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Editor's Notes

• #8: GFR/SCr algorithm. AKD, acute kidney disease/disorder; AKI, acute kidney injury; CKD, chronic kidney disease; GFR, glomerular filtration rate; NKD, no known kidney disease; SCr, serum creatinine.
• #9: GFR/SCr algorithm. AKD, acute kidney disease/disorder; AKI, acute kidney injury; CKD, chronic kidney disease; GFR, glomerular filtration rate; NKD, no known kidney disease; SCr, serum creatinine.
• #12: Red circles represent stages of AKI. Yellow circles represent potential antecedents of AKI, and the pink circle represents an intermediate stage (not yet defined). Thick arrows between circles represent risk factors associated with the initiation and progression of disease that can be affected or detected by interventions. Purple circles represent outcomes of AKI. ‘‘Complications’’ refers to all complications of AKI, including efforts at prevention and treatment, and complications in other organ systems. AKI, acute kidney injury; GFR, glomerular filtration rate.
• #14: The pathophysiology of AKI may be divided into microvascular and tubular components; the former can be further divided into preglomerular and outer medullary vessel components. With AKI, there is enhanced vasoconstriction and decreased vasodilatation in response to agents that are present in the postischemic kidney. With increased endothelial and vascular smooth muscle cellular damage, there is enhanced leukocyte-endothelial adhesion leading to activation of the coagulation system and vascular obstruction with leukocyte activation and potentiation of inflammation. At the level of the tubule (described in Figure 2), there is cytoskeletal breakdown and loss of polarity followed by apoptosis and necrosis, intratubular obstruction, and backleak of glomerular filtrate through a denuded basement membrane. In addition, the tubule cells generate inflammatory vasoactive mediators that, in turn, can affect the vasculature to enhance vascular compromise. A positive feedback mechanism ensues whereby the vascular compromise results in decreased oxygen delivery to the tubules that, in turn, generate vasoactive inflammatory mediators to enhance the vaso constriction and the endothelial-leukocyte interactions.
• #19: Various pathophysiological states and medications can contribute to reduction of RBF, causing generalized or localized ischemia to the kidney leading to AKI.
• #20: Postischemic arteriole is more sensitive to vaso constrictive agents and less sensitive to vasodilatory agents. In addition, whereas a normal arteriole has a vasodilatory autoregulatory response to a decrease in perfusion pressure, the post ischemic arteriole vasoconstricts.
• #23: In the initiation phase of AKI there is ATP depletion resulting in proximal tubule, endothelial, and smooth muscle injury and apoptosis. The extension phase of AKI occurs with persistent ischemia, vascular congestion, and ongoing hypoxia. Endothelial damage and activation result in an imbalance in vasoactive mediators and persistent vasoconstriction, particularly in the outer medulla. These mediators and endothelial damage lead to an increase in permeability, which increases interstitial pressure and decreases capillary blood fl ow. This results in continued hypoxia during reperfusion and enhanced tubular cell injury and death via apoptosis in this area. The end result of these various pathophysiologic processes is further worsening of the GFR. The extension phase is followed by a prolonged maintenance phase in which BUN and creatinine continue to rise. If there is no further injury the recovery phase begins in 1–2 weeks. Apoptosis occurs in all phases leading to remodeling of injured tubules and facilitating their return to a normal structural and functional state. Most cells recover by cellular repair. However, some epithelial cells dedifferentiate, replicate, and migrate to fi ll the epithelial defect. Thereafter they spread out, become attached to the tubular membrane, and reestablish their polarized differentiated structure.
• #24: Normal nephron, corticomedullary oxygen gradient, and outer medullary microvascular anatomy. (A) Anatomy of nephron with regions identified. Outer medulla vasculature is shown with capillaries in red and venous system in blue. (B) The vasa recta with countercurrent exchange of oxygen resulting in a gradient of decreasing oxygen tension.
