(A) Human kidney biopsy with ischemic AKI (cortical area). Note the expanded interstitium, microvascular plugging, dilated tubules, and patchy nature of injury. (B) Under physiologic conditions, coordinated communication and cell-cell interactions maintains homeostasis with normal kidney function. Epithelial injury leads to apoptotic and necrotic cell death that is accompanied by cytokine, chemokine, and ROS release. These factors initiate the release of exogenous and endogenous DAMPS by resident cells, leading to activation and further injury. These signals also initiate the infiltration of professional inflammatory cells such as PMNs and monocytes, leading to enhanced inflammation and further cell injury and destruction. Inflammatory signals produce alterations in the endothelium, resulting in loss of cell-cell contact and breakdown of the ECM. Additionally, there is marked microvascular plugging mediated by adherent wbcs and rouleaux formation, leading to reduced flow and worsening ischemia. Subsequently, there is migration of some of these cells into the interstitium. Pericytes dissociate from underlying ECs and convert into myofibroblasts, which lay down collagen to initiate the fibrotic cycle.