Chronic kidney disease (CKD) is more likely to develop in people who take proton pump inhibitors (PPIs), even if they do not first experience acute kidney injury (AKI), according to a new study.

Previously, researchers had suggested that unrecovered AKI is the sole mediator of chronic renal damage among PPI users. The acid-suppressing drugs are known to increase AKI and acute interstitial nephritis. New findings published in Kidney International hint that PPIs may harm the kidneys gradually, independent of AKI.

Using the Veterans Affairs databases, Ziyad Al-Aly, MD, of the VA St. Louis Health Care System, and colleagues identified a national cohort of 144,032 first-time consumers of acid suppression therapy. Of these, 125,596 received a new prescription for a PPI (e.g., esomeprazole, lansoprazole, omeprazole, pantoprazole, or rabeprazole) and 18,436 received a prescription for a histamine H2 receptor antagonist (e.g., ranitidine, cimetidine, and famotidine). All of the veterans had normal kidney function at the start.

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To evaluate PPI use and chronic renal outcomes in the absence of AKI, the investigators created survival models and alternately censored anyone with an episode of AKI (defined as an increase in serum creatinine above 50% or 0.3 mg/dL) within 5 years of the study or before development of CKD.

Compared with patients who took an H2 blocker, PPI users had a 19% increased risk of estimated glomerular filtration rate (eGFR) falling below 60 mL/min/1.73m2 and a 26% increased risk of CKD (defined as an eGFR below 60 on 2 separate occasions at least 90 days apart, based on the Chronic Kidney Disease Epidemiology Collaboration equation). In addition, veterans taking PPIs were 22% more likely to experience CKD progression (eGFR decline above 30%), and 30% more likely to experience eGFR decline above 50% or end-stage renal disease (ESRD). All findings were statistically significant. The risks of chronic renal damage increased along with duration of PPI use.

AKI accounted for just half of episodes of kidney impairment, CKD development, eGFR decline of more than 30%, and eGFR decline of more than 50% or ESRD. Results remained consistent when AKI was defined by Kidney Disease Improving Global Outcomes (KDIGO) criteria, ICD-9 codes, and the NHS England algorithm.

“Reliance on antecedent AKI as a warning sign to guard against the risk of the development of CKD and progression to ESRD among PPI users is not sufficient as a sole risk mitigation strategy, Dr Al-Aly and colleagues stated. “Exercising vigilance in PPI use, even in the absence of AKI, and careful attention to kidney function in PPI users may be a reasonable approach.”

The investigators acknowledged that they could not account for subclinical or unrecognized AKI or use of over-the-counter PPIs. They also had no information on urine flow and did not distinguish interstitial nephritis.

Given a shortage of seminal research, the possible mechanisms tying PPI use with chronic renal damage still are unclear. 

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1. Xie Y, Bowe B, Li T, Xian H, Yan Y, and Al-Aly Z. Long-term kidney outcomes among users of proton pump inhibitors without intervening acute kidney injury. Kidney Int. doi: 10.1016/j.kint.2016.12.021.