The development of renal ischemia has been postulated to be a main cause of the progressive nature of kidney diseases. In recent years, it has become clear that inappropriate and sustained activation of the endothelium could mediate this phenomenon. Endothelial activation will result in leucostasis and can compromise peritubular flow. The associated sustained redox signaling will also accelerate the development of endothelial senescence. In addition, risk factors for renal disease progression can reduce endothelial repair. In the course of these events, loss of capillary structure and rarefaction develops, which drives the further development of nephron loss. In this mini review, the evidence for this pathophysiological concept as well as the possibility to detect such endothelial activation in the clinical arena is summarized.