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      Chronic kidney disease (CKD) patients are exposed to more proton pump inhibitor (PPI)s compared to non-CKD patients

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          Abstract

          Background

          Proton pump inhibitor use is associated with incident chronic kidney disease, chronic kidney disease progression and end-stage renal disease. However, the extent of proton pump inhibitor prescriptions to chronic kidney disease patients is still unclear.

          Method

          In a retrospective study, we enrolled patients (>18 years old) who received proton pump inhibitor in the out-patient setting from 2014 through 2015. All data was obtained from electronical medical records of Soonchunhyang Medical Center. The prescription patterns and characteristics of proton pump inhibitors were analyzed according to individual estimated glomerular filtration rate of the patients.

          Result

          During the study period 178,228 patients visited the out-patient clinic. Proton pump inhibitors were prescribed to 9,109 (5.11%) patients. In our sample, 50% were females and 9.8% were chronic kidney disease (eGFR<60mL/min/1.73 m 2) patients. Among the patients with chronic kidney disease, 730 (8.0%) were categorized as stage 3 or 4 and 166 (1.8%) were categorized as stage 5 or end-stage renal disease. The prevalence of proton pump inhibitors prescription among chronic kidney disease patients was higher than in the non-chronic kidney disease group (p<0.001). Median duration of usage was 120 [interquartile range 63–273] days in the stage 3–4 group, 106 [56–266] days in the stage 5-end-stage renal disease group and 90 [56–176] days in the non-chronic kidney disease group. Patients in stage 3–4 group were prescribed longer duration of proton pump inhibitors than the non-chronic kidney disease group even after adjusting for age and sex (p<0.001). The main departments of medicine which prescribed proton pump inhibitors for the stage 3–4 group were gastroenterology (40.0%), cardiology (29.6%), nephrology (9.5%) and neurology (4.8%). Compared to the non-chronic kidney disease group, the stage 3–4 and stage 5-end-stage renal disease group were taking larger number of drugs simultaneously (6.90±4.17 vs4.54±2.43; p<0.001, 5.64±2.87 vs 4.54±2.34; p<0.001, respectively).

          Conclusion

          Chronic kidney disease patients are taking proton pump inhibitors for a much longer duration compared to non-chronic kidney disease patients. Physicians should pay careful attention when prescribing proton pump inhibitors to high risk groups.

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          Most cited references17

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          Risk of death among users of Proton Pump Inhibitors: a longitudinal observational cohort study of United States veterans

          Objective Proton pump inhibitors (PPIs) are widely used, and their use is associated with increased risk of adverse events. However, whether PPI use is associated with excess risk of death is unknown. We aimed to examine the association between PPI use and risk of all-cause mortality. Design Longitudinal observational cohort study. Setting US Department of Veterans Affairs. Participants Primary cohort of new users of PPI or histamine H2 receptor antagonists (H2 blockers) (n=349 312); additional cohorts included PPI versus no PPI (n=3 288 092) and PPI versus no PPI and no H2 blockers (n=2 887 030). Main outcome measures Risk of death. Results Over a median follow-up of 5.71 years (IQR 5.11–6.37), PPI use was associated with increased risk of death compared with H2 blockers use (HR 1.25, CI 1.23 to 1.28). Risk of death associated with PPI use was higher in analyses adjusted for high-dimensional propensity score (HR 1.16, CI 1.13 to 1.18), in two-stage residual inclusion estimation (HR 1.21, CI 1.16 to 1.26) and in 1:1 time-dependent propensity score-matched cohort (HR 1.34, CI 1.29 to 1.39). The risk of death was increased when considering PPI use versus no PPI (HR 1.15, CI 1.14 to 1.15), and PPI use versus no PPI and no H2 blockers (HR 1.23, CI 1.22 to 1.24). Risk of death associated with PPI use was increased among participants without gastrointestinal conditions: PPI versus H2 blockers (HR 1.24, CI 1.21 to 1.27), PPI use versus no PPI (HR 1.19, CI 1.18 to 1.20) and PPI use versus no PPI and no H2 blockers (HR 1.22, CI 1.21 to 1.23). Among new PPI users, there was a graded association between the duration of exposure and the risk of death. Conclusions The results suggest excess risk of death among PPI users; risk is also increased among those without gastrointestinal conditions and with prolonged duration of use. Limiting PPI use and duration to instances where it is medically indicated may be warranted.
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            Cardiovascular outcomes and all-cause mortality: exploring the interaction between CKD and cardiovascular disease.

