Patients with chronic kidney diseases have multiple cellular dysfunctions leading to increased atherosclerosis, impaired immunity, and disturbed metabolism. However, it is unclear what is the fundamental signaling served as a marker or as a mediator for the dysregulated function in their leukocytes or tissues. Here we hypothesized that the N-6-Methyladenosine (m(6)A) modification of the RNA in the leukocytes is responsible for the cellular dysfunction in chronic kidney diseases. Patients with chronic kidney diseases had significantly less m(6)A abundances in leukocytes and elevated RNA demethylase FTO proteins. The uremic toxin, indoxyl sulfate, activated the autophagy flux through modulation of FTO and m(6)A modifications in RNA. Notably, knockdown of FTO or inhibit the m(6)A by 3-deazaadenosine blocks the effects of indoxyl sulfate on autophagy activation in cells. These findings provide new insights into the mechanisms underlying chronic kidney disease-associated cellular dysfunction. Targeting RNA m(6)A modification may be a novel strategy for the treatment of chronic kidney diseases and autophagy. (C) 2020 Elsevier Inc. All rights reserved.