Do Acid-Reducing Drugs Cause Kidney Failure?

Proton pump inhibitors possibly linked to kidney disease

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Recently, a lot of attention has been drawn by popular media to the results of a study that was published in the Journal of the American Society of Nephrology detailing a possible link between use of medications, called "proton pump inhibitors," and kidney disease. Proton pump inhibitors (PPIs) are common drugs, and some happen to be available over-the-counter—you might have heard of names like Prilosec, or Nexium, or Prevacid.

 Proton pump inhibitors have been around since the 1980s when they were initially developed, with omeprazole being one of the first ones to be launched in the market in 1989.

PPIs work by reducing acid production in the stomach. Yes, our stomachs have acid, specifically something called "hydrochloric acid," which has an important role in digestion. Too much acid, or acid in the wrong location (think your food pipe, the esophagus, instead of the stomach), and you start running into problems. Therefore, PPIs are used for treating common disorders like gastroesophageal reflux disease (GERD), gastric ulcers, heartburn, and Barrett's esophagus. It is, therefore, no surprise that PPIs are one of the most widely used drugs, with omeprazole being on WHO's (World Health Organization) Essential Medication List.

Unfortunately, a significant proportion of patients use these drugs inappropriately (wrong indication/dose/duration).

 Quite understandably then, if a popular class of medications is noted to have an association with a disease (chronic kidney disease, in this case), it is bound to raise eyebrows, even if the risk is small. 

Proton pump inhibitors have always had a checkered history as far as kidney function is concerned.

Given the good overall safety profile of these drugs, potential side effects on the kidneys have not been particularly highlighted. However, as a kidney doctor, in the nephrology world, this has always been part of standard teaching for a few decades now.

The potential of proton pump inhibitors to cause an inflammatory reaction in the kidney, called acute interstitial nephritis (AIN), was noted almost 25 years ago. Some other kidney-related problems (electrolyte disorders) that have been associated with proton pump inhibitors are low magnesium and low sodium levels in the blood, as well as high calcium level

How Do Proton Pump Inhibitors Hurt the Kidneys? 

Acute interstitial nephritis, as mentioned above, is one of the common mechanisms by which proton pump inhibitor medications (like omeprazole/rabeprazole/pantoprazole, for instance) could impact kidney function. Think of it as an allergic reaction set off by these medications, except that the allergy is confined to the kidneys and therefore you may not notice it superficially.

By the way, proton pump inhibitors are not the only medications that cause acute interstitial nephritis. In principle, any medication could do it, but the classical culprits are antibiotics, NSAIDs, allopurinol, furosemide, etc.

But what makes the issue even more complicated when it comes to proton pump inhibitors is the fact that you might not have the classical signs or symptoms that one might expect to see in the typical drug-induced acute interstitial nephritis (these are: fever, rash, elevated level of a certain kind of blood cells called eosinophils, etc).

How Would You Diagnose PPI-Induced Interstitial Nephritis? 

In the absence of reliable signs or symptoms, your physician/nephrologist might notice an otherwise unexplained increase in your blood creatinine level (the chemical measured in the blood to assess your kidney function).

Of course, that is a very generic finding which in no way is conclusive of interstitial nephritis due to a proton pump inhibitor. Hence, if no other explanation is found, the only definitive way to diagnose this entity is really a kidney biopsy, a procedure that entails sticking a needle into your kidney to get a small piece of tissue for analysis. As you might imagine, most patients would not be great fans of this procedure, which in other words implies that we do not really have a reliable, non-invasive way to confirm PPI-related acute interstitial nephritis.

So, imagine this scenario: You start taking a PPI drug (like omeprazole) for a vague acid reflux/heartburn symptom. As you continue to take the medication, interstitial nephritis develops in the kidney after some time, except that you have no inkling that it is going on. You may or may not get blood tests, but either way many physicians might not pay attention to a PPI as a possible cause of kidney damage (especially if the medication you're taking is over-the-counter). This is especially true where you might have used a PPI in the past, but are not currently using one, since prior long term use could potentially lead to permanent damage.

