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

• Published in: PLoS medicine Vol. 17; no. 6; p. e1003140
• Main Authors: Douwes, Rianne M, Gomes-Neto, António W, Eisenga, Michele F, Van Loon, Elisabet, Schutten, Joëlle C, Gans, Rijk O B, Naesens, Maarten, van den Berg, Else, Sprangers, Ben, Berger, Stefan P, Navis, Gerjan, Blokzijl, Hans, Meijers, Björn, Bakker, Stephan J L, Kuypers, Dirk
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 15-06-2020; Public Library of Science (PLoS)
• Subjects: Ambulatory care facilities; Biobanks; Biology and Life Sciences; Cohort analysis; Dosage; Dose-Response Relationship, Drug; Drug dosages; Female; Funding; Health aspects; Hospitals; Humans; Immunology; Internal medicine; Kaplan-Meier Estimate; Kidney transplantation; Kidney Transplantation - mortality; Kidney transplants; Kidneys; Male; Medical centers; Medicine; Medicine and Health Sciences; Middle Aged; Mortality; Nephrology; Nutrition; Omeprazole; Organ transplant recipients; Physical Sciences; Proportional Hazards Models; Prospective Studies; Proton pump inhibitors; Proton Pump Inhibitors - adverse effects; Proton Pump Inhibitors - therapeutic use; Regression analysis; Risk Factors; Supervision; Belgium; Netherlands
• ISSN: 1549-1676; 1549-1277; 1549-1676
• DOI: 10.1371/journal.pmed.1003140

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