CHRONIC PPI USE INCREASE KIDNEY INJURY RISK

More evidence has linked the use of proton pump inhibitors (PPIs) to an increased risk of developing chronic kidney disease, disease progression, and end-stage renal disease (ESRD). And the longer the duration of use, the greater the risk, analysis of a national comprehensive database indicates.

"The results emphasize the importance of limiting PPI use to only when it is medically necessary, and also limiting the duration of use to the shortest duration possible," senior author Ziyad Al-Aly, MD, from the Veterans Administration St. Louis Health Care System in Missouri, noted in a news release. "A lot of patients start taking PPIs for a medical condition and they continue much longer than necessary."

First author Yan Xie, MPH, also from the Veterans Administration St. Louis Health Care System, and colleagues published their findings online April 14 in the Journal of the American Society of Nephrology.

National Veterans Administration Database

Investigators used national Veterans Administration databases to identify 173,321 new users of a PPI and 20,270 new users of a histamine 2 receptor antagonist (H2 blocker). As the study authors note, both classes of drugs are generally used for the same indication.

Over the course of 5 years of follow-up, individuals who were prescribed a PPI were 22% more likely to drop below an estimated glomerular filtration rate (eGFR) of 60 mL/minute per 1.73 m² than participants in the H2 blocker group (hazard ratio [HR], 1.22; 95% confidence interval [CI], 1.18 - 1.26).

Moreover, PPI users were 28% more likely to develop CKD than the H2 blocker group (HR, 1.28; 95% CI, 1.23 - 1.34).

Patients who had received a PPI were also 53% more likely to experience a doubling of serum creatinine (6.21% of patients affected in PPI group vs 3.74% in H2 group); 32% more likely to have a decline in their eGFR of more than 30% (19.48% affected vs 25.30%), and 96% more likely to progress to ESRD than their H2 blocker counterparts (0.12% vs 0.19%).

Longer Exposure Equals Higher Risk

"Furthermore, we detected a graded association between duration of PPI exposure and risk of renal outcomes among those exposed to PPI for 31-90, 91-180, 181-360, and 361-720 days compared with those exposed for ≤30 days," Dr Xie and colleagues write.

Table. Duration of Exposure to PPI and Renal Endpoints

	Less Than or Equal to 30 Days	31-90 Days	91-180 Days	181-360 Days	361-720 Days	More Than 720 Days
CKD	13.63%	17.24%	10.58%	11.62%	13.44%	33.48%
Doubling of Serum Creatinine	11.31%	15.71%	9.80%	11.03%	13.62%	38.53%
Greater Than 30% Decline in eGFR	13.13%	16.90%	10.51%	11.80%	14.06%	33.61%
ESRD	10.69%	15.27%	9.61%	10.84%	13.56%	40.03%
ESRD or More Than 50% Decline in eGFR	11.42%	15.78%	9.87%	11.11%	13.67%	38.15%

The investigators were careful to note that although the association between PPI use and adverse renal endpoints was significant, incident CKD, doubling of serum creatinine, and a decline in eGFR of more than 30% occurred relatively infrequently in their analysis. As such, "findings should not deter from prescription and use of PPI where medically indicated," they stress.

Significant CKD Risk

An earlier observational study from JAMA Internal Medicine reported by Medscape Medical News also found a significant 35% increase in CKD risk associated with ever using a PPI compared with no PPI use (P < .001). Asked by Medscape Medical News whether findings from these two studies in any way surprised him, Mark Perazella, MD, professor of medicine, Yale University School of Medicine, New Haven, Connecticut, who is an expert on the effect of drugs on the kidneys, noted that he was familiar with both studies, having seen the abstracts and posters for both studies at last year's American Society of Nephrology's Kidney Week in San Diego, California. "So as you might guess, I was not surprised by these findings," Dr Perazella said.

However, as Dr Perazella cautioned, neither study proves that the PPIs actually cause adverse renal outcomes. "It must be remembered that these are epidemiologic studies that don't prove causation," he stressed. Indeed, the JAMA Internal Medicine authors themselves note that their study was observational in nature and did not provide evidence of causality.

In contrast, as more than 15 million Americans used prescription PPIs in 2013, with 70% of them being prescribed without indication, a causal relationship between PPI use and CKD could have a considerable public health effect, as Dr Xie and colleagues suggest.

As to whether patients whose kidney function deteriorates while receiving a PPI might recover if the PPI were discontinued, Dr Perazella said such a recovery has been described in the setting of acute kidney injury from acute interstitial nephritis caused by PPIs.

"But that is not CKD," he added. "No such data exist for CKD, as this is a new observation."

Research was funded by a grant from the US Department of Veterans Affairs. The authors and Dr Perazella have disclosed no relevant financial relationships.

J Am Soc Nephrol. Published online April 14, 2016.