In other words, once you go past a certain point in the development and evolution of interstitial nephritis, acute (short term, temporary) inflammation could change into chronic (long term, permanent) inflammation due to scar tissue formation, creating something called chronic interstitial nephritis. This could eventually lead to chronic kidney disease and a higher risk for progression to dialysis in a subset of patients. 

What the Data Tell Us 

So far, we have had more than one study raising the possibility of an association between proton pump inhibitor use and kidney disease, which is why the recent study published in the Journal of American Society of Nephrology in April 2016 is pertinent. What makes the study even more important is the fact that it attempted to answer how proton pump inhibitors would impact not just the development of kidney disease, but also its progression and eventual decline to end-stage kidney disease.

The study used a Department of Veteran Affairs database to identify new users of proton pump inhibitors, (over 170,000 people) and compared them against new users of histamine H2 receptor antagonists (another common class of meds used to treat stomach acid related disorders, about 20,000 people). These patients were then followed for five years and their kidney function was tracked. Here are the results:

PPIs and Development and Progression of Kidney Disease

The study found that people who used proton pump inhibitors, as compared to those who used histamine H2 blockers had a higher risk (hazard ratio 1.22) of development of new kidney disease, even if they were started off with perfectly normal kidneys (kidney disease for this situation was defined as a GFR less than 60). They were also at a higher risk of doubling serum creatinine level and of decline of kidney function to end-stage kidney disease. The risk seems to go up with longer duration of exposure to proton pump inhibitors.

Hence, this study concludes that using proton pump inhibitors might increase the risk of development of kidney disease, as well as cause a faster decline of kidney function to end-stage kidney disease.

How Long You Use PPIs Might Make a Difference 

As per the study results, it looks like it's not just use of these medications, but also how long you use them for that is an important factor. The study actually compared people who used these medications for less than 30 days against longer term users. There did seem to be a graded association between duration of exposure and risk of kidney disease, and this increased up to about 720 days of exposure to these drugs.

What Does This All Mean for You as a Patient? 

The results of the above described study, as well as prior data, provide food for thought. I do want to emphasize that this is an observational study, which by definition cannot prove causation. Regardless of that however, there seems to be an association between PPI use and kidney disease, which merits attention. The data are also consistent with prior observations.

It is entirely possible that a large population of patients using proton pump inhibitors might have undiagnosed acute interstitial nephritis to begin with, that eventually progresses to chronic interstitial nephritis and therefore chronic kidney disease. Given the problems involved in making an accurate diagnosis of interstitial nephritis (especially with proton pump inhibitors, as described above), a lot of patients out there might not even know that they are hurting their kidneys with these medications.

I do not want to sound alarmist here, but no matter how small the relative risks might be, just the fact that these medications are taken by millions of patients, sometimes inappropriately and often over-the-counter without the knowledge of a physician, makes this a big deal.

I would encourage you to discuss the following with your doctor now that you are aware of the possibility of links between PPIs and kidney disease: 

  • Make sure your physicians are aware that you take proton pump inhibitors, especially if you're taking them over the counter
  • Ask your doctor if switching over to an H2 receptor blocker (like famotidine, or Pepcid, etc) might be a safer option
  • Verify that you are indeed taking a PPI for an appropriate indication. We already have some clinical data that suggest that proton pump inhibitors are often prescribed inappropriately without an adequate indication.
  • You would also want to check if you need to take these meds consistently, or only on an as needed basis (as the study results above tell us, duration of exposure is an important factor in determining risk of kidney disease)
  • If you must take a proton pump inhibitor, make sure that your kidney function is being monitored by either your primary doctor or by a nephrologist. I would highly recommend this in patients who have other risk factors for kidney disease (like diabetes, hypertension, heart disease, obesity, or those who use NSAIDs chronically, etc).


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