            Chronic kidney disease (CKD) is a risk factor for cardiovascular disease (CVD). Concurrently, CVD may promote CKD, resulting in a vicious cycle. We evaluated this hypothesis by exploring whether CKD and CVD have an additive or synergistic effect on future cardiovascular and mortality outcomes. Patients were pooled from 4 community-based studies: Atherosclerosis Risk in Communities, Framingham Heart, Framingham Offspring, and Cardiovascular Health Study. CKD is defined by an estimated glomerular filtration rate less than 60 mL/min/1.73 m(2) (<1 mL/s/1.73 m(2)). Baseline CVD included myocardial infarction, angina, stroke, transient ischemic attack, claudication, heart failure, and coronary revascularization. The primary outcome is a composite of cardiac events, stroke, and death. Secondary outcomes included individual components. Multivariable analyses using Cox regression examined differences in study outcomes. The interaction of CKD and CVD was tested. The study population included 26,147 individuals. During 10 years, 4% (n = 2,927) of individuals with no CKD or CVD developed the primary outcome, 33% (n = 518) with only CKD, 37% (n = 1,260) with only CVD, and 66% (n = 459) with both. Both CKD (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.16 to 1.35; P < 0.0001) and CVD (HR, 1.83; 95% CI, 1.72 to 1.95; P < 0.0001) were independent risk factors for the primary outcome. The interaction term CKD x CVD was not statistically significant (HR, 0.98; 95% CI, 0.85 to 1.13; P = 0.74). Similar results were obtained for secondary outcomes. CKD and CVD are both strong independent risk factors for adverse cardiovascular and mortality outcomes in the general population. Although individuals with both risk factors are at extremely high risk, there does not appear to be a synergistic effect of CKD and CVD on outcomes.
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              Long-term kidney outcomes among users of proton pump inhibitors without intervening acute kidney injury.

              Proton pump inhibitor (PPI) use is associated with an increased risk of acute kidney injury (AKI), incident chronic kidney disease (CKD), and progression to end-stage renal disease (ESRD). PPI-associated CKD is presumed to be mediated by intervening AKI. However, whether PPI use is associated with an increased risk of chronic renal outcomes in the absence of intervening AKI is unknown. To evaluate this we used the Department of Veterans Affairs national databases to build a cohort of 144,032 incident users of acid suppression therapy that included 125,596 PPI and 18,436 Histamine H2 receptor antagonist (H2 blockers) consumers. Over 5 years of follow-up in survival models, cohort participants were censored at the time of AKI occurrence. Compared with incident users of H2 blockers, incident users of PPIs had an increased risk of an estimated glomerular filtration rate (eGFR) under 60 ml/min/1.73m(2) (hazard ratio 1.19; 95% confidence interval 1.15-1.24), incident CKD (1.26; 1.20-1.33), eGFR decline over 30% (1.22; 1.16-1.28), and ESRD or eGFR decline over 50% (1.30; 1.15-1.48). Results were consistent in models that excluded participants with AKI either before chronic renal outcomes, during the time in the cohort, or before cohort entry. The proportion of PPI effect mediated by AKI was 44.7%, 45.47%, 46.00%, and 46.72% for incident eGFR under 60 ml/min/1.73m(2), incident CKD, eGFR decline over 30%, and ESRD or over 50% decline in eGFR, respectively. Thus, PPI use is associated with increased risk of chronic renal outcomes in the absence of intervening AKI. Hence, reliance on antecedent AKI as warning sign to guard against the risk of CKD among PPI users is not sufficient as a sole mitigation strategy.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Writing – original draft
                Role: ConceptualizationRole: Data curation
                Role: Data curationRole: InvestigationRole: Methodology
                Role: Data curationRole: Formal analysis
                Role: SoftwareRole: Validation
                Role: SupervisionRole: Visualization
                Role: InvestigationRole: MethodologyRole: Visualization
                Role: MethodologyRole: Project administrationRole: Supervision
                Role: ConceptualizationRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                13 September 2018
                2018
                : 13
                : 9
                : e0203878
                Affiliations
                [1 ] Department of Internal medicine, Soonchunhyang University Seoul Hospital, Seoul, Korea
                [2 ] Department of Biostatistics, Soonchunhyang University Seoul Hospital, Seoul, Korea
                [3 ] Hyonam Kidney Laboratory, Soonchunhyang University Seoul Hospital, Seoul, Korea
                Hospital Universitario de la Princesa, SPAIN
                Author notes

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

                [¤]

                Current address: Division of Nephrology, Hyonam Kidney Laboratory, 59 Daesagwan-ro, Youngsan-gu, Soonchunhyang University Hospital, Seoul, Korea

                Author information
                http://orcid.org/0000-0002-4114-4196
                Article
                PONE-D-18-08602
                10.1371/journal.pone.0203878
                6136773
                30212538
                90f574d6-c978-4087-bed5-6fa9eaac9405
                © 2018 Lee 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.

                History
                : 21 March 2018
                : 29 August 2018
                Page count
                Figures: 2, Tables: 3, Pages: 10
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100002560, Soonchunhyang University;
                Award Recipient :
                This research was partily supported by National Research Foundation of Korea(NRF) funded by the Ministry of Education(NRF-2017R1D1A3B03029800) and Soonchunhyang University research fund. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Nephrology
                Chronic Kidney Disease
                Medicine and health sciences
                Pharmacology
                Drugs
                Analgesics
                NSAIDs
                Medicine and health sciences
                Pain management
                Analgesics
                NSAIDs
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Cell Membranes
                Membrane Proteins
                Proton Pumps
                Biology and Life Sciences
                Anatomy
                Renal System
                Kidneys
                Medicine and Health Sciences
                Anatomy
                Renal System
                Kidneys
                Medicine and Health Sciences
                Pharmaceutics
                Drug Therapy
                Antiplatelet Therapy
                Medicine and Health Sciences
                Gastroenterology and Hepatology
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                Cardiology
                People and Places
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