Disequilibrium syndrome (DS) is a central nervous system disorder described in hemodialysis (HD) patients. The authors present 4 cases of elevated blood urea nitrogen (BUN); the first patient passed away from suspected DS, whereas the other 3 patients were identified as having a high risk of developing DS on the basis of their BUN. The authors tried to lower their BUN slowly and prevent rapid correction by different methods. This is the first study in which DS has been studied in patients who are not on HD, and methods are described to identify and prevent DS in such patients. They also review the existing literature on the pathogenesis of DS and highlight the importance of recognizing this syndrome in non-HD patients, while suggesting some innovative ways to prevent it.