Renal oxygenation in clinical acute kidney injury

Renal oxygenation is defined as the relationship between renal oxygen delivery (DO2) and renal oxygen consumption (VO2) and it can easily be shown that the inverse of this relationship is equivalent to renal extraction of O2 (O2Ex). An increase in renal O2Ex means that renal DO2 has decreased in relation to renal VO2, i. e., renal oxygenation is impaired, and vice versa. When compared to other major organs, renal VO2 is relatively high, second only to the heart. In sedated, mechanically ventilated patients, renal VO2 is two-thirds (10 ml/min) that of myocardial oxygen consumption (15 ml/min) (Table 1) [1, 2]. Renal blood flow, which accounts for approximately 20 % of cardiac output, is three times higher than myocardial blood flow in this group of patients. Renal O2Ex in the non-failing kidney is therefore low, 10 %, compared with, e.g., the heart, in which O2EX is 55 % (Table 1).


Determin a nts of renal oxygenation
It is well known from experimental studies that tubular sodium reabsorption is the major determinant of renal VO 2 [3] and tha t under normal physiological conditions, approximately 80 % is used to drive active tubular transport of particularly sodium, but also glucose, amino acids and other solutes. Tubular transport processes are highly load-dependent and it has been shown in experimental studies [4] and in p atients [2,[5][6][7] that the re i s a close linear correlation between glomerular fi ltration rate (GFR), renal sodium reabsorption and renal VO 2 (Fig. 1). Th e fi l tered load of sodium is, thus, an important determi nant of renal VO 2 and maneuvers that decrease GFR and the tubular sodium load act to decrease tubular sodium reabsorption and renal VO 2 , and vice versa [8]. It has b een shown that renal O 2 Ex remains stable over a wide range of renal blood fl ows, which means that changes in renal DO 2 , caused by changes in renal blood fl ow, are directly off set by changes in renal VO 2 [9], i. e., r enal VO 2 is fl ow-dependent. Th us, unlike other organs where increases in blood fl ow will improve oxygenation, increased renal blood fl ow augments GFR and the fi ltered load of sodium, which will increase renal VO 2 . Due to this fl ow-dependency of renal VO 2 , renal oxygenation will re main constant, as long as renal blood fl ow and GFR change in parallel.

Regional intrarenal oxygenation and medullary hypoxia
Th e relatively high renal blood fl ow is directed preferentially to the cortex to optimize the fi ltration process and solute reabsorption. In contrast, blood fl ow in the outer medulla is less than 50 % of the cortical blood fl ow to preserve osmotic gradients and to enhance urinary concentration [10]. Th e combi nation of low me dullary perfusion, high oxygen consumption of the medullary thick ascending limbs (mTAL) and the countercurrent exchange of oxygen within the vasa recta, results in a poorly oxygenated outer medulla [11]. Oxygen av ailability is, therefore, low in the outer medulla, which has an oxygen tissue partial pressure (PO 2 ) of 10-20 mm Hg compared to 50 mm Hg in the cortex. Th us, as the outer medulla is on the border of hypoxia already under normal conditions, it is particularly sensitive to prolonged or intermittent episodes of low renal DO 2 , caused by hypoperfusion or hemodilution. Th is condition may occur, in particular, after major surgery (especially cardiac or vascular surgery) or severe heart failure, which are common causes of ischemic acute kidney injury (AKI) in the intensive care unit (ICU). Cardiovascular surgery is a 'clinical model' of human AKI. Because it is known when postoperative AKI may occur, in this group of patients, timely, therapeutic interventions for prevention and treatment of early AKI could be instituted. In this situation, it would be logical to improve the renal oxygen supply/demand relationship by augmenting renal DO 2 and/or reducing renal VO 2 , i. e., to improve renal oxygenation.

