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Proton pump inhibitors linked to chronic kidney disease

Publish date: January 11, 2016
By
Amy Karon
MDedge News

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Con: Tread carefully with PPIs Pro: When used as indicated, PPIs are good medicine

Available evidence suggests that proton pump inhibitor use is associated with an increased risk of both acute and chronic kidney disease, hypomagnesemia, Clostridium difficile infection, and osteoporotic fractures. Caution in prescribing PPIs should be used in patients at high risk for any of these conditions. Given the association with kidney disease and low magnesium levels, serum creatinine and magnesium levels probably should be monitored in patients using PPIs, especially those using high doses.

Given the evidence that PPI use is linked with a number of adverse outcomes, we recommend that patients and clinicians discuss the potential benefits and risks of PPI treatment, as well as potential alternative regimens such as histamine H2 receptor antagonists or lifestyle changes, before PPIs are prescribed. In patients with symptomatic gastrointestinal reflux, ulcer disease, and severe dyspepsia, the benefits of PPI use likely outweigh its potential harms. For less serious symptoms, however, and for prevention of bleeding in low-risk patients, potential harms may outweigh the benefits. 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. Adam J. Schoenfeld and Dr. Deborah Grady are with the University of California, San Francisco. They had no disclosures. These comments were taken from their editorial (JAMA Intern Med. 2016 Jan 11. doi: 10.1001/jamainternmed.2015.7927).

The bottom line is that PPIs should be used continually for the three specific conditions for which they are known to be beneficial – hypersecretory states, gastroesophageal reflux disease (in all its manifestations), and NSAID/aspirin prophylaxis. As with all drugs, treatment always should be at the lowest effective dose. Although it is quite appropriate to limit chronic PPI use to these groups, given the potential association (no causality identified) with various putative side effects including renal disease, in my opinion, the risks of denying PPIs when indicated are higher than the low risks of renal or other possible side effects.

Dr. David C. Metz is associate chief for clinical affairs, GI division; codirector, esophagology and swallowing program; director, acid-peptic program; codirector, neuroendocrine tumor center; and professor of medicine at the Hospital of the University of Pennsylvania, Philadelphia.


 

FROM JAMA INTERNAL MEDICINE

References

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.

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