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Aim: Renal tissue hypoxia during cardiopulmonary bypass could contribute to the pathophysiology of acute kidney injury. We tested whether renal tissue hypoxia can be alleviated during cardiopulmonary bypass by the combined increase in target pump flow and mean arterial pressure. Method(s): Cardiopulmonary bypass was established in eight instrumented sheep under isoflurane anaesthesia, at a target continuous pump flow of 80 mL.kg-1 min-1 and mean arterial pressure of 65 mmHg. We then tested the effects of simultaneously increasing target pump flow to 104 mL.kg-1 min-1 and mean arterial pressure to 80 mmHg with metaraminol (total dose 0.25-3.75 mg). We also tested the effects of transitioning from continuous flow to partially pulsatile flow (pulse pressure ~15 mmHg). Result(s): Compared with conscious sheep, at the lower target pump flow and mean arterial pressure, cardiopulmonary bypass was accompanied by reduced renal blood flow (6.8 +/- 1.2 to 1.95 +/- 0.76 mL.min-1 kg-1) and renal oxygen delivery (0.91 +/- 0.18 to 0.24 +/- 0.11 mL.O2 min-1 kg-1). There were profound reductions in cortical oxygen tension (PO2) (33 +/- 13 to 6 +/- 6 mmHg) and medullary PO2 (31 +/- 12 to 8 +/- 8 mmHg). Increasing target pump flow and mean arterial pressure increased renal blood flow (to 2.6 +/- 1.0 mL.min-1 kg-1) and renal oxygen delivery (to 0.32 +/- 0.13 mL.O2 min-1kg-1) and returned cortical PO2 to 58 +/- 60 mmHg and medullary PO2 to 28 +/- 16 mmHg; levels similar to those of conscious sheep. Partially pulsatile pump flow had no significant effects on renal perfusion or oxygenation. Conclusion(s): Renal hypoxia during experimental CPB can be corrected by increasing target pump flow and mean arterial pressure within a clinically feasible range.Copyright © 2020 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd

Introduction: The renal medulla is susceptible to hypoxia during cardiopulmonary bypass (CPB), which may contribute to the development of acute kidney injury. But the speed of onset of renal medullary hypoxia remains unknown. Method(s): We continuously measured renal medullary oxygen tension (MPO2) in 24 sheep, and urinary PO2 (UPO2) as an index of MPO2 in 92 patients, before and after induction of CPB. Result(s): In laterally recumbent sheep with a right thoracotomy (n = 20), even before CPB commenced MPO2 fell from (mean +/- SEM) 52 +/- 4 to 41 +/-5 mmHg simultaneously with reduced arterial pressure (from 108 +/- 5 to 88 +/- 5 mmHg). In dorsally recumbent sheep with a medial sternotomy (n = 4), MPO2 was even more severely reduced (to 12 +/- 12 mmHg) before CPB. In laterally recumbent sheep in which a crystalloid prime was used (n = 7), after commencing CPB, MPO2 fell abruptly to 24 +/-6 mmHg within 20-30 minutes. MPO2 during CPB was not improved by adding donor blood to the prime (n = 13). In patients undergoing cardiac surgery, UPO2 fell by 4 +/- 1 mmHg and mean arterial pressure fell by 7 +/- 1 mmHg during the 30 minutes before CPB. UPO2 then fell by a further 12 +/- 2 mmHg during the first 30 minutes of CPB but remained relatively stable for the remaining 24 minutes of observation. Conclusion(s): Renal medullary hypoxia is an early event during CPB. It starts to develop even before CPB, presumably due to a pressure-dependent decrease in renal blood flow. Medullary hypoxia during CPB appears to be promoted by hypotension and is not ameliorated by increasing blood hemoglobin concentration.Copyright © The Author(s) 2021.

