Sherry Haynes is currently pursuing a PharmD degree and has experience in both the clinical and management sides of pharmacy.
Connection of common acid reflux medicines with the risk of developing kidney injury has gained increased attention from the researchers in the past few years.
A recent study in a large population reports, yet again, suggested the link of these drugs with kidney diseases. The study was published in Pharmacotherapy: The Journal of Pharmacology and Drug Therapy, Volume 39, Issue 4.
The researchers at the University at Buffalo reviewed the medical records of more than 170,000 patients older than 18 years. The patients included those who were started on PPIs and were continuously enrolled for at least 12 months and identified via the health maintenance organization (HMO) database of Western New York.
Here's what the study found: The risk of acute kidney disease was ten times higher in the PPI users compared to nonusers and the risk of chronic kidney failure was four times higher in the user group compared to the nonuser group.
OTC PPIs are only intended for a 14 day course of treatment and can be used up to 3 times per year.
— FDA Official Website : Drug Information for Consumers
PPIs use as the treatment of choice for heartburn is as old as the hills and so is its association with illnesses. Previously, PPIs were reported to be associated with pneumonia and risk of bone fractures including hip, spine or wrist.
PPIs which are available as prescription drugs, as well as OTC, are used by millions of people around the world. Often these medicines are used by patients over-the-counter without a proper need, for many months or years.
According to ClinCalc DrugStats, omeprazole (Prilosec, an OTC drug for heartburn), a common PPI is among the top 10 most prescribed drugs in the US and pantoprazole is making it to the top 30 in the list.
Only a fraction of people using PPIs are aware of their use terms as advised by the FDA.
OTC Proton pump inhibitors (PPIs) are used to treat frequent heartburn and work by reducing the amount of acid in the stomach. In contrast, prescription PPIs are used to treat conditions like gastoesophageal reflux disease (GERD), stomach and small intestine ulcers, and inflammation of the esophagus. -FDA Official Website
This is not the first study to have found such a correlation between PPIs and kidney disease. Two other large studies reported similar results. The first study by Lazarus B. et al included more than 10,000 participants from the US who were given an outpatient prescription of PPI or have self-reported of using PPIs. This group was compared with those taking other class of acid reflux medicines called H2RAs. The participants were followed for 14 years. The incidence of chronic kidney disease was 20-50% higher in patients receiving PPIs compared to those using H2RAs. 
Another study was done in the population of Sweden. The researchers aimed to investigate the association of PPI use with the progression of CKD. The disease was evaluated in terms of increased creatinine levels to at least two folds and a reduction in the glomerular filtration rate (GFR).  The study found that the PPI user group had both increased creatinine levels as well as a reduction in the estimated GFR rate by 30%.
In another study that was performed to find out the relationship between the dose of PPI and the time of use with risk of CKD development, the risk was observed to have increased with high doses and after three months of continuous PPI use. 
Currently, there is no proven mechanism that can explain the association of PPIs with kidney disease.
One factor that possibly explains the link between the PPIs and kidney disease is the development of drug-induced acute interstitial nephritis (AIN). It is the inflammation of the area of the kidney known as interstitium. Drug-induced AIN is a common cause of acute kidney injury (AKI). It affects about 20% of the patients with unexplained AKI and may lead to CKD and end-stage renal disease (ESRD). This was confirmed by an Australian study that detected 18 cases of biopsy-proven AIN that led to the development of AKI. Later several studies that assessed the incidence of AIN in PPI users suggested the connection between PPIs and acute kidney injury.
Although these drugs have an excellent safety profile using them inappropriately in the ways mentioned above and the high number of patients using these drugs has made them one of the most common causes of developing acute interstitial nephritis which can progress into chronic kidney injury.
However, acute interstitial nephritis is a very rare cause of chronic kidney disease so it would be difficult to state that AIN explains the PPI and CKD association.
Do We Conclude That PPI Use is Llinked with Kidney Disease? Not Exactly.
The studies that have linked PPIs to development of kidney disease are observational studies. This type of studies do not prove causation and hence should be interpreted carefully.
Most of these are retrospective studies which means the research look backwards in time to assess if the PPIs use have caused the suspected risk which in this case is kidney disease. These studies include a large number of patients who might show considerable differences at the baseline which are difficult to be adjusted. Example, patients who use PPI are more likely to have diabetes or hypertension compared to those who don't or are more likely to be on more than one therapy. So these patients are more likely to use other medications that might be responsible for causing injury to the kidneys.
Such retrospective studies cannot adjust for these baseline differences which might be the reason for the disease and not the drugs themselves.
A recent review of ten observational studies with more than one million patients states that the evidence is inconclusive in establishing a true link. 
The current evidence related to the potential association of CKD with PPI use remains inconclusive in establishing true causality and should therefore not lead to unwarranted discontinuation of PPIs against established medical conditions such as GERD and PUD. - The author of the review conclude. 
The authors further suggests that while it is necessary to conduct further high quality research, the cautious use of these medicines should be adopted by the users in the meantime.
Most of these studies are based on the information that is obtained from huge databases such as FAERs that provide large diversity. So, these findings as diverse as they can be should not be neglected.
- Hart, E., Dunn T.E., Feuerstein, S., Jacobs, D.M.,. Proton Pump inhibitors and Risk of Acute and Chronic Kidney Kisease: A Retrospective Cohort Study. Pharmacotherapy;39(4):443-453.
- Lazarus, B., Chen, Y., Wilson, F. P., Sang, Y., Chang, A. R., Coresh, J., & Grams, M. E. (2016). Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease. JAMA internal medicine, 176(2), 238–246. doi:10.1001/jamainternmed.2015.7193
- Derk, C.F., Klatte, Alessandro, G., Xu, H., Deco, P., Trevisan, M., et al., Association Between Proton Pump Inhibitor Use and Risk of Progression of Chronic Kidney Disease(2017) Gastroenterology :153 (3); 707-710.
- Rodríguez-Poncelas, A., Barceló, M. A., Saez, M., & Coll-de-Tuero, G. (2018). Duration and dosing of Proton Pump Inhibitors associated with high incidence of chronic kidney disease in population-based cohort. PloS one, 13(10), e0204231. doi:10.1371/journal.pone.0204231
- Geevasinga, N., Coleman, P.L., Webster, A.C., Roger, S.D. Proton pump inhibitors and acute interstitial nephritis. Clin Gastroenterol Hepatol. 2006;4:597–604. doi: 10.1016/j.cgh.2005.11.004.
This content is accurate and true to the best of the author’s knowledge and is not meant to substitute for formal and individualized advice from a qualified professional.
Sherry Haynes (author) on September 13, 2019:
Thank you Liz! I am glad the early note was useful. I just didn't want to act like a lay press that brings more worry to the readers than real information.
Liz Westwood from UK on September 13, 2019:
As a PPI user I have read your article with interest. I appreciated the early warning to read to thd end. It seems like more research needs to be done on the issue.