The association between use of proton-pump inhibitors and excess mortality after kidney transplantation: A cohort study

PLoS Med. 2020 Jun 15;17(6):e1003140. doi: 10.1371/journal.pmed.1003140. eCollection 2020 Jun.

Abstract

Background: Chronic use of proton-pump inhibitors (PPIs) is common in kidney transplant recipients (KTRs). However, concerns are emerging about the potential long-term complications of PPI therapy. We aimed to investigate whether PPI use is associated with excess mortality risk in KTRs.

Methods and findings: We investigated the association of PPI use with mortality risk using multivariable Cox proportional hazard regression analyses in a single-center prospective cohort of 703 stable outpatient KTRs, who visited the outpatient clinic of the University Medical Center Groningen (UMCG) between November 2008 and March 2011 (ClinicalTrials.gov Identifier NCT02811835). Independent replication of the results was performed in a prospective cohort of 656 KTRs from the University Hospitals Leuven (NCT01331668). Mean age was 53 ± 13 years, 57% were male, and 56.6% used PPIs. During median follow-up of 8.2 (4.7-9.0) years, 194 KTRs died. In univariable Cox regression analyses, PPI use was associated with an almost 2 times higher mortality risk (hazard ratio [HR] 1.86, 95% CI 1.38-2.52, P < 0.001) compared with no use. After adjustment for potential confounders, PPI use remained independently associated with mortality (HR 1.68, 95% CI 1.21-2.33, P = 0.002). Moreover, the HR for mortality risk in KTRs taking a high PPI dose (>20 mg omeprazole equivalents/day) compared with patients taking no PPIs (HR 2.14, 95% CI 1.48-3.09, P < 0.001) was higher than in KTRs taking a low PPI dose (HR 1.72, 95% CI 1.23-2.39, P = 0.001). These findings were replicated in the Leuven Renal Transplant Cohort. The main limitation of this study is its observational design, which precludes conclusions about causation.

Conclusions: We demonstrated that PPI use is associated with an increased mortality risk in KTRs, independent of potential confounders. Moreover, our data suggest that this risk is highest among KTRs taking high PPI dosages. Because of the observational nature of our data, our results require further corroboration before it can be recommended to avoid the long-term use of PPIs in KTRs.

Trial registration: ClinicalTrials.gov Identifier: NCT02811835, NCT01331668.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Kidney Transplantation / mortality*
  • Male
  • Middle Aged
  • Proportional Hazards Models
  • Prospective Studies
  • Proton Pump Inhibitors / adverse effects*
  • Proton Pump Inhibitors / therapeutic use
  • Risk Factors

Substances

  • Proton Pump Inhibitors

Associated data

  • ClinicalTrials.gov/NCT02811835
  • ClinicalTrials.gov/NCT01331668

Grants and funding

Generation of this study was funded by Top Institute Food and Nutrition. RMD is supported by NWO/TTW in a partnership program with DSM, Animal Nutrition and Health, The Netherlands; project number: 14939. EVL holds a fellowship grant (1143919N) from the Research Foundation Flanders (F.W.O.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.