Glomerular filtration rate (GFR) is acutely increased following a high-protein meal or systemic infusion of amino acids. The mechanisms underlying this renal functional response remain to be fully elucidated. Nevertheless, they appear to culminate in preglomerular vasodilation. Inhibition of the tubuloglomerular feedback signal appears critical. However, nitric oxide, vasodilator prostaglandins, and glucagon also appear important. The increase in GFR during amino acid infusion reveals a "renal reserve,"which can be utilized when the physiological demand for single nephron GFR increases. This has led to the concept that in subclinical renal disease, before basal GFR begins to reduce, renal functional reserve can be recruited in a manner that preserves renal function. The extension of this concept is that once a decline in basal GFR can be detected, renal disease is already well progressed. This concept likely applies both in the contexts of chronic kidney disease and acute kidney injury. Critically, its corollary is that deficits in renal functional reserve have the potential to provide early detection of renal dysfunction before basal GFR is reduced. There is growing evidence that the renal response to infusion of amino acids can be used to identify patients at risk of developing either chronic kidney disease or acute kidney injury and as a treatment target for acute kidney injury. However, large multicenter clinical trials are required to test these propositions. A renewed effort to understand the renal physiology underlying the response to amino acid infusion is also warranted.Copyright © 2020 the American Physiological Society.

Agonists of alpha2-adrenoceptors are increasingly being used for the provision of comfort, sedation and the management of delirium in critically ill patients, with and without sepsis. In this context, increased sympathetic and inflammatory activity are common pathophysiological features linked to multi-organ dysfunction, particularly in patients with sepsis or those undergoing cardiac surgery requiring cardiopulmonary bypass. Experimental and clinical studies support the notion that the alpha2-adrenoceptor agonists, dexmedetomidine and clonidine, mitigate sympathetic and inflammatory overactivity in sepsis and cardiac surgery requiring cardiopulmonary bypass. These effects can protect vital organs, including the cardiovascular system, kidneys, heart and brain. We review the pharmacodynamic mechanisms by which alpha2-adrenoceptor agonists might mitigate multi-organ dysfunction arising from pathophysiological conditions associated with excessive inflammatory and adrenergic stress in experimental studies. We also outline recent clinical trials that have examined the use of dexmedetomidine in critically ill patients with and without sepsis and in patients undergoing cardiac surgery.Copyright © 2021 The British Pharmacological Society

Renal medullary hypoxia may contribute to the pathophysiology of acute kidney injury, including that associated with cardiac surgery requiring cardiopulmonary bypass (CPB). When performed under volatile (isoflurane) anesthesia in sheep, CPB causes renal medullary hypoxia. There is evidence that total intravenous anesthesia (TIVA) may preserve renal perfusion and renal oxygen delivery better than volatile anesthesia. Therefore, we assessed the effects of CPB on renal perfusion and oxygenation in sheep under propofol/fentanyl-based TIVA. Sheep (n = 5) were chronically instrumented for measurement of whole renal blood flow and cortical and medullary perfusion and oxygenation. Five days later, these variables were monitored under TIVA using propofol and fentanyl and then on CPB at a pump flow of 80 mL*kg-1*min-1 and target mean arterial pressure of 70 mmHg. Under anesthesia, before CPB, renal blood flow was preserved under TIVA (mean difference +/- SD from conscious state: -16 +/- 14%). However, during CPB renal blood flow was reduced (-55 +/- 13%) and renal medullary tissue became hypoxic (-20 +/- 13 mmHg versus conscious sheep). We conclude that renal perfusion and medullary oxygenation are well preserved during TIVA before CPB. However, CPB under TIVA leads to renal medullary hypoxia, of a similar magnitude to that we observed previously under volatile (isoflurane) anesthesia. Thus use of propofol/fentanyl-based TIVA may not be a useful strategy to avoid renal medullary hypoxia during CPB.Copyright © 2020 the American Physiological Society

