Risk of bias in non-randomized observational studies assessing the relationship between proton-pump inhibitors and adverse kidney outcomes: a systematic review

Abstract

Background: Proton-pump inhibitors (PPIs) are widely prescribed as acid-suppression therapy. Some observational studies suggest that long-term use of PPIs is potentially associated with certain adverse kidney outcomes. We conducted a systematic literature review to assess potential bias in non-randomized studies reporting on putative associations between PPIs and adverse kidney outcomes (acute kidney injury, acute interstitial nephritis, chronic interstitial nephritis, acute tubular necrosis, chronic kidney disease, and end-stage renal disease). Methods: We searched the medical literature within 10 years of 17 December 2020. Pre-specified criteria guided identification of relevant English language articles for assessment. Risk of bias on an outcome-specific basis was evaluated using the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool by two independent reviewers. Results: Of 620 initially identified records, 26 studies met a priori eligibility criteria and underwent risk of bias assessment. Nineteen studies were judged as having a moderate risk of bias for reported adverse kidney outcomes, while six studies were judged as having a serious risk of bias (mainly due to inadequate control of confounders and selection bias). We were unable to determine the overall risk of bias in two studies (one of which was assessed as having a moderate risk of bias for a different adverse kidney outcome) due to insufficient information presented. Effect estimates for PPIs in relation to adverse kidney outcomes varied widely (0.24–7.34) but associations mostly showed increased risk. Conclusion: Using ROBINS-I, we found that non-randomized observational studies suggesting kidney harm by PPIs have moderate to serious risk of bias, making it challenging to establish causality. Additional high-quality, real-world evidence among generalizable populations are needed to better understand the relation between PPI treatment and acute and chronic kidney outcomes, accounting for the effects of varying durations of PPI treatment, self-treatment with over-the-counter PPIs, and potential critical confounders.

Estimates of Chronic Kidney Diseases Associated with Proton-Pump Inhibitors Using a Retrospective Hospital-Based Cohort in Thailand

“…Regarding the systematic reviews across countries from the United States, Brazil, Taiwan, Sweden, and Denmark, effect estimates for the association between PPI treatment (compared with non-PPI users or H2 blocker users) and CKD ranged from an adjusted HR of 1.12 (95% CI 1.08-1.17) to 7.34 (95% CI 3.94-13.71). 23 As compared with this study, Guedes et al 10 resulted the HR was 7.34 (95% CI: 3.94-13.71) (Supplementary Table 3A), indicating a higher risk of worse stages of CKD in omeprazole users than in non-users. This is relevant to our sub-group analysis (Table 4) that HR among omeprazole as compared to H2RAs was 3.783 (95% CI: 2.404-5.952).…”

“…Regarding the systematic reviews across countries from the United States, Brazil, Taiwan, Sweden, and Denmark, effect estimates for the association between PPI treatment (compared with non-PPI users or H2 blocker users) and CKD ranged from an adjusted HR of 1.12 (95% CI 1.08–1.17) to 7.34 (95% CI 3.94–13.71). 23 …”

Repositioning of Lansoprazole as a Protective Agent Against Cisplatin-Induced Ototoxicity

“…Fourth, although we demonstrated that the incidence rate of CIO was significantly lower in patients treated with LPZ compared to those treated without LPZ in the EHRs of Mie University Hospital, the number of patients with CIO (n = 29) was relatively low among the total number of patients (n = 260). Additional real-world evidence among general populations is required to confirm whether LPZ or other PPIs can protect against CIO (Rajan et al, 2022). Fifth, we were not able to analyze the effect of LPZ on the survival of patients treated with CDDP.…”