In this study, we quantified and confirmed the association between PPI exposure and the increased risk of AKI, CKD, ESRD, and electrolyte abnormalities by utilizing updated adverse event reports in the FAERS/AERS database. Most interestingly, the extended set of reports revealed an association between PPI exposure and unexpected significant risk for nephrolithiasis and renal impairment (Fig. 1). For the first time there were sufficient records for analysis of the effects of individual PPIs and observed varying degrees of electrolyte and renal abnormalities (Figs 3 and 4).

Our analysis of renal adverse effects was in general agreement with previous studies that have documented an increased risk of incident AKI, incident CKD, CKD progression and ESRD in large observational cohorts. Klesper and colleagues performed a nested case-control study, including 184,480 patients, and found an increased risk of AKI with PPI prescription (OR 1.72, 95% confidence interval [CI] [1.27, 2.32], p < 0.001)22. In a population-based cohort study of 290,593 patients over the age of 65, Antoniou and colleagues confirmed the association of PPI use with AKI (hazard ratio [HR] 2.52, 95% CI [2.27, 2.79])29. In the Atherosclerosis Risk in Communities (ARIC) study Lazarus et al. performed a population based prospective cohort study with 10,482 patients and found an increased risk of incident AKI and CKD when comparing PPI users to H2RA users (HR, 1.58; 95% CI [1.05, 2.04]) and (HR, 1.39; 95% CI [1.01, 1.91]), respectively)21. These population-based studies utilized ICD coding data to define the outcome of incident AKI and CKD. Xie and colleagues evaluated a prospective cohort including 193,591 patients from the Veteran’s Affairs database and documented not only an increased risk of incident CKD (HR, 1.28; 95% CI [1.23, 1.34]) but also an increased risk for ESRD when comparing PPI users to H2RA users (HR, 1.96; 95% CI [1.21, 3.18])23 and in a later study demonstrated that CKD progression and ESRD can occur without intervening AKI28. The difference in values between different studies may be due to multiple factors including definitions of renal injury and the diagnostic criteria as well as the time dependent analyses using hazard ratios. The FAERS and AERS data derived frequencies are additionally influenced by the severity related threshold of the report submission. In summary we documented an OR of 4.2 for AKI with the lower 95% CI boundary of 2.9, OR values as large as 28.4, with the 95% CI between 12.7 and 63.5 for CKD and 35.5 with 95% CI between 5.0 and 250.0 for ESRD. Our results indicate significant increase in nephrolithiasis reports with (OR 2.8 (95% CI [1.3, 6.0]). Nephrolithiasis finding is of particular interest since it has been associated with AKI, CKD, and ESRD progression but it only accounts for a small subset of renal injury cases30,31,32.

Hypomagnesemia was reported in the initial clinical trials and on the FDA package insert for every PPI as a rare side effect11. Accordingly, the frequency of hypomagnesemia reports for PPI patients is low, but the relative frequency was dramatically higher, almost eighty-fold, than for the H2RA control group. Secondly, detection bias may underestimate this adverse effect, since magnesium concentrations are not routinely measured compared to sodium, potassium and calcium. All five studied PPIs had comparable and increased ORs, with omeprazole showing the largest magnitude. Omeprazole, being the first marketed and the first over-the-counter PPI, has been used for the longest time, therefore patients were likely to have longer drug exposure. It may be prudent to monitor magnesium levels in patients with ongoing PPI therapy and other risk factors for hypomagnesemia.

Previous studies examining the effect of PPIs’ on calcium levels were not consistent. Multiple small-scale studies have shown that PPIs decrease gastrointestinal calcium absorption33,34,35 and this deleterious effect is attenuated by administering acidic liquids36. However, other studies have noted that the change in gastric pH does not correlate with calcium levels37,38. In our analysis of 42,537 PPI and 8,309 H2RA cases, we found a clear increase in hypocalcemia in patients taking PPIs compared to patients receiving H2RAs. Although the mechanism for hypocalcemia is not clearly defined, we can conclude that all PPIs are significantly associated with hypocalcemia.

We evaluated alterations in serum potassium concentrations. The previous evidence for hypokalemia with PPI use was limited, mainly consisting of case reports39,40,41. We found that PPI utilization resulted in moderately increased hypokalemia, when compared to the H2RA cohort. As noted earlier, PPI utilization was correlated with CKD, known to cause fluctuations in electrolytes. While CKD can be associated with both hypokalemia (e.g. in the case of tubular dysfunction) and hyperkalemia42, we only observed a significant increase in hypokalemia. However, a small number of cases of hyperkalemia were reported out of 42,537 reports in FAERS/AERS. In conclusion, hypokalemia was more common than hyperkalemia in our analysis of patients receiving PPIs. Each PPI was shown to have increased odds of hypokalemia, except for rabeprazole which was not significant (OR 2.3 CI [0.27, 20]).

Hyponatremia has been reported as a rare post marketing adverse reaction in FDA package inserts for pantoprazole, omeprazole, and esomeprazole11,43,44. In a retrospective study of 302 individuals receiving PPIs for longer than a year, Buon and colleagues found moderate hyponatremia in 18.7–46.3% of elderly patients45. It should be noted that although dysnatremia is associated with CKD46, we observed only a minor yet significant increase in hyponatremia reports. Hypernatremia was not a significant adverse effect in PPI users. Our analysis showed hyponatremia effect to be most pronounced for omeprazole, followed by lansoprazole and rabeprazole.

The observed increased risks of renal and electrolyte adverse effects of PPIs warrant more careful consideration in clinical practice. The risk-benefit ratio should be considered for the individual patient with respect to the adverse effects. When clinically indicated, PPIs should be used for the shortest duration necessary and chronic use is not recommended except for treatment of pathological hypersecretory conditions including Zollinger-Ellison syndrome and maintenance healing of erosive esophagitis11,43,44,47,48,49,50,51,52,53,54. It should be noted that the above-mentioned indications are FDA recommendations. Off-label and over-the-counter use of PPIs for the treatment of gastroesophageal reflux disorder (GERD) should be limited to four weeks11,43,44,52,53,54 but is often continued beyond the recommended limit. Continued use can result in rebound acid hypersecretion and hypergastrinemia after 4–8 weeks of therapy55,56 leading to chronic use.