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Clonal Hematopoiesis of Indeterminate Potential is Associated with Acute Kidney Injury.
Saturday,2023-06-17 20:05 America/Los_Angeles — ecterry
| Title | Clonal Hematopoiesis of Indeterminate Potential is Associated with Acute Kidney Injury. |
| Publication Type | Journal Article |
| Year of Publication | 2023 |
| Authors | Vlasschaert, C, Robinson-Cohen, C, Kestenbaum, B, Silver, SA, Chen, J-C, Akwo, E, Bhatraju, PK, Zhang, M-Z, Cao, S, Jiang, M, Wang, Y, Niu, A, Siew, E, Kramer, HJ, Köttgen, A, Franceschini, N, Psaty, BM, Tracy, RP, Alonso, A, Arking, DE, Coresh, J, Ballantyne, CM, Boerwinkle, E, Grams, M, Lanktree, MB, Rauh, MJ, Harris, RC, Bick, AG |
| Journal | medRxiv |
| Date Published | 2023 May 17 |
| Abstract | <p>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 and 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 (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- 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 -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 -CHIP mice. Kidney macrophage infiltration was markedly increased in -CHIP mice and -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.</p> |
| DOI | 10.1101/2023.05.16.23290051 |
| Alternate Journal | medRxiv |
| PubMed ID | 37292692 |
| PubMed Central ID | PMC10246021 |
ePub date:
23/05