By Lea Borgi, MD
April 27, 2017
Proton pump inhibitors (PPI) are among the most prescribed medication in the United States1, with an increasing proportion of US adults reporting using prescription PPI (3.9% in 1999 to 7.8% in 2012) according to the National Health and Nutrition Examination Survey (NHANES).2 However, overall PPI use is most likely underestimated, given their widespread over-the-counter availability.
The long-term use of PPIs has been linked to multiple complications including higher risk of fractures, dementia, infections and renal disease.3 In a recent meta-analysis of over two million patients from four cohorts and five case-control studies, PPI users had a higher risk of developing acute kidney injury (AKI) and chronic kidney disease (CKD) when compared to non-PPI users (RR=1.44; 95% CI 10.08-1.91 and RR=1.36; 1.07-1.72, respectively).4 Acute interstitial nephritis is believed to be the most common cause of PPI-induced AKI and commonly has a subtle and subclinical presentation, without systemic symptoms.5 Unrecognized and untreated, chronic interstitial nephritis can ensue, leading to the development of CKD, and ultimately progression to end-stage renal disease (ESRD).
Indeed, in a study of Department of Veterans Affairs databases, comparing new PPI users to new H2-receptor antagonist users, PPI users had a 22% higher risk of incident CKD after five-year follow-up and almost double the risk of ESRD (RR=1.96; 1.21-3.18).6 A recently published analysis of the same cohort by Xie et al found that PPI use was associated with an increased risk of incident CKD, CKD progression, and ESRD in the absence of a previous episodes of AKI.7 These findings emphasize that PPI-induced kidney disease can be subtle, and can lead to PPI-induced CKD in the absence of overt AKI.
Few mechanisms have been proposed to explain the association of PPI to renal diseases. Aside from recurrent episodes of interstitial nephritis, alteration in gut microbiota, impaired lysosomal acidification leading to oxidative stress and endothelial cell dysfunction, and PPI-induced transepithelial leaks have been speculated to have a role in the development of renal disease in PPI users.8-10
In conclusion, while more research is needed to better understand the association of PPIs to AKI, CKD and ESRD, it would appear that judicious use of these agents is warranted, with shorter treatment courses, better patient education of potential risks, and conversion of patients to safer H2 blockers where possible. For those patients where long-term PPI use is truly necessary, kidney function should be regularly monitored to identify early changes in GFR.
1. Forgacs I, Loganayagam A. Overprescribing proton pump inhibitors. BMJ (Clinical research ed) 2008;336:2-3.
2. Kantor ED, Rehm CD, Haas JS, Chan AT, Giovannucci EL. Trends in Prescription Drug Use Among Adults in the United States From 1999-2012. JAMA 2015;314:1818-31.
3. Eusebi LH, Rabitti S, Artesiani ML, et al. PROTON PUMP INHIBITORS: RISKS OF LONG-TERM USE. Journal of gastroenterology and hepatology 2017.
4. Nochaiwong S, Ruengorn C, Awiphan R, et al. The association between proton pump inhibitor use and the risk of adverse kidney outcomes: a systematic review and meta-analysis. Nephrol Dial Transplant: official publication of the European Dialysis and Transplant Association – European Renal Association 2017.
5. Moledina DG, Perazella MA. PPIs and kidney disease: from AIN to CKD. Journal of Nephrology 2016;29:611-6.
6. Xie Y, Bowe B, Li T, Xian H, Balasubramanian S, Al-Aly Z. Proton Pump Inhibitors and Risk of Incident CKD and Progression to ESRD. Journal of the American Society of Nephrology: JASN 2016;27:3153-63.
7. Xie Y, Bowe B, Li T, Xian H, Yan Y, Al-Aly Z. Long-term kidney outcomes among users of proton pump inhibitors without intervening acute kidney injury. Kidney International 2017.
8. R. Poesen, B. Meijers, P. Evenepoel. Adverse effects of proton pump inhibitors in chronic kidney disease. JAMA Intern Med, 176 (2016), pp. 867–868.
9. G. Yepuri, R. Sukhovershin, T.Z. Nazari-Shafti, et al. Proton pump inhibitors accelerate endothelial senescence. Circ Res, 118 (2016), pp. e36–e42.
10. J.M. Mullin, M. Gabello, L.J. Murray, et al. Proton pump inhibitors: actions and reactions. Drug Discov Today, 14 (2009), pp. 647–660.
Dr. Borgi’s clinic research focuses on the link between nutrition and chronic diseases, such as hypertension and kidney disease. Dr. Borgi is also interested in food policy, and is completing a Master in Nutrition Sciences and Policy at the Friedman School of Nutrition Science and Policy at Tufts University. Dr. Borgi is currently interested in the recent changes made in food government programs regarding the inclusion of potatoes in food stamps.