Aim: Blood transfusion may improve renal oxygenation during cardiopulmonary bypass (CPB). In an ovine model of experimental CPB, we tested whether increasing blood haemoglobin concentration [Hb] from ~7 g dL-1 to ~9 g dL-1 improves renal tissue oxygenation. Method(s): Ten sheep were studied while conscious, under stable isoflurane anaesthesia, and during 3 hours of CPB. In a randomized cross-over design, 5 sheep commenced bypass at a high target [Hb], achieved by adding 600 mL donor blood to the priming solution. After 90 minutes of CPB, PlasmaLyte was added to the blood reservoir to achieve low target [Hb]. For the other 5 sheep, no blood was added to the prime, but after 90 minutes of CPB, 800-900 mL of donor blood was given to achieve a high target [Hb]. Result(s): Overall, CPB was associated with marked reductions in renal oxygen delivery (-50 +/- 12%, mean +/- 95% confidence interval) and medullary tissue oxygen tension (PO2, -54 +/- 29%). Renal fractional oxygen extraction was 17 +/- 10% less during CPB at high [Hb] than low [Hb] (P =.04). Nevertheless, no increase in tissue PO2 in either the renal medulla (0 +/- 6 mmHg change, P >.99) or cortex (-19 +/- 13 mmHg change, P =.08) was detected with high [Hb]. Conclusion(s): In experimental CPB blood transfusion to increase Hb concentration from ~7 g dL-1 to ~9 g dL-1 did not improve renal cortical or medullary tissue PO2 even though it decreased whole kidney oxygen extraction.Copyright © 2020 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd

Introduction: Urinary oxygen tension (PO2) may provide a useful estimate of renal medullary PO2 and thus risk of acute kidney injury (AKI). However, the relationship between urinary PO2 and medullary PO2 could be confounded by variations in urine flow and arterial PO2. In the current study we exploited data we had previously generated, from experimental studies in ovine septic AKI and in patients undergoing cardiac surgery requiring cardiopulmonary bypass (CPB), to perform a detailed analysis of the influences of urine flow and arterial PO2 on urinary PO2. We also investigated the potential for simultaneous measurement of urine flow and urinary PO2, during CPB, to improve prediction of AKI over that provided by measurement of each variable on its own. Method(s): In ovine septic AKI urine flow, urinary PO2, arterial PO2, and medullary PO2 were measured. In human patients undergoing cardiac surgery requiring CPB urinary PO2 and arterial PO2 were measured continuously and urine flow was estimated every 5 minutes. Result(s): In 28 conscious septic sheep breathing room air, urinary PO2 was more closely correlated with medullary PO2 (r2=0.29) than with arterial PO2 (r2=0.06) or urine flow (r2=0.03). The difference between medullary PO2 and urinary PO2 varied little with urine flow or arterial PO2. In 20 patients, urine flow increased abruptly from 2.81 +/- 0.24 mL/min to 6.53 +/- 0.30 mL/min upon commencement of CPB, usually coincident with a fall in urinary PO2 (Fig. 1). During hyperoxic CPB high values of urinary PO2 were often observed at low urine flow. In 65 patients, low urinary PO2 during CPB (<10 mmHg at any time during CPB) was associated with greater (4.5-fold) risk of AKI. However, the level of urine flow on bypass was not significantly associated with risk of AKI. [Figure presented] Conclusion(s): We developed a method for virtually continuous measurement of urine flow in the operating theatre. We found that urinary PO2 provides a relatively robust estimate of

Introduction: Renal medullary hypoxia may be a pathophysiological factor in cardiac surgery-associated acute kidney injury. However, the effects of cardiopulmonary bypass (CPB) on oxygenation of the renal medulla remain poorly understood. Furthermore, whether increased pump flow or arterial pressure can improve renal medullary oxygenation has not been determined. Therefore, in the current study we tested whether CPB causes medullary hypoxia and whether medullary oxygenation during CPB varies with pump flow and mean arterial pressure. Method(s): Twelve sheep were instrumented to allow measurement of whole kidney, medullary and cortical blood flow and oxygenation. The experiment was performed five days later, under isoflurane anesthesia. Sheep were first placed on CPB at a pump flow of 80 mL/kg/min and a target mean arterial pressure of 70 mmHg. Pump flow was then set at 60 and 100 mL/kg/min while mean arterial pressure was maintained at ~70 mmHg. Mean arterial pressure was then increased by infusion of metaraminol (0.2 mg/min) at a set pump flow of 80 mL/kg/min. Result(s): Transition to CPB at a pump flow of 80 ml/kg/min was associated with reduced total renal blood flow (RBF, -61% less than the conscious state), along with reduced perfusion in the cortex (-44%) and medulla (-40%), and reduced medullary PO2 (from 43 to 21 mmHg; Figure) but not cortical PO2. Changes in pump flow and arterial pressure were associated with changes in medullary PO2 (Figure). That is, decreasing pump flow from 80 to 60 mL/kg/min further decreased RBF (-16%) and medullary PO2 (to 14 mmHg). Increasing pump flow from 80 to 100 mL/kg/min increased RBF (17%) and medullary PO2 (to 29 mmHg). Metaraminol (0.2 mg/min) increased mean arterial pressure (from 63 to 90 mmHg), RBF (47%) and medullary PO2 (from 19 to 39 mmHg). [Figure presented] Conclusion(s): The renal medulla appears to be more susceptible to hypoxia during CPB than the renal cortex. However, medullary oxygenation can be improved by i

