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Review
. 2022 Feb 10:15:17562848221074183.
doi: 10.1177/17562848221074183. eCollection 2022.

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

Pradeep Rajan  1 , Kristy Iglay  2 , Thomas Rhodes  2 , Cynthia J Girman  2 , Dimitri Bennett  3 , Kamyar Kalantar-Zadeh  4
Affiliations
Review

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

Pradeep Rajan et al. Therap Adv Gastroenterol. .

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.

Keywords: acute interstitial nephritis; acute kidney injury; acute tubular necrosis; chronic kidney disease; end-stage renal disease; proton-pump inhibitors.

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Conflict of interest statement

Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Takeda Pharmaceuticals contracted with CERobs Consulting, LLC, a consulting firm with focus on real-world evidence observational research, comparative effectiveness research, pragmatic randomized trials, outcomes research, epidemiology, and clinical outcome assessments, including patient-reported outcomes. PR, KI, TR, and CJG consulted on this project through CERobs Consulting, LLC. KK-Z has received honoraria and/or support from Abbott, Abbvie, ACI Clinical (Cara Therapeutics), Akebia, Alexion, Amgen, Ardelyx, ASN (American Society of Nephrology), Astra-Zeneca, Aveo, BBraun, Chugai, Cytokinetics, Daiichi, DaVita, Fresenius, Genentech, Haymarket Media, Hofstra Medical School, IFKF (International Federation of Kidney Foundations), ISH (International Society of Hemodialysis), International Society of Renal Nutrition & Metabolism (ISRNM), JSDT (Japanese Society of Dialysis Therapy), Hospira, Kabi, Keryx, Kissei, Novartis, OPKO, NIH (National Institutes of Health), NKF (National Kidney Foundations), Pfizer, Regulus, Relypsa, Resverlogix, Dr Schaer, Sandoz, Sanofi, Shire, VA (Veterans’ Affairs), Takeda, Vifor, UpToDate, ZS-Pharma. DB is a salaried employee of Takeda Pharmaceuticals.

Figures

Figure 1.
Figure 1.
Preferred reporting items for systematic reviews and meta-analyses flow diagram.
Figure 2.
Figure 2.
Evaluation of the risk of bias using the ROBINS-I tool.
Figure 3.
Figure 3.
Forest plot of the reported associations between PPI use and kidney outcomes. AIN, acute interstitial nephritis; AKI, acute kidney injury; CI, confidence interval; CKD, chronic kidney disease; ESRD, end-stage renal disease; PPI, proton-pump inhibitor.
See this image and copyright information in PMC

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