Eff ects of diureti cs on renal oxygenation in the postoperative patient
It has repeatedly been shown in experimental studies that furosemide and other loop-diuretics (ethacrynic acid, bumetanide) inhibit renal sodium reabsorption and VO 2 in the mTAL (e.g., [12]). Th is decrease in reabsorptive work w ill increase oxygen availability and consequently increase the tissue PO 2 of the medulla [11]. Because of this decrease in renal oxygen demand, furosemide could potentially exert preventive renoprotective eff ects. Indeed, several reports have demonstrated that furose mide causes renoprotection in experimental ischemic AKI (e.g., [13,14]). Most likely this is mediated by a decrease in medullary VO 2 which will increase the tolerance to renal ischemia, but it has also been suggested that the greater urine fl ow may 'fl ush out' tubular casts and thereby reduce intratubular obstruction and the backleak of fi l tere d urine [15]. Prasad et al. demonstrated in conscious volunteers that 20 mg of furosemide increased medullary oxygenation, using the blood oxygen level-dependent magnetic resonance imaging technique (BOLD MRI) [16]. In contrast, acetaz olamide, which inhibits tubular reabsorption of the proximal tubules in the cortex and which does not aff ect medullary PO 2 in experimental studies, did not aff ect medullary oxygenation.
Swärd et al. evaluated the renal eff ects of a bolus dose of furosemide (0.5 mg/kg) followed by an infusion (0.5 mg/ kg/h) in the early p eriod after cardiac surgery with cardiopulmonary bypass (CPB), using the retrograde renal vein thermodilution technique and renal extraction of 51 chromium-ethylene-diaminetetraacetic acid ( 51 Cr-EDTA) for rapid bedside estimation of RBF and GFR without the need for urine collection [5] (Fig. 2). Furosemide incr eased fraction al excretion of sodium (excreted  sodium/fi ltered sodium) from 2 % to 25 % and caused a 10-fold increase in urine fl ow because of a 28 % decrease in tubular sodium reabsorption. Th ese changes were in turn associated with a 23 % decrease in renal VO 2 . Th us, furose mide decreased renal O 2 Ex and improved renal oxygenation as renal blood fl ow was not signifi cantly aff ected by the diuretic. Interestingly, GFR decreased by 12 % with furosemide, which could be explained by an increased delivery of sodium to the distal tubules activating the tubuloglomerular feedback mechanism, eventu ally inducing a constriction of the aff erent arterioles and a decrease in GFR [17]. Th is mechanism could explain the fi ndings of Lassnigg et al., who demonstrated in low-risk cardiac surgery patients with normal renal function that furosemide lowered creatinine clearance postoperatively [18]. Th e authors, therefore, sugges ted that loop-diuretics could be detrimental to the patients in terms of renal function and outcome. Another hypothesis would be that furosemide improves the renal oxygen demand/supply relationship and, thus, could increase the tolerance to peri operative renal ischemia, and that the mild to moderate fall in GFR with furosemide is a direct pharmacological consequence (tubuloglomerular feedback activa tion) of the agent which, if anything, would further decrease renal VO 2 . In future studies, the potential preventive renoprotective eff ects of furosemide should be evaluated in high-risk surgical patients. Furthermore, GFR or creatinine clearance should not be used as the early primary end-point in such studies, because of the furosemide-induced pharmacological activation of the tubuloglomerular feedback mechanism, which will per se decrease GFR. Instead markers of tubular injury should be measured, to evaluate whether or not the improved renal oxygenation with furosemide could prevent tubular ischemic cell injury in high-risk surgical patients.

