AbstractPatients with chronic kidney disease (CKD) are more likely to die of cardiovascular diseases, including cerebrovascular disease, than to progress to end‐stage kidney disease. Cerebrovascular dysfunction, characterized by reduced cerebrovascular reactivity, cerebral hypoperfusion, and increased pulsatile flow within the brain, precedes the onset of dementia and is linked to cognitive dysfunction. However, whether impaired cerebrovascular function is present in non‐dialysis dependent CKD is largely unknown. Using transcranial Doppler, we compared middle cerebral artery (MCA) blood velocity response to hypercapnia (normalized for blood pressure and end‐tidal CO2; a measure of cerebrovascular reactivity) and MCA pulsatility index (PI; a measure of cerebrovascular stiffness) in patients with stage 3–4 CKD vs. age‐matched healthy controls. We also administered the NIH cognitive toolbox (cognitive function), measured carotid‐femoral pulse‐wave velocity (PWV; aortic stiffness), and assessed ex vivo nitric oxide (NO) and reactive oxygen species (ROS) production from human brain endothelial cells incubated with serum obtained from study participants. MCA PI was higher in patients with CKD vs. controls; however, normalized MCA blood velocity response to hypercapnia did not differ between groups. Similar results were observed in a validation cohort of midlife and older adults divided by the median estimated glomerular filtration rate (eGFR). MCA PI was associated with greater large‐elastic artery stiffness (carotid‐femoral PWV), worse executive function (trails B time), lower eGFR, and higher ex vivo ROS production. These data suggest that impaired kidney function is associated with greater cerebrovascular stiffness, which may contribute to the known increased risk for cognitive impairment in patients with CKD.