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-1min-1 and target MAP of 70 mm Hg. Pump flow was then set at 60 and 100 mL kg-1min-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-1min-1. CPB at 80 mL kg-1min-1 reduced renal blood flow (RBF), -61% less than the conscious state, perfusion in the cortex (-44%) and medulla (-40%), and medullary PO2 from 43 to 27 mm Hg. Decreasing pump flow from 80 to 60 mL kg-1min-1 further decreased RBF (-16%) and medullary PO2 from 25 to 14 mm Hg. Increasing pump flow from 80 to 100 mL kg-1min-1 increased RBF (17%) and medullary PO2 from 20 to 29 mm Hg. Metaraminol (0.2 mg/min) increased MAP from 63 to 90 mm Hg, RBF (47%), and medullary PO2 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.Copyright © 2019 International Society of Nephrology

Introduction: Continuous measurement of urinary oxygen tension (PO2) in patients undergoing cardiac surgery may allow prediction of post-operative acute kidney injury (AKI). The predictive efficacy of urinary PO2 may be because it provides a good estimate of renal medullary PO2. Medications given during the perioperative period, particularly diuretics, could potentially alter medullary and/or urinary PO2. Thus, administration of furosemide may reduce the utility of urinary PO2 in predicting AKI. Therefore, we tested the effects of furosemide on urinary PO2 in patients recovering in the intensive care unit (ICU) after open heart surgery requiring cardiopulmonary bypass. Method(s): Bladder urinary PO2 was measured using a fibre optic probe, placed in the patient's bladder catheter at the time of induction of anaesthesia in the operating theatre. Urinary PO2 was measured in the ICU in 66 patients for up to 48 h (mean +/- SEM 38.9 +/- 2.6 h) after admission to the ICU. Of these, 39 patients received a bolus intravenous dose of furosemide (10-80 mg). Result(s): Urine flow in the hour before furosemide administration averaged 0.83 +/- 0.11 mL/min (mean +/- SEM) in the 23 patients who did not develop AKI during the five days after surgery (KDIGO criteria excluding urine flow criterion) and 0.57 +/- 0.11 mL/min in the 16 patients who did develop AKI (Figure 1A). In the two hours following administration of furosemide, urine flow increased to 2.10 +/- 0.37 mL/min in patients who did not develop AKI, and 1.97 +/- 0.44 mL/min in patients who did develop AKI. Urinary PO2 before administration of furosemide was lower in patients who developed AKI (20.2 +/- 2.0 mmHg) than those who did not (26.3 +/- 2.6 mmHg) (Figure 1B). Urinary PO2 did not change significantly in the first two hours following administration of furosemide in patients who did develop AKI (21.9 +/- 2.3 mmHg), or in patients who did not develop AKI (25.9 +/- 1.8 mmHg). There was also no significant relationship bet

