Acute Kidney Injury

Abstract

Acute kidney injury (AKI) is a global public health concern associated with high morbidity, mortality, and healthcare costs. Other than dialysis, no therapeutic interventions reliably improve survival, limit injury, or speed recovery. Despite recognized shortcomings of in vivo animal models, the underlying pathophysiology of AKI and its consequence, chronic kidney disease (CKD), is rich with biological targets. We review recent findings relating to the renal vasculature and cellular stress responses, primarily the intersection of the unfolded protein response, mitochondrial dysfunction, autophagy, and the innate immune response. Maladaptive repair mechanisms that persist following the acute phase promote inflammation and fibrosis in the chronic phase. Here macrophages, growth-arrested tubular epithelial cells, the endothelium, and surrounding pericytes are key players in the progression to chronic disease. Better understanding of these complex interacting pathophysiological mechanisms, their relative importance in humans, and the utility of biomarkers will lead to therapeutic strategies to prevent and treat AKI or impede progression to CKD or end-stage renal disease (ESRD).

Is Progressive Chronic Kidney Disease a Slow Acute Kidney Injury?

“…4,[11][12][13][14][15][16][17][18]20 Following an acute insult, injured tubular epithelial cells may become fatally injured and undergo necrosis or apoptosis, proliferate and regenerate the damaged epithelium, or undergo failed regeneration but survive cell death in a state of cell cycle G2/M arrest. 4,13,14,15,16,17,27 Arrested cells reprieved from apoptosis, however, fail to participate in regenerative repair and upregulate maladaptive signaling pathways for myofibroblast proliferation and fibrosis in the interstitium predisposing to progression of CKD.…”

“…17,21 Despite its high metabolic activity and oxygen requirements, the inner cortex and outer medullary segments of the kidney exist in a state of tenuous oxygenation which is highly regulated in health but subject to profound inadequacy with vascular compromise, hypoperfusion, and relative hypoxia.…”

“…More importantly, tubular epithelial injury subsequent to oxidative stress activates vasoconstrictive signals promoting a vicious cycle of heightened ischemia, progressive vascular rarefaction, and stimulation of growth factors which signal interstitial fibrosis and progressive hypoxia. 10,13,15,16,17,18 Cellular stress of various causes also stimulates a diverse spectrum of directed pathways leading to dysregulated apoptosis, local inflammatory responses, and/or interstitial fibrosis which have been associated with progressive CKD. 10,13,15,16,17,18 One of these maladaptive cellular responses is associated with accumulation of inappropriately processed or unfolded proteins in the endoplasmic reticulum (ER).…”

“…10,13,15,16,17,18 Cellular stress of various causes also stimulates a diverse spectrum of directed pathways leading to dysregulated apoptosis, local inflammatory responses, and/or interstitial fibrosis which have been associated with progressive CKD. 10,13,15,16,17,18 One of these maladaptive cellular responses is associated with accumulation of inappropriately processed or unfolded proteins in the endoplasmic reticulum (ER). 17,22 Cellular adaptations to ER dysregulation are initiated to adjust the translation, translocation, folding, and degradation of ER proteins as protective mechanisms, but they simultaneously promote cellular autophagy.…”

“…10,13,15,16,17,18 One of these maladaptive cellular responses is associated with accumulation of inappropriately processed or unfolded proteins in the endoplasmic reticulum (ER). 17,22 Cellular adaptations to ER dysregulation are initiated to adjust the translation, translocation, folding, and degradation of ER proteins as protective mechanisms, but they simultaneously promote cellular autophagy. 17,22 Autophagy is a cellular "cleanup" process in which damaged cytosolic constituents and organelles are encapsulated in autophagosomes and degraded for reutilization in cytosolic lysosomes.…”