Kidney ischemia

Kidney ischemia also known as renal ischemia is the acute reduction of blood flow in one or both kidneys or nephrons that produces hypoxia-induced vascular and tubular dysfunction. An intense and persistent renal vasoconstriction that reduces overall kidney blood flow to approximately 50% of normal has long been considered a hallmark of intrinsic acute kidney injury (AKI), prompting the previous designation of “vasomotor nephropathy” ¹. Renal ischemia reperfusion injury is a leading cause of acute kidney injury (AKI), which is still associated with high morbidity, mortality, and increased costs of treatment in both adult and pediatric population ². Renal ischemia reperfusion injury represents an important risk factor for progression of chronic kidney disease (CKD), which is defined as abnormalities of kidney structure or function, present for more than 3 months ³. A diagnosis of acute kidney injury (AKI) was found to be associated with an 8.8-fold excess risk of later development of chronic kidney disease (CKD) ⁴. Furthermore, the risk of later development of chronic kidney disease (CKD) increases with the severity of acute kidney injury (AKI) ⁴. Kidneys are subjected to ischemia-reperfusion injury in different medical conditions, characterized by the interruption of the renal blood flow followed by the subsequent restoration of perfusion, such as vascular and cardiac surgery, trauma, circulatory arrest with resuscitation, and kidney transplantation ⁵. Ischemia-reperfusion injury after kidney transplantation elicits cascades of pathophysiology processes that result in delayed graft function (DGF) and alloimmune-specific response to the graft, eventually leading to acute rejection and progression to chronic allograft nephropathy ⁶. Numerous studies conducted so far do not give precise answers on how to treat or prevent kidney ischemia-reperfusion injury implying inflammation and mediators of inflammation as potential target for therapy ⁵.

Although the pathophysiology of ischemia-reperfusion injury is not completely understood, several important mechanisms resulting in kidney failure have been mentioned. In ischemic kidney and subsequent of re-oxygenation, generation of reactive oxygen species (ROS) at reperfusion phase initiates a cascade of deleterious cellular responses leading to inflammation, cell death, and acute kidney failure ⁷. Mitochondria, as the major site of reactive oxygen species (ROS) production, are subjects of potential treatment of kidney ischemia-reperfusion injury using mitochondria-targeted antioxidants ⁸. Besides ROS, reactive nitrogen species, such as nitric oxide, are produced in kidney ischemia-reperfusion injury via the activity of inducible nitric oxide synthase (iNOS), which is considered as one of inflammatory mediators ⁹. Numerous experimental studies have shown an increased iNOS activity in kidney ischemia-reperfusion injury ¹⁰. Inducible nitric oxide synthase (iNOS) and a great array of proinflammatory cytokines, such as TNF-α, IL-1β, IL-6, and chemokines, are mainly elicited by the action of transcription factors NF-κB . This inflammatory response is sterile but shares many similarities with the immune response and inflammation provoked by pathogens ¹¹. Evidence supporting immunological mechanisms involved in pathogenesis of ischemia-reperfusion injury has accrued in recent years, pointing to the activation of both innate and acquired immune response ¹². In early phase of ischemia-reperfusion injury, inflammation is alloantigen independent and is characterized by activation of not just only classical cells belonging to what we call the immune system, such as macrophages, dendritic cells, and lymphocytes, but also resident renal cells, such as endothelial cells and tubular epithelial cells, which are extremely sensitive to oxidative stress. Interplay and time-dependent changes between proinflammatory and anti-inflammatory mediators, secreted by kidney resident cells and recruited inflammatory cells, determine the faith of renal injury, namely, tissue repair or progression to chronic kidney disease (CKD) ¹³.

References

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