Proton pump inhibitors (PPIs) are amongst the most frequently prescribed medications with an estimated 15 million in the US taking prescription PPIs, making the estimated prevalence around 7.8% of the adult population. This number doesn’t even account for over-the-counter usage. Sure, there are some patients that are on pantoprazole for an H. pylori infection, peptic ulcer disease, or severe esophagitis, but then there are those who ended up on it after hospital discharge when they were put on omeprazole for stress ulcer prophylaxis, or were prescribed it as a trial for reflux symptoms, and now are on the medication indefinitely and don’t even know it.

PPI use has been linked to several adverse effects including Clostridium difficile infections, vitamin malabsorption, atrophic gastritis, and even dementia and cardiovascular disease. From a kidney perspective, it has long known to be associated with acute interstitial nephritis and hypomagnesemia. However, more recently there are large epidemiologic data that suggest a link between PPI use and CKD progression. This even made major news headlines over the past few years, and most of us have had patients ask us as health care providers if it’s safe for them to continue taking their Protonix.

Box 1 from Al Aly et al, AJKD © National Kidney Foundation.

In a recent AJKD In-Practice, Al-Aly et al address the potential adverse kidney outcomes and offer deprescription guidelines for patients who no longer need this medication.

PPIs and Acute Interstitial Nephritis (AIN)

We’ve all been taught this and have likely passed this association on to trainees over the years. Although AIN is not a common phenomenon, the high prevalence of the use of PPI medications brings this association closer to the surface. Because of how often these medicines are used, the exact incidence is tough to pin down, but some studies suggest that this class may be the leading cause of drug-induced AIN. In a single-center UK study of 24 biopsy-confirmed cases of tubulointerstitial nephritis, 14 cases were thought to be drug-induced, and 8 of 14 (57%) were presumed to be related to omeprazole or lansoprazole. Other studies have consistently reproduced this association as well. For the small subset of patients that experience AIN from this class of medications, it should be listed as a true allergy and they should not be re-challenged. If continued acid suppression therapy is needed, H₂ blockers can be considered. Here’s a case I had from a few years back in a patient we biopsied for AKI who was taking a PPI:

Biopsy slide showing a case of acute interstitial nephritis (AIN) associated with proton pump inhibitor (PPI) use.

PPIs and CKD Progression

This one is a bit tougher to nail down, but several large cohort studies have suggested that PPI use is associated with CKD progression. Meta-analyses also support this association, and interestingly, the mechanism is not thought to be related to interstitial nephritis, but rather a direct pathway leading to indolent damage. The biologic mechanism for this chronic damage is unclear, but hypotheses include alteration to the gut microbiome, impairment of tubule regeneration, or upregulation of heme oxygenase-1.

It’s important to note that these studies linking adverse kidney outcomes to PPI use are observational in nature and have not been validated in randomized controlled trials (RCTs). However, due to the low incidence and slow progression of CKD, no RCTs involving PPIs have been powered sufficiently to detect adverse kidney outcomes. Nonetheless, the observational cohort data does allow us as providers to examine the risk/benefit ratio of this medication, and to consider deprescription.

Table 1 from Al Aly et al, AJKD © National Kidney Foundation.

Deprescribing PPIs

“Many of my patients are taking too much medicine, but it’s so much easier to start something than to stop it.” – Helen Salisbury

Deprescription is the planned stoppage of medication to improve the health of the patient, and/or to reduce the risk of an adverse outcome. While PPIs certainly have beneficial effects, overuse of these drugs is not harmless in both a financial and patient-oriented lens. The fact that these medications are available over the counter likely contributes to the perception that these medications are “safe” — we saw where that led us with NSAIDs!

Broad deprescription guidelines show patients falling into 5 broad classes:

1. No indication or PPI use
2. Indication unknown
3. Mild/moderate esophagitis or GERD
4. Well-defined indication (e.g., peptic ulcer disease, H pylori infection) but remained on treatment beyond the indicated period
5. Conditions requiring long-term PPI use (e.g., bleeding ulcers, severe esophagitis)

For those in Class 1, the answer is simple, and we should stop the medicine. Class 2 can also be stopped, but patient should monitor for symptoms, and should be followed for re-evaluation. Class 3 patients can be instructed to use PPIs on demand, or to lower the dose and see if symptoms are manageable. Class 4 patients that had a clear benefit to PPI use, where their condition is now treated, should also be deprescribed. To be honest, when I look at these classifications, the majority of my patients on this class of medication should be counselled on deprescription! Figure 1 below summarizes these classes and recommendations.

A deprescribing algorithm for proton pump inhibitors (PPIs). Abbreviations: GERD, gastroesophageal reflux disease; H pylori, Helicobacter pylori; NSAID, nonsteroidal anti-inflammatory drug. Based on information in Farrell et al. Figure 1 from Al Aly et al, AJKD © National Kidney Foundation.

Lastly, although the observational studies above linked PPI use to CKD progression, there is no evidence suggesting that kidney function will improve after cessation of PPIs. This is important information for us to communicate to our patients with CKD — ensuring that they understand that stopping this medication is not going to improve their GFR is an often misunderstood point. Generally, if PPIs are prescribed, there should be a clear indication, and for most indications, PPI use should be limited to short-term treatment for which the risk for adverse events is relatively low. Given their ubiquitous use, providers should be on the lookout for hypomagnesemia, interstitial nephritis, and more indolent in nature, potential CKD progression. Reducing un-indicated exposure should be no different to us than employing other “nephroprotective” strategies, and should be deprescribed when these drugs are no longer necessary.

– Post prepared by Timothy Yau, AJKD Social Media Editor. Follow him @Maximal_Change.

To view the Al Aly et al In Practice (subscription required), please visit AJKD.org.

Title: Proton Pump Inhibitors and the Kidney: Implications of Current Evidence for Clinical Practice and When and How to Deprescribe
Author: Ziyad Al-Aly, Geetha Maddukuri, and Yan Xie
DOI: 10.1053/j.ajkd.2019.07.012

In Practice is a focused review providing in-depth guidance on a clinical topic that nephrologists commonly encounter. Using clinical vignettes, these articles illustrate a complex problem for which optimal diagnostic and/or therapeutic approaches are uncertain.