Investigating the association of proton pump inhibitors with chronic kidney disease and its impact on clinical practice and future research: a review

Abstract

Background Proton pump inhibitors (PPIs) are used worldwide for the treatment of gastroesophageal reflux disease (GERD) and peptic ulcer disease (PUD). Although considered to be widely safe, PPIs have been associated with the potential risk of adverse effects such as infections including pneumonia and Clostridium difficile , malabsorption of vitamins and minerals, dementia and more recently with chronic kidney disease (CKD). Evidence including large cohort studies suggests that there is a greater risk of developing CKD in chronic users of PPIs. However, the association of CKD with PPI use reported in these studies is weak and does not establish a clear causality. This review aims to further investigate the association of CKD with PPI use by including studies with various study designs. Methods A literature search of published articles with no start date restrictions was undertaken in May 2018 in three electronic databases (PubMed, ScienceDirect, Google Scholar). Search terms included ‘Proton Pump Inhibitors’, ‘chronic kidney disease’, and ‘association’. Both observational and randomised controlled trials (RCTs) investigating the association of CKD with PPI use were eligible for inclusion. Results Ten observational studies with 1,005,899 patients contributed to the review. No experimental study was available for inclusion in the review. Of the included studies, six used a retrospective study design, while the rest were prospective (two) or a case-controlled studies (two). A large prospective cohort study with 144,032 patients conducted in the USA reported that PPI use compared to no PPI use was associated with an increased risk of CKD Hazard ratio [HR] 1.28; 95% Confidence Interval [CI] 1.22–1.34. However, the observational study design of this study together with other studies included in the review suggests that the strength of evidence associating PPI use with CKD is weak and does not establish true causality. Conclusions The current evidence related to the potential association of CKD with PPI use remains inconclusive in establishing true causality. Further prospective studies including randomised controlled trials and cohort studies would be required to confirm the findings reported in this review and to draw any conclusions.

Proton pump inhibitors and risk of all‐cause and cause‐specific mortality: A cohort study

“…Residual confounding may explain the wide-ranging associations with PPI use observed both in the literature, where PPIs have been associated with over a dozen conditions, and in this study with causespecific mortality from a number of causes. [1][2][3][4][5][6][7][8][9][38][39][40] Notably, noninterventional research on the interaction between clopidogrel and PPIs similarly suffered from hard to account for confounding, and ultimately randomised trials suggested the harmful associations detected in many studies were not causal. 13,41 Our study has several strengths.…”

“…Concern over the safety of PPIs has grown, given associations observed in noninterventional studies between PPI use and a range of outcomes including pneumonia, chronic kidney disease, cancer and alcoholic liver disease 1–9 . Furthermore, recent noninterventional studies identified associations between PPI prescription and increased all‐cause and cause‐specific mortality 7,10–12 …”

“…Concern over the safety of PPIs has grown, given associations observed in noninterventional studies between PPI use and a range of outcomes including pneumonia, chronic kidney disease, cancer and alcoholic liver disease. [1][2][3][4][5][6][7][8][9] Furthermore, recent noninterventional studies identified associations between PPI prescription and increased allcause and cause-specific mortality. 7,[10][11][12] Previous safety concerns about PPIs have highlighted important limitations of statistical techniques used to account for differences between PPI users and nonusers in noninterventional studies; several studies identified a harmful association between combined clopidogrel and PPI use, whilst randomised controlled trials (RCTs) found no clinically relevant interaction.…”

Proton Pump Inhibitors and the Risk of Chronic Kidney Diseases: A Critical Review

“…Another potential possible mechanism by which PPI use can lead to CKD is through promoting hypomagnesemia causing endothelial cell dysfunction, oxidative stress and inflammation leading to renal interstitial tubular injury and decline in renal function. Further studies and more investigations are needed to gain a better understanding of this relationship and its mechanisms [18][19][20].…”

Proton Pump Inhibitors, Kidney Damage, and Mortality: An Updated Narrative Review

“…The Western New York study concluded that using PPIs was associated with a 20% higher risk of CKD after adjustment for confounders (OR 1.20, 95% CI 1.12–1.28, p < 0.0001). Individuals who used PPIs and H2 antagonists (H2A) had higher AKI and CKD risks; however, PPIs seem to have had a more significant risk than H2As [ 70 , 74 , 75 ].…”