Eff ects of dopaminergic agents on renal oxygenation in the postoperative patient
Dopamine has been used to prevent acute renal dysfunction in cardiac surgery in the belief that dopamine increases renal blood fl ow. Th e preventive eff ect has, however, been questioned [19][20][21]. A prospective, random ized controlled trial showed that low-dose dopamine did not aff ect renal outcome in septic patients with early AKI [22]. It has also been speculated that a dopamine-induced inhibition of pro ximal tubular Na + reabsorption may increase delivery of Na + to potentially ischemic distal tubular cells in the medulla, which would increase their oxygen demands [19]. Th us, a dopamine-induced increase in renal V O 2 may have the potential to impair renal oxygenation, which could be d etrimental in the treatment of early ischemic acute renal failure [19]. Redfors et al. recently studied the eff ects of low-dose (2-4 μg/kg/min) dopamine on renal blood fl ow, GFR, tubular sodium reabsorption, renal VO 2 and the renal oxygen demand/supply relationship in post-cardiac surgery patients [23]. Renal blood fl ow was estimated by two independent techniques, the retrograde renal vein thermodilution technique and the paraaminohippuric acid (PAH) infusion clearance technique, with correction for renal extraction of PAH. Interestingly, low-dose dopamine induced pronounced renal vasodilation with a 45-55 % increase in renal blood fl ow. One would expect that such a marked increase in renal blood fl ow would be accompanied by a proportional increase in GFR (Fig. 3). However, GFR was not signifi cantly aff ecte d by dopamine. Th us, because of the lack of eff ect of dopamine on GFR, renal VO 2 was not aff ected and, consequently, renal oxygena tion was improved (Fig. 3). Th us, the hypothesis put forward by Jones and Bellomo [19], that dopamine may impair renal oxygenation is not s upported by the data from Redfors et al. [23]. Th e lack of eff ect of dopamine on GFR in postoperative patients highlig hts th e common misunderstanding that an increase in renal blood fl ow by a renal vasodilator is always accompanied by an increase in GFR. Th e eff ect of a renal vasodilator on GFR is dependent on its eff ect on the longitudinal distribution of renal vascular resistance. Th e dopamine-induced increase in renal blood fl ow with no signifi cant eff ect on GFR is explained by a renal vasodilatory action on pre-and postglomerular resistance vessels. Experimental studies have revealed that dopamine-mediated renal vasodilation predominantly is eff ected at the post-synaptic dopamine-1 (DA-1) receptors and that dopamine and other DA-1-receptor agonists dilate aff erent and eff erent arterioles to the same degree [24]. Studies on the eff ects of low-dose dopamine in volunteers or patients on renal plasma fl ow and GFR, as measured by clearance techniques are listed in Table 2.
Note that in all studies, renal plasma fl ow increased, whereas in half the studies, GFR was not aff ected; in the remaining half, the increase in GFR was considerably lower than th e increase in renal plasma fl ow.
Th e capacity of dopamine to improve renal oxygenation in postoperative patients would make it suitable for prevention of AKI, as it would increase the tolerance to renal ischemia in major surgery. However, the potential preventive eff ect of dopamine has not been evaluated in high-risk cardiovascular surgery. Although interest in the use of dopamine for renoprotection has decreased, interest in the use of another dopaminergic agent, fenol dopam, which exerts the same renal eff ects as dopamine [24], is, strangely enough, increasing. Fenoldopam is a selective dopamine-1 receptor agonist with no β-1 or α-adrenergic receptor agonistic eff ects and similar to dopamine, it increases renal plasma fl ow with no eff ects on GFR, as demonstrated in healthy volunteers [25]. In three pre ventive, randomized controlled trials in abdomi nal aortic surgery [26] and high-risk cardiac surgery [27], fenoldopam improved creatinine clearance compared to placebo. Th ese bene fi cial eff ects on renal outcome with fenoldopam and the lack of similar benefi cial eff ects with dopamine (see above), despite similar pharmacological actions, could be explained by the fact that the potential preventive renal eff ects with dopamine and fenoldopam were evaluated in low-risk and high-risk patients, respect ively. Bove et al. compared the preventive eff ects of fenoldopam and dopamine (2.5 μg/kg/min) on renal excretory function in high-risk cardiac surgery and found, not surprisingly, no diff er ence between the two dopami nergic agents on percentage postoperative increase in serum creatinine [28].

