Impact of Clonal Hematopoiesis on the Progression of Kidney Disease

克隆性不确定电位造血（CHIP）是一种新认识的疾病

Clonal hematopoiesis of indeterminate potential (CHIP) is a newly recognized disorder characterized by the ontogenesis of a genetically distinct, proliferative clonal leukocyte population. The prevalence of CHIP increases with older age and is associated not only with risk of hematologic cancers, but with fibrosis, systemic inflammation, and atherosclerotic cardiovascular diseases. Recapitulation of CHIP in mice by transplantation of clonal leukocytes results in accelerated atherosclerosis, cardiac fibrosis and direct tissue infiltration of clonal macrophages and stimulation of interstitial fibrosis. Age is a dominant risk factor for chronic kidney disease (CKD), which is associated with accelerated cardiovascular disease, premature death, and progression to dialysis dependence. The biological mechanisms conferring this age-associated risk are incompletely understood. The final common pathologic process in progressive CKD is tubulointerstitial fibrosis, which is characterized by the accumulation of inflammatory infiltrates and fibroblasts within the kidney interstitium and permanent loss of tubular epithelial cells. Tubulointerstitial fibrosis also represents the central underlying lesion in the progression of acute kidney injury (AKI) to chronic disease. Based on mechanistic links between CHIP and atherogenesis, kidney interstitial inflammation, and fibrosis, we hypothesize that CHIP is a novel biological risk factor for CKD progression. To test this hypothesis, we propose to determine the associations of CHIP with kidney disease progression in established cohorts of CKD and AKI. In parallel, we propose to delineate potential causal mechanisms using recognized animal models of chronic and acute kidney disease. The identification of clonal leukocytes as a novel mechanism of CKD progression would represent a new disease pathway that could motivate future targeted interventions.