Structural abnormalities of the brain are common in hemodialysis (HD) patients, as are a wide range of severe functional deficiencies of cerebral function. Both depression and increasing dependency are highly prevalent in HD patients and worsen severely within the first 12 months of dialysis initiation. HD, as it is commonly practiced, is associated with significant recurrent episodes of circulatory stress. This results in acute injury to the heart, skin, kidney and gut, and drives longer term end-organ chronic injury. This article aims to explore the hypothesis that the cerebral microcirculation is also sensitive to dialysis-based circulatory stress (and other multiorgan consequences of recurrent dialysis-induced ischemia), and that this may drive specific patterns of brain injury with resultant psychiatric and functional consequences.