Renal oxygenation in clinical ischemic acute kidney injury
Patients undergoing cardiac surgery with CPB are at high risk of developing postoperative AKI, with a reported  incidence of 15-30 %, causing signifi cant morbidity and mortality [29,30]. In patients undergoing major cardiovascular s urgery , even minor changes in serum creatinine are associated with increased in-patient mortality [31]. Postoperative AKI in this group of patients is c onsidered a consequence of impaired renal DO 2 , in turn caused by intra-operative hypotension and hemodilution-induced anemia [32], as well as perioperative low cardiac output [29] . It has provocatively been stated that "acute ren al failure is acute renal success" [33,34], as a reduction in GFR in AKI should lead to a reduction in the renal reabsorptive workload, thus preserving medullary oxygenatio n wi th a reduced risk of further aggravation of ischemia. In patients with AKI, there are few data on renal VO 2 , renal blood fl ow, GFR and renal oxygenation and current views on renal oxygenation are presumptive and largely based on experimental studies.
Redfors et al. recently studied renal perfusion, fi ltration and oxygenation in patients with preoperative normal renal function developing early AKI (50-200 % increase in serum creatinine) after complicated cardiac surgery [2]. Renal blood fl ow was measured by renal vein retrogr ade thermodilution and by infusion clearance of PAH corrected for renal extraction of PAH. In spite of a normali zation of cardiac index (CI) with inotropic treatment with or without intra-aortic balloon pump (IABP), renal oxygenation was severely impaired in patients with early AKI, as demonstrated by a 70 % relative increase in renal O 2 Ex, compared to uncomplicated post-cardiac surgery patients with normal renal function Th is was, in turn, caused by a pronounced renal vasoconstriction and a 40 % lower renal blood fl ow, in combination with a renal VO 2 that was not signifi cantly diff erent from the control group, despite the 60 % decrease in GFR and renal tubular sodium reabsorption (Table 3). Th us, the renal VO 2 of the AKI patients was 1.9 ml/mmol re absorbed sodium, a value that was 2.4 times higher than in the uncomplicated control group (0 .82 ml/mmol reabsorbed sodium). Figure 4 shows the close c orrelation between GFR and renal VO 2 in patient s with early AKI after cardiac surgery versus those undergoing uncomplicated surgery with no renal impairment. According to the "acute renal success"hypothesis [42][43][44], as put forward by several researchers, AKI patients s hould operate on the lower part of the regression line of the control patients. However, the regression line of the AKI patients is clearly shifted to the left, i. e., at a certain GFR, renal VO 2 is higher, speaking against this hypothesis. On the contrary, the 40 % decrease in renal DO 2 in combination with a tubular sodium reabsorption at a high oxygen demand, suggests that renal hypoxia is present after the initiation phase of ischemic AKI.
One can only speculate on the mechanisms underlying the leftward shift of the GFR/renal VO 2 relationship in AKI patients. A potential explanation could be loss of epithelial cell-polarization and tight junction integrity in AKI, as has been shown in experimental studies and after human renal transplantation [35], making tubular sodium reabsorption less effi cient [36]. Another explana tion may be diminished renal nitric oxide (NO) genera tion because of endothelial damage and downregulation of endothelial NO synthase (eNOS/NOS-3). NO is a major regulator of microvascular oxygen supply and renal VO 2 [37]. Th rough vasodilation, NO increases renal blood fl ow and hence DO 2 . Furthermore, contemporary wor k suggests that NO acts as a 'brake' on oxidative metabolism at various sites, including direct competition of NO with oxygen for mitochondrial respiration and inhibition of cytochrome c oxidase [38].

