Clonal Hematopoiesis of Indeterminate Potential is Associated with Acute Kidney Injury.

• Authors: Caitlyn Vlasschaert, Queen's University; Cassianne Robinson-Cohen, Vanderbilt University; Bryan Kestenbaum, University of Washington, Seattle; Samuel A Silver, Queen's University; Jian-Chun Chen, Vanderbilt University; Elvis Akwo, Vanderbilt University; Pavan K Bhatraju, University of Washington, Seattle; Ming-Zhi Zhang, Vanderbilt University; Shirong Cao, Vanderbilt University; Ming Jiang, Vanderbilt University; Yinqiu Wang, Vanderbilt University; Aolei Niu, Vanderbilt University; Edward Siew, Vanderbilt University; Holly J Kramer, Loyola University Chicago; Anna Kottgen, University of Freiburg; Nora Franceschini, University of North Carolina, Chapel Hill; Bruce M Psaty, University of Washington, Seattle; Russell P Tracy, University of Vermont, Burlington; Alvaro Alonso, Emory University; Dan E Arking, John Hopkins University School of Medicine; Josef Coresh, Johns Hopkins University; Christie M Ballantyne, Baylor College of Medicine; Eric Boerwinkle, University of Texas Health Science Center at Houston; Morgan Grams, Johns Hopkins University; Matthew B Lanktree, McMaster University; Michael J Rauh, Queen's University; Raymond C Harris, Vanderbilt University; Alexander G Bick, Vanderbilt University
• Journal Title: medRxiv
• Publisher: medRxiv | 2023-05-17
• Type of Work: Article | Preprint: Prior to Peer Review
• Publisher DOI: http://doi.org/10.1101/2023.05.16.23290051
• Subjects: Health Sciences, Medicine and Surgery; Health Sciences, Epidemiology; Chemistry, Biochemistry
• Keywords: Acute Kidney Injury

Abstract

Age is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown and to date no genetic mechanisms for AKI have been established. Clonal hematopoiesis of indeterminate potential (CHIP) is a recently recognized biological mechanism conferring risk of several chronic aging diseases including cardiovascular disease, pulmonary disease and liver disease. In CHIP, blood stem cells acquire mutations in myeloid cancer driver genes such as DNMT3A, TET2, ASXL1 and JAK2 and the myeloid progeny of these mutated cells contribute to end-organ damage through inflammatory dysregulation. We sought to establish whether CHIP causes acute kidney injury (AKI). To address this question, we first evaluated associations with incident AKI events in three population-based epidemiology cohorts (N = 442,153). We found that CHIP was associated with a greater risk of AKI (adjusted HR 1.26, 95% CI: 1.19-1.34, p<0.0001), which was more pronounced in patients with AKI requiring dialysis (adjusted HR 1.65, 95% CI: 1.24-2.20, p=0.001). 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, p<0.0001). 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 (HR 2.3, 95% CI: 1.14-4.64, p = 0.03). To gain mechanistic insight, we evaluated the role of Tet2 -CHIP to AKI in ischemia-reperfusion injury (IRI) and unilateral ureteral obstruction (UUO) mouse models. In both models, we observed more severe AKI and greater post-AKI kidney fibrosis in Tet2 -CHIP mice. Kidney macrophage infiltration was markedly increased in Tet2 -CHIP mice and Tet2 -CHIP mutant renal macrophages displayed greater pro-inflammatory responses. In summary, this work establishes CHIP as a genetic mechanism conferring risk of AKI and impaired kidney function recovery following AKI via an aberrant inflammatory response in CHIP derived renal macrophages.