction of unnecessary use of PPIs (BMJ. 2008;336:2-3).”

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the National Heart, Lung, and Blood Institute, both of which are part of the National Institutes of Health. The researchers had no disclosures.