Proton pump inhibitors and traditional nonsteroidal anti‐inflammatory drugs and the risk of acute interstitial nephritis and acute kidney injury

Abstract

Purpose This study aims to examine the associations between proton pump inhibitors (PPIs), traditional nonsteroidal anti-inflammatory drugs (tNSAIDs), PPI + tNSAID co-exposure, and the development of the following: (i) acute interstitial nephritis (AIN), a specific kidney injury often attributed to these drugs, and (ii) acute kidney injury (AKI), a general kidney injury encompassing AIN. Methods Two retrospective case-control studies were conducted, one for each outcome, within the General Practice Research Database. Cases were diagnostic-coded AIN (primary outcome) or AKI (secondary outcome) events. Controls were matched on age, sex, and general practitioner practice. Exposures were defined by the presence/absence of the following mutually exclusive therapies on the index date: (i) PPI alone; (ii) tNSAID alone; (iii) PPI + tNSAID; or (iv) neither PPI nor tNSAID (referent). Results Sixty-eight AIN cases and 3347 controls were identified. The adjusted odds ratios (ORs) for PPI and tNSAID exposures alone were 3.20 (0.80-12.79) and 1.90 (0.65-5.51), respectively. Numerous sensitivity analyses produced adjusted ORs for AIN between 3.0 and 7.7, and 1.6 and 1.9, respectively. We identified 27 982 AKI cases and 1 323 850 controls. The adjusted ORs for PPI alone, tNSAID alone, and PPI + tNSAID exposures were 1.05 (0.97-1.14), 1.31 (1.25-1.37), and 1.33 (1.07-1.64), respectively. Numerous sensitivity analyses produced adjusted ORs for AKI between 1.0 and 1.1, 1.1 and 1.3, and 1.3 and 1.4, respectively.Conclusions Proton pump inhibitor exposure may increase the odds of AIN, but this result was not definitive and should be confirmed in a dataset with more AIN cases to allow for increased statistical precision. tNSAIDs, yet not PPIs, were associated with a significantly increased odds of AKI.

Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease

“…14–18 Our study adds to the existing literature by describing an association between PPI use and incident CKD, suggesting a 20–50% higher risk among PPI users. We note that our study is observational, and thus does not provide evidence for causality.…”

“…9, 10 Since the introduction of PPIs to the US market in 1990, several observational studies have linked PPI use to uncommon but serious adverse health outcomes, including hip fractures, 11 community acquired pneumonia, 12 Clostridium difficile infections, 13 acute interstitial nephritis (AIN), 14, 15 and acute kidney injury (AKI). 16–18 It is plausible that PPI use may also be a risk factor for CKD, potentially mediated by recurrent AKI 19, 20 or hypomagnesemia, which has been associated with both PPI use 21 and incident CKD. 22 To the best of our knowledge, no population-based studies have evaluated the relationship between PPI use and the risk of CKD.…”

Proton pump inhibitors and the risk of acute kidney injury in older patients: a population-based cohort study

“…Our findings are in general agreement with those of 3 previously reported nested case-control studies, but provide the first estimate of the risk of drug rechallenge among patients admitted with acute kidney injury shortly after initiating PPIs. [7][8][9] Our study has important implications for public health. Given the millions of individuals who take PPIs each year and the fact that more than half of such prescriptions may not be clinically indicated, [17][18][19][20] even a small absolute increase in risk of interstitial nephritis outweighs any benefits that might be derived from these drugs in many patients for whom they are prescribed.…”

“…4 Evidence for this association is limited to anecdotal reports, case series and 3 observational studies, one of which was based on only 5 cases of acute interstitial nephritis and one which examined the risk of acute kidney injury only. [4][5][6][7][8][9] Importantly, because classic systemic features of drug-induced acute interstitial nephritis are often absent in PPI-associated cases, the causal role of these drugs may be overlooked.…”

Individual non-steroidal anti-inflammatory drugs and risk of acute kidney injury: A systematic review and meta-analysis of observational studies

“…Acute kidney injury (AKI) associated with the use of NSAIDs has been well-documented by several population-based studies as well, with the relative risks compared with non-user ranging from 1.6 to 2.2 [10][11][12]. However, little is known about the risk of individual NSAIDs, including specific COX-2 inhibitors.…”