The effects of prolonged warm ischaemia and endothelin receptor antagonism in an ex-vivo porcine model of renal transplantation

Persistent organ shortage remains a major challenge in organ transplantation. Uncontrolled donation after circulatory death donors provide a large potential source of kidneys but there is reluctance to use them due to prolonged warm ischaemia (WI) and associated poor outcomes. Endothelin-1, a potent vasoconstrictor, is a major contributor to the pathogenesis of ischaemia-reperfusion injury. In the first part of the study, porcine kidneys underwent 15, 60, 90 and 120min (n = 6, 6, 6, 4) warm ischaemia (WI) and 2hrs cold ischaemia followed by reperfusion with autologous blood for 3hrs. In the second part, porcine kidneys underwent 60min WI and 2hrs cold ischaemia followed by reperfusion with 500μg BQ-123, a selective ETA endothelin receptor antagonist (n=6). Renal haemodynamics, function, metabolism, inflammation and injury were analysed. Prolonged WI caused an initial reduction in renal blood flow (RBF), loss of renal function and substantial renal injury but these improved with reperfusion. The urine output (UO), creatinine clearance and fractional excretion of sodium improved significantly in the 15, 60 and 90min groups but not the 120min group. Total UO and creatinine fall were significantly lower in the 90min group than the 60min group. BQ-123 caused an initial increase in RBF and UO but this was not sustained and the total RBF and UO were comparable between the two groups. BQ-123 also resulted in lower levels of urinary NGAL and endothelin-1 but no difference was seen in the other injury parameters.

Kidneys can tolerate longer absolute warm ischaemia than is currently accepted. Kidneys recovered after up to 90min of WI, although the kidneys in this group showed significantly lower function than the 60min group. Sixty minutes is recommended as a safe limit of tolerable WI. Despite an initial increase in renal perfusion and function with BQ-123, a significant overall benefit was not seen.