Study challenges link between proton pump inhibitors and kidney disease risk

By Dr. Priyom Bose, Ph.D.Dec 5 2023Reviewed by Benedette Cuffari, M.Sc.

A recent Scientific Reports study investigates whether the association between proton pump inhibitors (PPIs) and the use of histamine-2 receptor antagonists (H2RA) affects the risk of chronic kidney disease (CKD).

Study: Proton pump inhibitors and chronic kidney disease risk: A comparative study with histamine-2 receptor antagonists. Image Credit: Iryna Imago / Shutterstock.com

Background

PPIs are one of the most common medications used to manage peptic ulcers and gastroesophageal reflux disease. Mechanistically, PPIs irreversibly suppress hydrogen (H⁺)/potassium (K⁺)-ATPase in the stomach and subsequently reduce acid secretion.

In addition to the beneficial effects of PPI use, recent studies have highlighted several adverse effects linked with the long-term use of this medication. Some of the adverse outcomes of long-term PPI use include acute kidney injury (AKI), hypomagnesemia, and acute tubular interstitial nephritis (ATIN).

Millions of people throughout the world have been affected by CKD, which has a significant effect on mortality, morbidity, and healthcare burden. It is important to elucidate the precise biological mechanism that correlates PPI use and the incidence of CKD.

About the study

The current study explored the association between long-term PPI use and the risk of CKD based on the multicenter electronic health record (EHR) database and the National Health Insurance Service-National Sample Cohort (NHIS-NSC). These datasets were converted to the Observational Medical Outcomes Partnership Common Data Model (OMOP-CDM) format.

Recently, scientists have developed a standardized research network known as the Common Data Model (CDM), which offers a consistent data format. The standardized CDM-based vocabulary was designed by the Observational Health Data Sciences and Informatics (OHDSI) organization.

The current study utilized a national population-based cohort in the OMOP-CDM format for the analysis. Adult individuals who were new users of PPIs or H₂RAs for over 180 days were recruited.

Importantly, the study participants were using one of the medications without a gap of more than 30 days between prescriptions. None of the candidates had a history of glomerulonephritis, CKD, or kidney transplantation.

The target cohort was exposed to pantoprazole, dexlansoprazole, omeprazole, rabeprazole, esomeprazole, and lansoprazole. Subsequently, the comparative cohort received H₂Ras, including famotidine, cimetidine, ranitidine, and nizatidine.

Study findings

A total of 1,125,700 participants were included in the NHIS-NSC CDM database between 2002 and 2013, whereas the six-hospital CDM databases offered more extensive data, comprising 10,083,608 subjects between 1999 and 2018. To control for potential confounding factors and balance the baseline characteristics between PPI and H₂RA groups, large-scale propensity score matching (PSM) was performed. Based on eligibility, 5,967 participants were selected for both groups.

PPI use was not associated with an increased risk of CKD compared to H₂RAs. Although previous studies have indicated an association between PPI use and the incidence of CKD, the mechanism responsible for this association remained elusive.

It is possible that unclear mechanisms and contradictory observational studies resulted in the link between long-term PPI use and CKD. In addition, these studies failed to determine the duration and quantity of PPI use that increased the risk of developing CKD.

The sensitivity analysis revealed that patients who used PPIs for a prolonged period of more than 365 days might have a lower propensity to develop CKD as compared to individuals using H₂RAs. Importantly, this observation was not statistically significant.

A subgroup analysis that included patients with diabetic mellitus (DM) from both databases was also conducted. To this end, no significant link between PPI use and CKD risk as compared to H₂RA use was observed.

PPI use had no significant effect on DM patients with regard to the risk of CKD development. Notably, this observation was based on the estimated glomerular filtration rate (eGFR) of six-hospital CDM databases alone, as this data was unavailable in the NHIS-CDM database. The limited data affected the generalizability of the safety profile of PPIs in highly vulnerable groups and would require further validation.

Limitations

The current study has some limitations, including the presence of unmeasured confounding factors, which could affect the link between PPI use and CKD development. For example, the researchers did not consider lifestyle factors such as physical activity, smoking, or alcohol consumption that could positively influence the incidence of CKD.

Another limitation was the assumption that H₂RA use does not influence CKD development. Since the current study did not include patients with confirmed CKD, the precise effect of PPI use was unclear.

Conclusions

The present study provided important insights into the association between PPI use and CKD development. There was no significant association between long-term use of PPIs and CKD development compared to H₂RA use. Considering that diabetes is a potential risk factor for CKD, the safety profile of PPIs for this group of individuals could positively help in clinical decision-making.