PPI: Blockbuster Delivers Kidney Punch

8. March 2016

The use of proton pump inhibitors (PPI) is possibly linked to an increased risk of getting chronic kidney disease. The gastric acid inhibitors, regarded until now as well tolerated, have come under criticism lately on account of various side effects.

A study published on January 11 in JAMA [Paywall] Internal Medicine gives us an opportunity at present to have a rethink about the overly careless use of proton pump inhibitors. In their study, researchers from Johns Hopkins University in Baltimore observed an association between the use of PPIs and chronic kidney disease (CKD). PPI are among the most commonly prescribed medication and as OTCs as well they are genuine blockbuster items for pharmacies: Looking at the past 20 years, the number of prescriptions, going by the number of packaging units produced, have increased by around 19 fold. The new study raises the question of whether the wide-scale use of proton pump inhibitors is justified in view of its potential risks.

In producing the submitted study [Paywall] the research team led by Dr. Morgan Grams consulted two sources: The first cohort was derived from the observational study “Atherosclerosis Risk In Communities “(ARIC) and included 10,482 participants with an average age of 63 years. The patients were studied regularly over a period of 14 years. From among a total of 322 participants who were taking gastric acid blocker at the beginning of the investigation, 56 fell victim to chronic kidney failure. This corresponds to an incidence rate of 14.2 kidney disease cases in 1,000 person-years. Of 10,160 participants who were not taking PPIs, 1,382 people developed chronic renal failure (CKD), which corresponds to an incidence rate of 10.7 per 1,000 person-years. According to these results, the absolute risk of disease over 10 years for the PPI users was 11.8%, whereas for the non-users there was only 8.5% chance of ending up with CKD within 10 years.

Grams’ research team was also able to underpin its results [Paywall] with the evaluations from the second cohort. This group included data from a total of 248 751 individuals insured by GeisingerHealth Systems in Pennsylvania; these individuals were evaluated for six years. Of the 16,900 PPI users 1,921 came to suffer from chronic renal failure whereas from among 231,851 non-users 28,226 were CKD cases. The absolute risk of disease over 10 years for patients using gastric acid inhibitors was therefore 15.6%, while for the comparison group without PPI it amounted to 13.9%.

The dose makes up the poison

In addition, what stood out to the scientists from Baltimore was the relationship between the administered dose and the presence of kidney disease: patients who swallowed proton pump inhibitors twice daily showed a higher risk of chronic renal failure than study participants who took only one dose per day. The observed dose-response relationship is significant not least due to the fact that it underpins a possible – and as yet unproven – causality between the use of PPIs and the occurrence of chronic renal failure. The fact that proton pump inhibitors may play a causative role here is something also suggested by the comparison with H2receptor antagonists: here again PPI users had a higher risk of disease than patients who received H2 blockers for inhibiting gastric acids. The latter inhibit the production of gastric acid less strongly than PPI.

The authors of the new study comment on its outcomes as follows: “We note in our study that what we have here is an observational study which does not provide evidence of causation. Nevertheless a causal relationship between the use of PPIs and CKD in view of the wide-scale use could have a significant effect on the health of the population”. He adds: “In 2013 more than 15 million Americans took prescribed PPI, the related costs being more than 10 billion US dollars. Study results lead us to assume that 70% of these prescriptions are made out without indication and that 25% of long-term PPI users could end their therapy without developing symptoms”.

When sour is not funny any more

Proton pump inhibitors reduce the formation of gastric acid through their blocking of the proton-potassium pump in the parietal cells of the stomach. The various active agents carry out their work essentially in the same therapeutic application areas as the treatment and prevention of ulcers of the stomach and duodenum, of gastro-esophageal reflux disease as well as of the rare Zollinger-Ellison Syndrome. Since market launch, the use of PPI has increased rapidly, in some countries an enormous wave of prescriptions of this class has been observed. So PPI is counted in the US among the most prescribed medicines: in 2013 alone approximately 15 million US citizens took PPI. A major role in the growing number of regulations is played here by the previously good image of the PPI in terms of safety and tolerability.

Controversy about risks and side effects

In recent years however, several studies have provided evidence that the range of side effects of proton pump inhibitors may possibly be being underestimated. Scientists discuss whether the use of PPIs is associated with an elevated risk of pneumonia and Clostridium difficile infections. Evidence of a causal relationship is however currently not at hand. In contrast there is however an increasing accumulation of evidence for a causal link between the long-term intake of PPIs and an increased risk of osteoporosis-related bone fractures as a result of a calcium deficiency. Other studies suggest that there exists a causal link between the duration of intake of proton pump inhibitors and serious magnesium deficiency, that can carry with it in part serious consequences, such as arrhythmias and seizures. Possible rebound effects after longer treatment periods are also discussed.

On The Sense and Nonsense of PPI

There’s no doubt that proton pump inhibitors have won a great amount of use in the treatment of certain diseases. Thus the current German guideline on gastro-oesophageal reflux disease (GERD) recommends its use in interval therapy form, which can under certain circumstances also be employed over the longer term. In addition, the current situation is such that concomitant administration of PPI is deemed valid and standard as part of antibiotic eradication therapy for Helicobacter pylori infections. For those patients who permanently take traditional non-steroidal drugs (traditional NSAID) and carry at least one additional risk factor (z. B. age, co-medication) in most cases the benefits of PPIs predominate over risks.

Problems are seen by researchers however, in view of the current study results with respect to the mass prescription of PPI without such grounds. Scientists Jacob Schoenfeld and Deborah Grady of the University of California, San Francisco, commented on the use of PPI as such: “A large number of patients are taking PPIs for no apparent reason – often because of moderate symptoms of indigestion or heartburn, which have since disappeared by themselves. With these patients, PPIs should be discontinued in order to elicit whether symptomatic treatment is necessary”.

No wonder that the scientists from Baltimore indicate, in relation to their newly published publication, that “in fact there already are calls to reduce the unnecessary use of PPI”. Whether doctors and patients will comply with this call is however yet to be seen.

Original publication:

Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease [Paywall]
Benjamin Lazarus et al.; Internal Medicine, doi: 10.1001/jamainternmed.2015.7193; 2016

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