• #25: Endothelial injury in ischemia/reperfusion AKI. (A) Normal epithelium and endothelium separated by a small interstitial compartment. A glycocalyx coats the endothelium. (B) Ischemia/reperfusion causes swelling of endothelial cells; disruptions of the glycocalyx and endothelial monolayer; and upregulation of adhesion molecules such as ICAMs, VCAMs, and selectins, resulting in enhanced leukocyte-endothelium interactions. There is formation of microthrombi, and some leukocytes migrate through the endothelial cells into the interstitial compartment. The interstitial compartment is expanded with enhanced numbers of inflammatory cells and interstitial edema forms.
• #26: The injured tubular epithelium releases proinflammatory cytokines and chemokines, which aid in recruiting immune cells. Epithelial cells also express adhesion molecules, TLRs, and T cell costimulatory molecules, which activate the immune cells and amplify the inflammatory responses. Neutrophils, macrophages, and natural killer T (NKT) cells cause direct injury to tubular epithelial cells. DCs are involved in both the innate and adaptive immune responses through secretion of inflammatory cytokines and presentation of antigens to T lymphocytes.
• #27: The current understanding of tubular injury and repair after ischemic AKI. With IRI, the normally highly polar epithelial cell loses its polarity and brush border with proteins mislocated on the cell membrane. With increasing time/severity of ischemia, there is cell death by either necrosis or apoptosis. Some of the necrotic debris is released into the lumen. Viable epithelial cells migrate and cover denuded areas of the basement membrane. These cells undergo division and replace lost cells. Ultimately, the cells go on to differentiate and reestablish the normal polarity of the epithelium.
• #28: Abnormal repair in ischemic AKI. Repair after AKI can result in incomplete repair and fibrotic lesions, which may result in progressive renal dysfunction. Factors including long-term hypoxia and hypertension result from chronic loss of peritubular microvessels. Sustained production of profibrotic cytokines such as IL-13, arginase, and TGF-β1 from the chronically activated macrophages (MΦ) contribute to postischemic fibrosis. Renal tubular epithelial cells also play a critical role in the development of fibrosis through fundamental changes in their proliferation processes, including cell cycle arrest in the G2/M phase. This results in a secretory phenotype that facilitates the production by the epithelial cells of profibrotic growth factors (including TGF-β1 and CTGF). Fibrogenesis is stimulated, and progression to chronic renal failure is accelerated.
• #29: With injury to the kidney, an early response is loss of the brush border and the polarity of the epithelial cell with mislocation of adhesion molecules and Na+/K+-ATPase and other proteins. With increasing injury, there is cell death by either necrosis or apoptosis. Some of the necrotic debris is then released into the lumen, where it interacts with luminal proteins and can ultimately result in obstruction. In addition, with the mislocation of adhesion molecules, viable epithelial cells lift off the basement membrane and are found in the urine. The kidney can respond to the injury by initiating a repair process, if there are sufficient nutrients and sufficient oxygen delivery, and the basement membrane integrity has not been altered irreparably. Viable epithelial cells migrate and cover denuded areas of the basement membrane. The source of these cells appears to be from the kidney itself and not from the bone marrow. Bone-marrow cells may contribute to the interstitial cellular infiltrate and may produce factors to modulate inflammation and facilitate repair. Cells replacing the epithelium may derive from differentiated epithelial cells or from a subpopulation of progenitor cells in the tubule; the cells undergo division and replace lost cells. Ultimately, the cells go on to differentiate and reestablish the normal polarity of the epithelium.
• #30: Abnormal repair in ischemic AKI. Repair after AKI can result in incomplete repair and fibrotic lesions, which may result in progressive renal dysfunction. Factors including long-term hypoxia and hypertension result from chronic loss of peritubular microvessels. Sustained production of profibrotic cytokines such as IL-13, arginase, and TGF-β1 from the chronically activated macrophages (MΦ) contribute to postischemic fibrosis. Renal tubular epithelial cells also play a critical role in the development of fibrosis through fundamental changes in their proliferation processes, including cell cycle arrest in the G2/M phase. This results in a secretory phenotype that facilitates the production by the epithelial cells of profibrotic growth factors (including TGF-β1 and CTGF). Fibrogenesis is stimulated, and progression to chronic renal failure is accelerated.