Proton pump inhibitors (PPIs) are associated with increased risk for chronic kidney disease (CKD), according to two population-based analyses published online January 11 in JAMA Internal Medicine. The authors suggest the widely used drugs might be part of the reason CKD prevalence has risen faster than would be expected from the trends in known CKD risk factors, such as diabetes mellitus and hypertension.

"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," write Benjamin Lazarus, MBBS, from the Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland, and the Department of Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Australia, and colleagues. "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."

The researchers compared rates of incident CKD between patients taking PPIs and those not taking PPIs among 10,482 subjects in the Atherosclerosis Risk in Communities (ARIC) study. Patients were followed up for a median of 13.9 years. At baseline, 322 (3.1%) of the ARIC participants were taking PPIs.

The investigators replicated the approach using data from 248,751 subjects in the Geisinger Health System in Pennsylvania, who were followed up for a median of 6.2 years. At baseline, 16,900 (6.8%) of the Geisinger patients had prescriptions for outpatient PPIs.

Researchers excluded participants in both studies who had baseline estimated glomerular filtration rates of below 60 mL/min per 1.73 m2 or were missing data for estimated glomerular filtration rates. In both studies, PI users were more often white, obese, and taking antihypertensive medications. Hazard ratios were adjusted for demographic, socioeconomic, and clinical variables and also were analyzed with PPI ever-use modeled as a time-varying variable.

The first PPI in the United States, omeprazole, was launched in 1988. The authors note that PPI use increased dramatically in both cohorts. For example in the ARIC cohort, between baseline data collection in 1996 through 1999 and final follow-up in 2011, PPI use climbed from 3.1% to more than 25%.

During follow-up, 56 baseline PPI users developed CKD (14.2 per 1000 person-years), as did 1382 baseline nonusers (10.7 per 1000 person-years. After adjustment for demographics, socioeconomic status, clinical measurements, prevalent comorbidities, and concomitant use of other medications, baseline PPI users had a CKD hazard ratio (HR) of 1.50 (95% confidence interval [CI], 1.14 - 1.96) compared with baseline nonusers (P = .003).

To account for the increase in PPI use over time, the researchers modelled PPI as a time-varying ever-use variable. This also showed a significant increase in CKD risk associated with ever using PPIs (HR, 1.35; 95% CI, 1.17 - 1.55; P < .001) compared with no PPI use.

"The 10-year estimated absolute risk of CKD among the 322 baseline PPI users was 11.8% while the expected risk had they not used PPIs was 8.5% (absolute risk difference, 3.3%)," the authors write.

Similarly, in the Geisinger Health System cohort, there were 1921 incident CKD cases among 16 900 baseline PPI users (20.1 per 1000 person-years) compared with 28,226 incident cases among 231,851 baseline nonusers (18.3 per 1000 person-years. Adjusted for potential confounders, the CDK HR was 1.17 (95% CI, 1.12 - 1.23; P < .001). In the time-varying ever-use model, the adjusted HR was 1.22 (P < .001).

The 10-year absolute risk for CKD was 15.6% in baseline PPI users vs 13.9% if they had not taken PPIs (absolute risk difference, 1.7%).

Because CKD is often preceded by recurrent acute kidney injury (AKI), the researchers also analyzed the association between PPI use and AKI in both cohorts. Adjusted for potential confounders, the ARIC subjects who used PPIs at baseline had 1.64 times (95% CI, 1.22 - 2.21) the risk for incident AKI as non-baseline users (P < .001). In the replication cohort, the adjusted risk was 1.31 (95% CI, 1.22 - 1.42; P < .001). There was also a dose effect apparent in the replication cohort: Adjusted HR for AKI with twice-daily PPI dosing was 1.62 (95% CI, 1.32 - 1.98) vs 1.28 (95% CI, 1.18 - 1.39) for once-daily dosing (P < .001).

The authors note that the risk appears to be tied to PPI use itself and not the underlying causes of PPI uses, as histamine ¬2 receptor antagonists, which are also used to treat gastroesophageal reflux, disease did not show a similar association.

In an accompanying editorial, Adam Jacob Schoenfeld, MD, from the University of California, San Francisco, and Deborah Grady, MD, MPH, from the University of California, San Francisco, and VA Medical Center, San Francisco, urge clinicians to recommend alternatives such as histamine H2 receptor antagonists or lifestyle changes before prescribing PPIs. They write, "A large number of patients are taking PPIs for no clear reason — often remote symptoms of dyspepsia or 'heartburn' that have since resolved. In these patients, PPIs should be stopped to determine if symptomatic treatment is needed."

Dr Schoenfeld and Dr Grady also reviewed evidence linking PPIs to acute interstitial nephritis, hypomagnesemia, Clostridium difficile infection, community-acquired pneumonia, and osteoporotic fractures. They note that most of these studies, similar to the article by Dr Lazarus and colleagues, were observational rather than randomized studies, but suggest that adverse effects have been documented by "multiple high-quality observational studies and are likely causal."

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases and by the National Heart Lung, and Blood Institute. The authors and editorialists have disclosed no relevant financial relationships.

JAMA Intern Med. Published online January 11, 2016. Article abstract, Editorial extract