Objectives: Acute kidney injury (AKI) develops in ~30% of patients following cardiac surgery on cardiopulmonary bypass (CPB). There are no interventions to prevent post-operative AKI, because its pathophysiology remains unclear. Our aims are (1) to determine the effects of CPB on the renal macro-and micro-circulation and (2) to determine the effects of altering pump flow on global and regional-kidney perfusion and oxygenation during CPB. Method(s): We implanted a flow probe on the renal artery and laser Doppler/oxygen-sensing probes in the cortex and medulla in sheep (N = 10). After baseline recordings in conscious sheep, animals were anesthetized, then placed on CPB with inspired oxygen fraction (FiO2) maintained at 0.6. From a baseline level of 80 mL/kg/min, pump flow was altered to 60, 80 and 100 mL/kg/min in random order. Result(s): During CPB, renal blood flow (RBF; 287 +/- 21 to 109 +/- 19 mL/ min), medullary perfusion (720 +/- 127 to 222 +/- 42 BPU) and medullary oxygenation (48 +/- 5 to 22 +/- 7 mmHg) were all reduced, compared with conscious sheep. Cortical oxygenation increased during CPB (46 +/- 3 to 70 +/- 17 mmHg), despite reduced perfusion (1954 +/- 378 to 872 +/- 112 BPU). Reducing pump flow exacerbated medullary hypoxia (to 11 +/- 3 mmHg), while increasing pump flow tended to improve medullary oxygenation (to 29 +/- 7 mmHg). Conclusion(s): CPB had detrimental effects on RBF, medullary and cortical perfusion and medullary oxygenation. Cortical oxygenation was maintained by the high FiO2. Medullary hypoxia may be a crucial mediator of post-CPB AKI. Thus, avoiding medullary hypoxia, by optimizing perfusion conditions on CPB, may be a feasible strategy to mitigate post-operative AKI.

Aim: Urinary oxygen tension (uPO2) may provide an estimate of renal medullary PO2 (mPO2) and thus risk of acute kidney injury (AKI). We assessed the potential for variations in urine flow and arterial PO2 (aPO2) to confound these estimates. Method(s): In 28 sheep urine flow, uPO2, aPO2 and mPO2 were measured during development of septic AKI. In 65 human patients undergoing cardiac surgery requiring cardiopulmonary bypass (CPB) uPO2 and aPO2 were measured continuously during CPB, and in a subset of 20 patients, urine flow was estimated every 5 minutes. Result(s): In conscious sheep breathing room air, uPO2 was more closely correlated with mPO2 than with aPO2 or urine flow. The difference between mPO2 and uPO2 varied little with urine flow or aPO2. In patients, urine flow increased abruptly from 3.42 +/- 0.29 mL min-1 to 6.94 +/- 0.26 mL min-1 upon commencement of CPB, usually coincident with reduced uPO2. During hyperoxic CPB high values of uPO2 were often observed at low urine flow. Low urinary PO2 during CPB (<10 mm Hg at any time during CPB) was associated with greater (4.5-fold) risk of AKI. However, low urine flow during CPB was not significantly associated with risk of AKI. Conclusion(s): uPO2 provides a robust estimate of mPO2, but this relationship is confounded by the simultaneous presence of systemic hyperoxia and low urine flow. Urine flow increases and uPO2 decreases during CPB. Thus, CPB is probably the best time to use uPO2 to detect renal medullary hypoxia and risk of post-operative AKI.Copyright © 2019 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd

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.Copyright © 2017 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd

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.

Oxygen tension (Po2) of urine in the bladder could be used to monitor risk of acute kidney injury if it varies with medullary Po2 Therefore, we examined this relationship and characterized oxygen diffusion across walls of the ureter and bladder in anesthetized rabbits. A computational model was then developed to predict medullary Po2 from bladder urine Po2 Both intravenous infusion of [Phe(2),Ile(3),Orn(8)]-vasopressin and infusion of N(G)-nitro-l-arginine reduced urinary Po2 and medullary Po2 (8-17%), yet had opposite effects on renal blood flow and urine flow. Changes in bladder urine Po2 during these stimuli correlated strongly with changes in medullary Po2 (within-rabbit r(2) = 0.87-0.90). Differences in the Po2 of saline infused into the ureter close to the kidney could be detected in the bladder, although this was diminished at lesser ureteric flow. Diffusion of oxygen across the wall of the bladder was very slow, so it was not considered in the computational model. The model predicts Po2 in the pelvic ureter (presumed to reflect medullary Po2) from known values of bladder urine Po2, urine flow, and arterial Po2 Simulations suggest that, across a physiological range of urine flow in anesthetized rabbits (0.1-0.5 ml/min for a single kidney), a change in bladder urine Po2 explains 10-50% of the change in pelvic urine/medullary Po2 Thus, it is possible to infer changes in medullary Po2 from changes in urinary Po2, so urinary Po2 may have utility as a real-time biomarker of risk of acute kidney injury.