Renal medullary hypoxia may contribute to cardiac surgery-associated acute kidney injury (AKI). However, the effects of cardiopulmonary bypass (CPB) on medullary oxygenation are poorly understood. Here we tested whether CPB causes medullary hypoxia and whether medullary oxygenation during CPB can be improved by increasing pump flow or mean arterial pressure (MAP). Twelve sheep were instrumented to measure whole kidney, medullary, and cortical blood flow and oxygenation. Five days later, under isoflurane anesthesia, CPB was initiated at a pump flow of 80 mL kg -1 min -1 and target MAP of 70 mm Hg. Pump flow was then set at 60 and 100 mL kg -1 min -1 , while MAP was maintained at approximately 70 mm Hg. MAP was then increased by vasopressor (metaraminol, 0.2-0.6 mg/min) infusion at a pump flow of 80 mL kg -1 min -1 . CPB at 80 mL kg -1 min -1 reduced renal blood flow (RBF), -61% less than the conscious state, perfusion in the cortex (-44%) and medulla (-40%), and medullary PO 2 from 43 to 27 mm Hg. Decreasing pump flow from 80 to 60 mL kg -1 min -1 further decreased RBF (-16%) and medullary PO 2 from 25 to 14 mm Hg. Increasing pump flow from 80 to 100 mL kg -1 min -1 increased RBF (17%) and medullary PO 2 from 20 to 29 mm Hg. Metaraminol (0.2 mg/min) increased MAP from 63 to 90 mm Hg, RBF (47%), and medullary PO 2 from 19 to 39 mm Hg. Thus, the renal medulla is susceptible to hypoxia during CPB, but medullary oxygenation can be improved by increasing pump flow or increasing target MAP by infusion of metaraminol.A KI occurs in more than 20% of adult patients after cardiac surgery requiring CPB. 1 The ability to decrease the risk of AKI associated with cardiac surgery is hampered by our lack of knowledge of the effects of CPB on renal perfusion and oxygenation. 2 Evolving evidence shows that renal medullary hypoxia contributes to the development of AKI. 3,4 Mathematical models predict renal medullary hypoxia during CPB, 5,6 and medullary hypoxia has been observed in a rat model of CPB 7 and in a pilot study of 2 pigs subjected to CPB. 8 However, there have been no systematic investigations of renal global and regional (i.e., cortical and medullary) perfusion and oxygenation in a clinically relevant large animal model of CPB. Furthermore, although evidence shows that goaldirected perfusion can mitigate risk of postoperative AKI 9-11 and that the increase in renal fractional oxygen extraction during CPB can be alleviated by increasing pump flow, 12,13 the potential for perfusion conditions to be

AKI is a common complication of sepsis and is significantly associated with mortality. Sepsis accounts for more than 50% of the cases of AKI, with a mortality rate of up to 40%. The pathogenesis of septic AKI is complex, but there is emerging evidence that, at least in the first 48 hours, the defects may be functional rather than structural in nature. For example, septic AKI is associated with an absence of histopathological changes, but with microvascular abnormalities and tubular stress. In this context, renal medullary hypoxia due to redistribution of intra-renal perfusion is emerging as a critical mediator of septic AKI. Clinically, vasopressor drugs remain the cornerstone of therapy for maintenance of blood pressure and organ perfusion. However, in septic AKI, there is insensitivity to vasopressors such as norepinephrine, leading to persistent hypotension and organ failure. Vasopressin, angiotensin II, and, paradoxically, α -adrenergic receptor agonists (clonidine and dexmedetomidine) may be feasible adjunct therapies for catecholamine-resistant vasodilatory shock. In this review, we outline the recent progress made in understanding how these drugs may influence the renal microcirculation, which represents a crucial step toward developing better approaches for the circulatory management of patients with septic AKI.

Acute kidney injury (AKI) is a common complication following cardiac surgery performed on cardiopulmonary bypass (CPB) and has important implications for prognosis. The aetiology of cardiac surgery-associated AKI is complex, but renal hypoxia, particularly in the medulla, is thought to play at least some role. There is strong evidence from studies in experimental animals, clinical observations and computational models that medullary ischaemia and hypoxia occur during CPB. There are no validated methods to monitor or improve renal oxygenation during CPB, and thus possibly decrease the risk of AKI. Attempts to reduce the incidence of AKI by early transfusion to ameliorate intra-operative anaemia, refinement of protocols for cooling and rewarming on bypass, optimization of pump flow and arterial pressure, or the use of pulsatile flow, have not been successful to date. This may in part reflect the complexity of renal oxygenation, which may limit the effectiveness of individual interventions. We propose a multi-disciplinary pathway for translation comprising three components. Firstly, large-animal models of CPB to continuously monitor both whole kidney and regional kidney perfusion and oxygenation. Secondly, computational models to obtain information that can be used to interpret the data and develop rational interventions. Thirdly, clinically feasible non-invasive methods to continuously monitor renal oxygenation in the operating theatre and to identify patients at risk of AKI. In this review, we outline the recent progress on each of these fronts.