Why Observational Studies Are Misleading & PPI Association with Kidney Stones

M Simonov et al. Clin Gastroenterol Hepatol 2021; 19: 72-79. Use of Proton Pump Inhibitors Increases Risk of Incident Kidney Stones

Commentary: P Moayyedi. Clin Gastroenterol Hepatol 2021; 19: 41-42. Full Text Link: Leaving No Stone Unturned in the Search for Adverse Events Associated With Use of Proton Pump Inhibitors

 The retrospective study by Simonov et al used data from the Women’s Veteran’s Cohort Study (1999-2017) with 465,891 patients. Key findings:

  • Overall, 2.4% of the cohort developed kidney stones. PPI use was associated with kidney stones in the unadjusted analysis, hazard ratio [HR], 1.74 (95% CI, 1.67–1.82), and persisted in the adjusted analysis with HR, 1.46 (CI, 1.38–1.55). The association was maintained in a propensity score-matched subset of PPI users and nonusers (adjusted HR, 1.25; CI 1.19–1.33).
  • H2RAs were also associated with increased risk with adjusted HR, 1.47

While this study is interesting, the editorial provides a great deal of insight into how this study and many others can be misleading. Key points:

  • “It seems that every few months a new issue arises, with the list of problems that PPIs might cause becoming ever longer, including pneumonia, fracture, heart disease, Clostridium difficile–associated diarrhea, dementia, chronic kidney disease, low B12 levels, gastric cancer, and even all-cause mortality.”
  • If the findings in the study are correct, with the unadjusted HR, “this translates to a number needed to harm (NNH) of 365 patients who need to take PPIs for 1 year to observe 1 extra episode of kidney stones…if the adjusted HR is used …the NNH was 1550.”


  • Confounding variables are hard to eliminate in an observational study. “Studies usually show that patients who are prescribed PPIs are, on average, sicker than those who are not taking these drugs.”
  • In the only large randomized controlled study (>17,000 patients over 3 years) of PPIs, there was no difference in pneumonia, Clostridium difficile infection, fracture, gastric atrophy, chronic kidney disease, dementia, cardiovascular disease, cancer, hospitalizations, and all-cause mortality in the PPI compared with the placebo arms.”Enteric infections, which were slightly more common in patients randomized to PPIs, but even there the NNH was more than 900 per year.”
  • Biases undermine the interpretation of observational studies. One example for PPIs is its association with pneumonias in prior observational studies.
    • “The effect was strongest within the first week of prescription when the odds ratio was approximately 4, although this was reduced to approximately 1.5 after 1 month. This marked reduction in risk over a relatively short period of time is not biologically plausible and a more likely explanation is that the association is the result of protopathic bias. Patients presenting to the clinician with a cough may be diagnosed with silent reflux and given a PPI. A few days later other symptoms develop, and pneumonia is made as the final diagnosis. This will not be apparent when simply interrogating a database where the researcher will observe that a PPI was prescribed before the onset of pneumonia and will imply the association is causal when this is not the case.”
  • This same type of bias could be present with the association between PPI and kidney stones.
    •  “Patients may present with abdominal pain and be given a PPI as a therapeutic trial, assuming the pain may be acid-related when subsequently it is found that the pain relates to kidney stones. Simonov et al reported that 3% were prescribed PPIs within 1 month of the diagnosis of kidney stones, but did not provide the analysis that would allow us to interpret whether protopathic bias may play a role in the associations observed”

My take: It is unlikely that PPIs cause kidney stones; however, if this is a risk factor, it is very rare. Understanding how PPIs have been incorrectly linked to a multitude of problems is a valuable lesson for any practitioner and emphasizes the need for randomized controlled studies to determine medication safety.

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2 thoughts on “Why Observational Studies Are Misleading & PPI Association with Kidney Stones

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