Treatment of clinical ischemic AKI
Th e major goal in the managem ent of early AKI is to in crease GFR. However, because of the close association between GFR, tubular sodium reabsorption and renal VO 2 in humans [5][6][7], a pharmacologically-induced increase in GFR will increase renal VO 2 an d po tentially further impair renal oxygenation in patients with AKI. Th us, an ideal agent to treat ischemic AKI would be one that increases both renal blood fl ow and GFR, i. e., an agent that preferentially induces vasodilation of the preglomerular resistance vessels. Such an agent will not only increase GFR but also meet the increased renal metabolic demand of the medulla by an increase in renal DO 2 . It is not likely that the potent renal vasodilator, dopamine, will improve GFR in early clinical ischemic AKI as it exerts a non-specifi c renal vasodilation of preand postglomerular resistance vessels with a pronounced eff ect on total renal vascular resistance and renal blood fl ow but with no or minor eff ects on glomerular hydraulic pressure and GFR (see above). Th is could explain why low-dose dopamine (2 μg/kg/min) does not improve renal outcome, measured as peak serum creatinine, in ICU patients with systemic infl ammatory response syndrome and early AKI [22]. Atrial natriuretic peptide (ANP) is a renal vasodilator, which causes a balanced 30-40 % increase in both renal blood fl ow and GFR in patients with early ischemic AKI after complicated cardiac surgery [39]. Although , the eff ects of ANP on renal oxygenation have not been studied, it is less likely that ANP would impair renal oxygenation because of its preferential action on the preglomerular resistance vessels. Th is is further supported by the fi ndings from a prospective, randomized, blinded trial by Swärd et al., who showed that infusion of ANP enhanced renal excretory function, decreased the probability of dialysis and improved dialysis-free survival in early, ischemic AKI after complicated cardiac surgery [40] (Figs. 5 and 6).
Another approach for the treatment of clinical ischemic AKI would be to target the vascular endothelium and tubular epithelium. Experimen tal studies have shown that mannit ol may decrease ischemia-induced swelling of tubular cells, which might obstruct the tubular lumen [41]. Mannitol treatment has been shown to increase GFR in patients after severe trauma or surgery [42]. In addition, our group has shown that mannitol increases GFR in postoperative cardiac surgery patients possibly by a de-swelling eff ect on tubular cells [6]. Furthermore, it has been suggested that outer medullary hypoxia may cause endoth elial ischemic injury and endothelial cell swelling contributing to congestion and impaired perfusion of this region [43], which could, at least to some extent, explain the high renal vascular resis tance seen i n clinical early AKI [2]. Th e eff ects of mannitol treatment  on renal perfusion, fi ltration and oxygenation were recently studied in patients with normal preoperative creatinine, who developed early AKI after complicated cardiac surgery, requiring inotropic support with or without IABP [44]. Mannitol induced a 60 % increase in diuresis, which was accompanied by decrease in renal vascular resistance and a 12-15 % increase in rena l blood fl ow, while no eff ects were seen on cardiac index or cardiac fi lling pressures. Mannitol did not aff ect fi ltration fraction or renal oxygenation, suggestive of balanced increases in perfusion/fi ltration and renal oxygen demand/ supply (Fig. 7).

Vasodilatory shock and AKI: role of norepinephrine
Vasodilatory shock is not uncommon after complicated cardiac surgery with CPB and occurs often in conjunction with postoperative heart failure [45]. Th e recommended agent for treatment of volume-resuscitated vasodilatory shock is norepinephrine [46]. Patients with vasodilatory shock after cardiac surgery with CPB may suff er from conco mi tant AKI. Th e use of norepinephr ine for treatment of vasodilatory shock in patients with ischemic AKI with impaired renal oxygenation is a "two-edged sword" as it may further aggravate renal ischemia. On the other hand, too low a dose of norepinephrine may result in an arterial blood pressure that may be below the limit of renal autoregulation, i. e., when renal blood fl ow becomes pressure-dependent. In a recent study in post-cardiac surgery patients with norpinephrine-dependent vasoplegia and concomitant AKI, the eff ects of norepinephrine on renal perfusion, fi ltration and oxygenation were evaluated [47]. Nor epineph rine infusion rate was randomly and sequentially titrated to target a mean arterial pressures (MAP) of 60, 75 and 90 mm Hg. At each target MAP, data on renal blood fl ow, GFR and renal O 2 Ex were obtained by the renal vein thermodilution technique and by renal extraction of 51 Cr-EDTA. At a target MAP of 75 mm Hg, renal DO 2 (13 %), GFR (27 %) and urine fl ow were higher and renal O 2 Ex was lower (-7.4 %) compared with a target MAP of 60 mm Hg. However, the renal variables did not diff e r when compared at target MAPs of 75 and 90 mm Hg (Fig. 8). Th us, restoration of MAP from 60 to 75 mm Hg improves renal DO 2 , GFR and renal oxyge nation in patie nts with vasodilatory shock and AKI. Th e pressure-dependent renal perfusion, fi ltration and oxygenation at levels of MAP below 75 mm Hg refl ect a more or less exhausted renal autoregulatory reserve.

