title: Long-term kidney outcomes among users of proton pump inhibitors without intervening acute kidney injury.
abstract: 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/1.73m2(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/1.73m2, 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.
authors.affiliation: Clinical Epidemiology Center, Research and Education Service, VA Saint Louis Health Care System, St. Louis, Missouri, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Clinical Epidemiology Center, Research and Education Service, VA Saint Louis Health Care System, St. Louis, Missouri, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bowe
authors.affiliation: Clinical Epidemiology Center, Research and Education Service, VA Saint Louis Health Care System, St. Louis, Missouri, USA; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Tingting
authors.initials: T
authors.lastname: Li
authors.affiliation: Clinical Epidemiology Center, Research and Education Service, VA Saint Louis Health Care System, St. Louis, Missouri, USA; Department of Biostatistics, College for Public Health and Social Justice, Saint Louis University, St. Louis, Missouri, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Xian
authors.affiliation: Clinical Epidemiology Center, Research and Education Service, VA Saint Louis Health Care System, St. Louis, Missouri, USA; Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Clinical Epidemiology Center, Research and Education Service, VA Saint Louis Health Care System, St. Louis, Missouri, USA; Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA; Nephrology Section, Medicine Service, VA Saint Louis Health Care System, St. Louis, Missouri, USA; Institute for Public Health, Washington University in St. Louis, St. Louis, Missouri, USA. Electronic address: zalaly@gmail.com.
authors.forename: Ziyad
authors.initials: Z
authors.lastname: Al-Aly
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000175:diagnosis / Q000453:epidemiology; D000328:Adult; D000368:Aged; D015897:Comorbidity; D016208:Databases, Factual; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006635:Histamine H2 Antagonists / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D015994:Incidence; D007668:Kidney / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000139:chemically induced* / Q000175:diagnosis / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D054328:Proton Pump Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D012307:Risk Factors; D013997:Time Factors; D014481:United States / Q000453:epidemiology; D014493:United States Department of Veterans Affairs
chemical_list: D006635:Histamine H2 Antagonists; D054328:Proton Pump Inhibitors
keywords: acute kidney injury; chronic kidney disease; clinical nephrology