Acute ischemic injury to the renal microvasculature in human kidney transplantation

Abstract

Increased understanding of the pathophysiology of ischemic acute kidney injury in renal transplantation may lead to novel therapies that improve early graft function. Therefore, we studied the renal microcirculation in ischemically injured kidneys from donors after cardiac death (DCD) and in living donor kidneys with minimal ischemia. During transplant surgery, peritubular capillaries were visualized by sidestream darkfield imaging. Despite a profound reduction in creatinine clearance, total renovascular resistance of DCD kidneys was similar to that of living donor kidneys. In contrast, renal microvascular perfusion in the early reperfusion period was 42% lower in DCD kidneys compared with living donor kidneys, which was accounted for by smaller blood vessel diameters in DCD kidneys. Furthermore, DCD kidneys were characterized by smaller red blood cell exclusion zones in peritubular capillaries and by greater production of syndecan-1 and heparan sulfate (main constituents of the endothelial glycocalyx) compared with living donor kidneys, providing strong evidence for glycocalyx degradation in these kidneys. We conclude that renal ischemia and reperfusion is associated with reduced capillary blood flow and loss of glycocalyx integrity. These findings form the basis for development of novel interventions to prevent ischemic acute kidney injury.

kidney transplantation is inevitably associated with ischemia and reperfusion injury. Depending on the severity of injury, 20–80% of recipients of deceased donor kidneys require dialysis treatment in the first week after transplantation, which is referred to as delayed graft function (26). This condition complicates patient management and is associated with a 40% increased rate of graft loss in kidneys from donors after brain death (45). Liberal use of donations after cardiac death greatly expands the number of available donor kidneys and may even eliminate transplant waiting lists (37). However, kidneys from these donors suffer extensive ischemic injury from circulatory arrest until organ preservation, which almost invariably leads to delayed graft function after transplantation. More importantly, up to 15–25% of these kidneys will never regain function, unnecessarily exposing recipients to the risks of major surgery and immunological sensitization (43).

Adequate reperfusion is essential for functional recovery of donor kidneys and prevents ongoing ischemic tissue injury after revascularization. In rodent models of ischemic acute kidney injury, it has been demonstrated that the peritubular microcirculation suffers endothelial injury and functional impairment after reperfusion (5, 44), which has recently been observed in humans as well (13, 21, 31). The endothelium is covered by the glycocalyx, a dynamic network of proteoglycans and glycoproteins that determines vascular permeability, transduces shear stress to the endothelium, and prevents interaction of leukocytes and platelets with the vascular wall (29). Loss of endothelial glycocalyx integrity after ischemia and reperfusion has been observed in experimental models (8, 24, 27) and in patients undergoing aortic surgery (28). Degradation of the endothelial glycocalyx by infusion of hyaluronidase causes capillary perfusion defects in rodents (7). Taken together, ischemic injury to endothelial cells and glycocalyx of peritubular capillaries may play a major role in the pathophysiology of acute kidney injury by reducing tissue perfusion and propagating inflammation in the reperfused kidney.

In the current manuscript, we studied the human renal microcirculation after clinical kidney transplantation by direct visualization of cortical peritubular capillaries and by measuring renal arteriovenous gradients of the main constituents of the endothelial glycocalyx. We found that ischemically injured kidneys from donors after cardiac death (DCD) were characterized by reduction of capillary blood flow and loss of glycocalyx integrity compared with a control group of kidneys from living donors with minimal ischemia. These findings form the basis for development of interventions that increase microvascular perfusion and protect the endothelial glycocalyx.