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Publication Information
Affiliation
1 Department of Medicine, Queen's University, Kingston, Ontario, Canada.
2 Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt O'Brien Center for Kidney Disease, School of Medicine, Vanderbilt University, Nashville, Tennessee.
3 Kidney Research Institute, Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington.
4 Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, Washington.
5 Departments of Public Health Sciences and Medicine, Loyola University Chicago, Maywood, Illinois, USA.
6 Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
7 Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland.
8 Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina.
9 Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, USA
10 Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
11 Pathology and Biochemistry, University of Vermont, Burlington, Vermont, USA.
12 Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia.
13 The McKusick-Nathans Institute, Department of Genetic Medicine, John Hopkins University School of Medicine, Baltimore, MD.
14 Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, MD.
15 Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
16 Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
17 Division of Nephrology, Department of Internal Medicine, Johns Hopkins University, Baltimore, MD.
18 Department of Medicine and Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada
19 St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada
20 Population Health Research Institute, Hamilton, Ontario, Canada.
21 Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.
22 Department of Veterans Affairs, Nashville, Tennessee.
23 Division of Genetic Medicine, Department of Medicine, School of Medicine, Vanderbilt University, Nashville, Tennessee.
Authors
Akwo E, Alonso A, Arking DE, Ballantyne CM, Bhatraju PK, Bick AG, Boerwinkle E, Cao S, Chen J, Coresh J, Francheschini N, Grams M, Harris Jr RC, Jiang M, Kestenbaum B, Kottgen A, Kramer HJ, Lanktree MB, Liu A, Psaty B, Rauh M, Robinson-Cohen C, Siew E, Silver S, Tracy RP, Vlasschaert C, Wang Y, Zhang M
Studies
Abstract
Clonal hematopoiesis of indeterminate potential (CHIP) is a recently recognized risk factor for several chronic diseases of aging including cardiovascular disease and chronic kidney disease. In these contexts, clonal populations of mutated myeloid cells contribute to end-organ damage through inflammatory dysregulation. Our understanding of the role of CHIP in more acute processes is limited. We sought to investigate whether CHIP was associated with acute kidney injury (AKI). To address this question, we first evaluated associations with incident AKI events in three cohorts: UK Biobank, the Atherosclerosis Risk in Communities Cohort, and the Cardiovascular Health Study (total N = 442,153). We found that CHIP was associated with a greater risk of AKI (1.26, 95% CI: 1.19–1.34) as well as severe AKI requiring dialysis (HR 1.65, 95% CI: 1.24-2.20), in adjusted analyses. The risk was particularly high in the subset of individuals where CHIP was driven by mutations in genes other than DNMT3A (HR: 1.49, 95% CI: 1.37–1.61). We then examined the association between CHIP and recovery from AKI in the ASSESS-AKI cohort and identified that non-DNMT3A CHIP was more common among those with a non-resolving pattern of injury in adjusted analyses. Finally, we assessed severity of AKI in a mouse model of Tet2-CHIP. In ischemia-reperfusion injury (IRI) and unilateral ureteral obstruction (UUO) models, we observed more severe AKI and greater post-AKI kidney fibrosis in Tet2-CHIP mice compared to Tet2-wild type mice. Kidney neutrophil and macrophage infiltration was markedly increased in Tet2-CHIP mice, and Tet2-CHIP renal macrophages displayed greater pro-inflammatory gene upregulation. This work identifies CHIP as a novel and potentially targetable risk factor for AKI.