Low-dose vasopressin and renal oxygenation
Resistance to norepinephrine and other catecholamines ma y develop in vasodi latory shock because of adrenergic receptor downregulation and endogenous vaso dilators. Furthermore, plasma levels of vasopressin are low in post-cardiotomy vasodilatory shock and in septic shock in contrast to hypovolemic and cardiogenic shock [48]. Vaso pressin has, therefore, been suggested as an additional or an alternative therapy in catecholaminedependent vasodilatory shock [49]. It has also been reported that vasopressin increases creatinine clearance, a surrogate variable of GFR, in these patients [50]. A more detailed analysis on the eff ects of low-dose vasopressin on renal oxygenation is lacking.
Bragadottir et al. evaluated the renal eff ects of lowdoses (1.2, 2.4, 4.8 U/h) of vasopressin in post-cardiac surgery patients, doses that did not aff ect systemic blood pressure [7]. Vasopr essin exerted a dose-dependent increase i n GFR, sod ium reabsorption, renal VO 2 , renal O 2 Ex and renal vascular resistance, whereas renal blood fl ow decreased. Th us, vasopressin considerably impaire d renal oxygenation by postglomerular vasoconstriction, which induced a decrease in renal blood fl ow and an increase in both GFR and renal VO 2 (Fig. 9). From a renal point of view, vasopressin should be used with caution in the treatment of vasodilatory sho ck, because it has the potential to cause considerable renal oxygen supply/demand mismatch.

Conclusion
In spite of the apparent luxury oxygenation of the kidneys, with a high renal DO 2 in relati on to renal VO 2 , the outer medulla is on the border of hypoxia in the normal situation. Outer medullary hypoxia, caused by low medullary perfusion, high VO 2 of the medullary thick ascending limbs and the countercurrent exchange of oxygen, is the price the kidneys have to pay for the urine concentration mechanism. Th e outer medulla is, therefore, particularly sensitive to prolonged or intermittent episodes of low renal DO 2 . Dopaminergic agents (dopamine/ fenoldopam) and loop-diuretics im prove renal oxygenation, and potentially prevent ischemic AKI, whereas vasopressin impairs renal oxygenation in postoperative patients.
Renal oxygenation is impaired in early clinical ischemic AKI because of a low renal blood fl ow, caused by vasoconstriction and endothelial swelling, in combination with a tubular reabsorption at a high oxygen demand. ANP is ideally suited for treatment of ischemic AKI, as it preferentially dilates the preglomerular resistance vessels; this will increase GFR but also renal blood fl ow, meeting the increased oxygen demand of the medulla by an increase in renal DO 2 . Mannitol increases renal blood fl ow and GFR in clinical ischemic AKI most likely by endothelial and epithelial de-swelling eff ects. Restoration of MAP from 60 to 75 mm Hg improves renal oxygen delivery, GFR and the renal oxygen supply/demand relationship. This pressure-dependent renal perfusion, fi ltration and oxygenation at levels of MAP below 75 mm Hg refl ec t a more or less exhausted renal autoregulatory reserve. Data from [47]. Vasopressin caus es a constriction of renal eff erent arterioles with a decrease in RBF and an increase in GFR and RVO 2 .Vasopressin impairs the renal oxy gen demand/ supply relationship as refl ect ed by the increa se in RO 2 Ex. From [7] with permission.