Red blood cell trapping mediates toxic kidney injury following ischemia

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Ischemic acute kidney injury (AKI) is common following periods of severe hypotension, shock or renal ischemia and is a major clinical problem with a high rate of mortality. There is currently no effective treatment for ischemic AKI. As such, the prognosis of patients with ischemic AKI remains poor, and patients that recover from AKI are at increased risk for developing chronic kidney disease, cardiovascular events and all-cause mortality. Red blood cell (RBC) trapping is a hallmark of severe ischemic AKI in humans and in animal models of ischemia/reperfusion injury (IRI). The outer-medullary (OM) capillaries drain into the large veins of the kidney cortex. Red blood cell (RBC) trapping in the kidney OM occurs due to a combination of collapse of these large cortical veins during ischemia, along with, the continued entry of blood into the OM capillaries. As blood continues to enter the OM, it is unable to drain, expanding and engorging these capillaries with blood. The increasing OM capillary hydrostatic pressure then forces extravasation of the plasma, leaving behind aggregates of tightly packed RBCs with little or no plasma separating them. Our recently published data indicate that RBC trapping results in devastating kidney injury early in reperfusion, including distal tubular heme cast formation and denudation of the OM tubules. As injury from RBC trapping mimics many of the pathological features of ischemic AKI observed in humans, understanding the processes driving injury from RBC trapping may be critical to understanding the pathogenesis of AKI in humans. The goals of this proposal are to address key gaps in our knowledge regarding the central role of OM RBC trapping in mediating ischemic AKI and to identify novel approaches to limit kidney injury from RBC trapping. Our central hypothesis is that ‘RBC trapping in the OM microvasculature results in the extravasation of toxic heme from RBC congested vessels, resulting in mitochondrial dysfunction, tubular injury and loss of kidney function. Denudation of the OM tubules and incomplete recovery of the tubular epithelium then results in the unobstructed back-leak of filtrate into the blood, greatly reducing urine output, despite maintenance of glomerular filtration. Aim 1 will test the hypothesis that RBC trapping induces tubular injury and cell sloughing, resulting loss of kidney function. Aim 2 will test the hypothesis that the extravasation and tubular uptake of heme from RBC is driven by high intravascular pressures in RBC congested OM vessels and tubular endocytosis. Our novel approach will, for the 1st time, allow us to investigate the effects of RBC trapping on kidney function at key early time points. Our findings have the potential to explain the synergistic effect of kidney ischemia and high cell-free hemoglobin on kidney injury in ischemic AKI. The impact of our research will be a change in the conceptual basis for the treatment of AKI by establishing RBC trapping and tubular heme toxicity as a primary mechanism driving OM injury and nephron loss in ischemic AKI.