Extravasation of Blood and Blood Toxicity Drives Tubular Injury from RBC Trapping in Ischemic AKI.

Red blood cell (RBC) trapping is common in ischemic acute kidney injury (AKI) and presents as densely packed RBCs that accumulate within and engorge the kidney medullary circulation. In this study, we tested the hypothesis that "RBC trapping directly promotes tubular injury independent of extending ischemia time." Studies were performed on rats. Red blood cell congestion and tubular injury were compared between renal arterial clamping, venous clamping, and venous clamping of blood-free kidneys. Vessels were occluded for either 15 or 45 min with and without reperfusion. We found that RBC trapping in the medullary capillaries occurred rapidly following reperfusion from renal arterial clamping and that this was associated with extravasation of blood from congested vessels, uptake of blood proteins by the tubules, and marked tubular injury. To determine if this injury was due to blood toxicity or an extension of ischemia time, we compared renal venous and arterial clamping without reperfusion. Venous clamping resulted in RBC trapping and marked tubular injury within 45 min of ischemia. Conversely, despite the same ischemia time, RBC trapping and tubular injury were minimal following arterial clamping without reperfusion. Confirming the role of blood toward tubular injury, injury was markedly reduced in blood-free kidneys with venous clamping. Our data demonstrate that RBC trapping results in the rapid extravasation and uptake of blood components by tubular cells, causing toxic tubular injury. Tubular toxicity from extravasation of blood following RBC trapping appears to be a major component of tubular injury in ischemic AKI, which has not previously been recognized.

Hidden in Plain Sight: Does Medullary Red Blood Cell Congestion Provide the Explanation for Ischemic Acute Kidney Injury?

Acute kidney injury (AKI) represents a sudden reduction in renal function and is a major clinical problem with a high mortality rate. Despite decades of research, there are currently no direct therapies for AKI. The failure of therapeutic approaches identified in rodents to translate to human beings has led to questions regarding the appropriateness of these models. Our recent data indicate that there are two distinct processes driving tubular injury in the commonly used rat model of warm bilateral renal ischemia reperfusion injury, which often is used to mimic ischemic AKI. One results from the period of warm ischemia, manifesting as sublethal injury and coagulative necrosis of the proximal tubules in the renal cortex. This is the predominate type of injury observed 24 hours after reperfusion and the most well studied. The other results from red blood cell congestion of the outer medullary vasculature. This type of injury manifests as cell sloughing, along with the later formation of heme casts that fill distal nephron segments. Cell sloughing from congestion is most prominent in the early hours after reperfusion and often is masked by regeneration of the tubular epithelium by 24 hours postischemia. In this review, we argue that injury from outer medullary red blood cell congestion reflects the pathology observed in human kidneys and likely is representative of injury in most cases of ischemic AKI after shock. Greater focus on this congestive injury is likely to lead to improved translation in AKI.