Red blood cell toxicity mediates medullary injury in ischemic acute kidney injury
The overall goal of our studies is to uncover vascular congestion and red blood cell toxicity as primary pathological process mediating ischemic kidney injury. Achieving this would represent a paradigm shift in the field, altering the way we think about and treat ischemic acute kidney injury. Acute kidney injury (AKI) is estimated to cause 1.8 million deaths reach year. Clinical trials targeting metabolism and hypoxia to limit ischemic injury to the kidney have failed. There is currently no treatment for acute kidney injury. Vascular congestion is the accumulation of many tightly packed red blood cells (RBC) in the renal outer-medulla of the kidney. Vascular congestion is a hallmark of ischemic acute tubular necrosis (severe AKI) in humans and rodent models. While vascular congestion has generally considered to occur secondary to hypoxic injury and not to be a major contributor to ischemic kidney injury, we challenge this concept. We propose that direct red blood cell toxicity from vascular congestion initiates injury in ischemic kidneys. Furthermore, we propose that vascular congestion itself is the initiating event in AKI following ischemia and results from hemodynamic disturbances that occur within the kidney during the ischemic period, rather than the inflammatory response to hypoxic injury. Specifically, we propose that retrograde pumping of blood into the kidney via the valveless renal veins during ischemia, which is driven by peristaltic movements of the renal calyx, packs the renal venous circulation with RBCs. This ischemic packing of blood into the renal medullary venous circulation then prevents blood from draining from the low-pressure medullary circulation upon reperfusion. As blood can enter, but not leave the medullary circulation, this results in expansion of the medullary circulation with red blood cells and medullary vascular congestion. The renal tubules then act to phagocytosis these RBCs, but are overwhelmed, resulting in toxic injury and death of the tubules. We will test our ground-breaking hypotheses using conceptually novel and innovative approaches including, functional in vivo studies and never before attempted multiphoton imaging of the ischemic outer-medulla. Successful completion of our aims would be paradigm shifting in the field of acute kidney injury, indicating that ischemic kidney injury results from toxicity of the renal tubular cells to RBC rather than hypoxic injury as long believed. As the vast majority of AKI studies currently focus on the role of hypoxia and cellular energy depletion in initiating kidney injury, this revelation would have a major impact on the way ischemic AKI is studied. Further, by demonstrating that ischemic kidney injury is a hemodynamic ‘plumbing’ problem rather than a tubular metabolism problem as currently believed, this revelation would alter the clinical approach to preventing and treating ischemic AKI.
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