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

Rianne M. Douwes  , António W. Gomes-Neto , Michele F. Eisenga, Elisabet Van Loon, Joëlle C. Schutten, Rijk O. B. Gans, Maarten Naesens, Else van den Berg, Ben Sprangers,
Stefan P. Berger, Gerjan Navis, Hans Blokzijl, Björn Meijers, Stephan J. L. Bakker, Dirk Kuypers

 

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.

Introduction

Renal transplantation is considered the preferred treatment for patients with end-stage renal disease, providing improved prognosis and quality of life at lower cost compared with dialysis treatment [1–3]. Although short-term outcomes after renal transplantation have tremendously improved over the last decades, long-term graft survival and mortality rates have shown little improvement [4–6]. Indeed, mortality rates in kidney transplant recipients (KTRs) are still 6 times higher than in the general population [7].

Methods

Design and study population

This is a post hoc analysis using data from a previously described cohort of 707 stable KTRs, registered as the TransplantLines Food and Nutrition Biobank and Cohort Study (ClinicalTrials.gov Identifier NCT02811835), which is a prospective cohort study intended to investigate the relationship between dietary acid load, ammoniagenesis, and its potential influence on blood pressure [29]. In summary, all adult KTRs with a functioning graft for at least 1 year after transplantation who visited the outpatient clinic of the University Medical Center Groningen (UMCG) between November 2008 and March 2011 were invited to participate in the study. KTRs were not considered eligible for the study in case of concurrent systemic illnesses, including malignancies other than cured skin cancer, opportunistic infections, and overt congestive heart failure. Of the initially 817 invited KTRs, 707 (87%) gave written informed consent. We excluded KTRs with missing data on PPI dosage (n = 1) or with on-demand PPI use (n = 3), leaving 703 KTRs eligible for the current post hoc analysis. All measurements were performed during a single study visit at the outpatient clinic. The primary endpoint of this study was all-cause mortality. In response to peer-review comments, we added cause-specific mortality (i.e., death due to cardiovascular diseases, infectious diseases, malignant diseases, and miscellaneous causes) and occurrence of graft failure as secondary endpoints. Follow-up was recorded until September 2015, and upon request of one of the reviewers, it was extended to December 31, 2018. Continuous surveillance of the outpatient program ensures up-to-date information on patient status, which was recorded in the UMCG Renal Transplantation Database and verified with the Dutch Civil Registration Office. Medical records, general practitioners, and nephrologist were consulted to establish cause of death. Cardiovascular mortality was defined as death due to cerebrovascular disease, ischemic heart disease, heart failure, or sudden cardiac death International Classification of Diseases, Ninth Revision (ICD-9) codes 410–447, infectious disease mortality was defined according to ICD-9 codes 1–139, and cancer mortality was defined according to a specified list of ICD-9 codes [30]. The study protocol was approved by the institutional review board of the UMCG (IRB identifier 2008–186). All study procedures were performed in accordance with the Declaration of Helsinki and the Declaration of Istanbul.

Discussion

This study shows that PPI use is associated with an increased mortality risk in 2 large independent cohort studies of stable KTRs. Although significant baseline differences between PPI users and KTRs who did not use PPIs were present, the association remained materially unchanged after adjustment for potential confounders. Moreover, we observed that the HR for mortality risk in KTRs taking a high PPI dose was higher than in KTRs taking a low PPI dose. Results from survival analysis in the Leuven Renal Transplant Cohort were similar to results obtained in the TransplantLines study.

Citation: Douwes RM, Gomes-Neto AW, Eisenga MF, Van Loon E, Schutten JC, Gans ROB, et al. (2020) The association between use of proton-pump inhibitors and excess mortality after kidney transplantation: A cohort study. PLoS Med 17(6): e1003140. https://doi.org/10.1371/journal.pmed.1003140

Academic Editor: Maarten W. Taal, Royal Derby Hospital, UNITED KINGDOM

Received: January 16, 2020; Accepted: May 13, 2020; Published: June 15, 2020

Copyright: © 2020 Douwes et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: The data underlying the results presented in this study can be made available by the data manager of the TransplantLines study, by mailing to [email protected] Data from the BIOBANK Renal Transplantation University Hospitals Leuven can be made available by mailing the ethics committee of the University Hospitals Leuven [email protected] Public sharing of individual participant data was not included in the informed consent forms of both studies, but data can be made available to interested researchers upon reasonable request.

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.

Competing interests: The authors have declared that no competing interests exist.

Abbreviations: BMI, body mass index; BPAR, biopsy proven acute rejection; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; CNI, calcineurin inhibitor; eGFR, estimated glomerular filtration rate; FDA, Food and Drug Administration; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; HLA, Human Leukocyte Antigen; HR, hazard ratio; ICD-9, International Classification of Diseases, Ninth Revision; ICD-10, International Classification of Diseases, Tenth Revision; IQR, interquartile range; KTR, kidney transplant recipient; LDL, low-density lipoprotein; NSAID, nonsteroidal anti-inflammatory drug; PPI, proton-pump inhibitor; STROBE, Strengthening the Reporting of Observational Studies in Epidemiology; TRIPOD, Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis; UMCG, University Medical Center Groningen.