Elsevier

Seminars in Nephrology

Volume 39, Issue 6, November 2019, Pages 543-553
Seminars in Nephrology

Renal Medullary Hypoxia: A New Therapeutic Target for Septic Acute Kidney Injury?

https://doi.org/10.1016/j.semnephrol.2019.10.004Get rights and content

Summary: Renal tissue hypoxia has been implicated as a critical mediatory factor in multiple forms of acute kidney injury (AKI), including in sepsis. In sepsis, whole-kidney measures of macrocirculatory flow and oxygen delivery appear to be poor predictors of microcirculatory abnormalities. Studies in experimental hyperdynamic septic AKI have shown that the renal medulla is particularly susceptible to hypoxia early in sepsis, even in the presence of increased global renal blood flow and oxygen delivery. It has been proposed that an early onset of progressive renal medullary hypoxia, leading to oxidative stress and inflammation, can initiate a downward spiral of cellular injury culminating in AKI. Recent experimental studies have shown that clinical therapies for septic AKI, including, fluids, vasopressors, and diuretics, have distinct effects on renal macrocirculation and microcirculation. Herein, we review the clinical and experimental evidence of alterations in global and regional kidney perfusion and oxygenation during septic AKI and associated therapies. We justify the need for investigation of the effects of therapies on renal microcirculatory perfusion and oxygenation. We propose that interventions that do not worsen the underlying renal pathophysiologic and reparative processes in sepsis will reduce the development and/or progression of AKI more effectively.

Section snippets

RENAL MACROCIRCULATORY ABNORMALITIES IN SEPSIS

Sepsis is characterized by systemic vasodilation mediated by increased production of vasodilators such as nitric oxide (NO) and prostaglandins, which can alter renal macrocirculatory and microcirculatory perfusion and oxygenation significantly. In rodent models of sepsis, characterized by hypodynamic circulation with decreases in cardiac output (CO), the development of AKI is associated with global renal ischemia, cellular damage, and acute tubular necrosis.7,8,10,11 However, in human beings12

HYPODYNAMIC VERSUS HYPERDYNAMIC SEPSIS AND THE EFFECTS OF ANESTHESIA

Renal tissue hypoxia is a common pathophysiologic feature of AKI in animal models of hypodynamic and hyperdynamic sepsis (Table 1). An important distinction in animal models of hypodynamic sepsis is that hypoxia is observed within both the renal cortex and medulla, which is not surprising considering the associated reductions in CO and RBF. In contrast, CO and RBF appear to remain either unchanged13,14,21 or even be increased22, 23, 24, 25, 26 in nonanesthetized, large animal models of

RENAL MICROCIRCULATORY ABNORMALITIES IN SEPSIS

Microcirculatory abnormalities are a hallmark of sepsis within vital organs, including the heart, gut, liver, and brain.34 There is now compelling evidence in conscious sheep with hyperdynamic sepsis that despite increased RBF, RDO2, and preserved renal cortical perfusion and tissue oxygen tension (Po2), selective ischemia and hypoxia occur within the renal medulla (Table 1).22, 23, 24, 25, 26 Within the renal microcirculation, reductions in renal cortical peritubular capillary flow in rodent

SUSCEPTIBILITY OF THE RENAL MEDULLA TO HYPOXIA

Multiple factors may render the renal medulla particularly susceptible to hypoxia under pathophysiologic settings.39 These include limitations in oxygen diffusion to the thick ascending limbs of the loop of Henle and collecting ducts owing to the topography of the vascular bundles in the renal medulla. For example, in the outer medulla the thick ascending limbs of Henle's loop lie at the periphery of these vascular bundles,40 however, they require an adequate supply of oxygen for active sodium

DOES MEDULLARY HYPOXIA REDUCE GFR?

Both renal medullary tissue hypoxia and reduced GFR are hallmarks not only of septic AKI, but also of other forms of AKI of diverse etiology.50 However, the mechanistic link between these two phenomena remains to be identified, although it is important to be aware that this may be different depending on the etiology of the AKI. One potential mechanism involves tubuloglomerular feedback (TGF). That is, hypoxia in the medullary thick ascending limb of Henle's loop could lead to reduced adenosine

GOAL-DIRECTED THERAPIES AND MEDULLARY OXYGENATION

Oxygen consumption in renal tissue is dominated by the energy requirements of the sodium-potassium adenosine triphosphatase needed to drive tubular sodium reabsorption. Consequently, renal oxygen consumption is linked directly to the filtered tubular load of sodium and thus GFR.39 Accordingly, any therapy that increases GFR theoretically should increase renal oxygen consumption and reduce renal medullary tissue Po2. Now that we appreciate the harmful effects of renal medullary hypoxia in the

FLUID RESUSCITATION

Hemodynamic management with fluid bolus therapy is the mandated first-line intervention for sepsis to improve organ perfusion and oxygenation.9 However, clinical trials in human beings with septic AKI, using aggressive fluid resuscitation protocols have all failed to show any improvement in renal outcomes.54, 55, 56 In anesthetized rodents, fluid therapy increased RBF and renal papillary tissue perfusion,57 which could increase RDO2 and renal tissue Po2. On the other hand, fluid-induced

NOREPINEPHRINE

Norepinephrine is endorsed as the first-choice vasopressor to restore blood pressure in septic patients with and without AKI.9 In human sepsis, norepinephrine consistently has been found to restore blood pressure with fewer adverse side effects than dopamine, vasopressin, epinephrine, or phenylephrine.63, 64, 65, 66 Similarly, in experimental ovine septic AKI, norepinephrine was found to be efficient at restoring blood pressure without any adverse effects on RBF and RDO2, at least at the

VASOPRESSIN

Vasopressin currently is recommended only as a rescue vasopressor for patients with sepsis who have become unresponsive to norepinephrine or epinephrine and/or for reducing the doses of such catecholamines.9 This is primarily owing to the concern that high doses of vasopressin (>0.05 IU/min) can induce myocardial, digital, and mesenteric ischemia.72 In accord, restoring blood pressure even with low-dose vasopressin (0.02 IU/min) reduced mesenteric blood flow and vascular conductance by

ANGIOTENSIN II

Angiotensin II is an endogenous circulating hormone that has a potent vasoconstrictor action, particularly on the renal vascular bed.75 Treatment with angiotensin II in early ovine septic AKI had a number of beneficial effects: it restored blood pressure to presepsis levels and improved urine flow and creatinine clearance without adverse effects on blood flow to vital organs or on blood lactate or renal bioenergetics.76,77 Similarly, in a pilot study in patients with sepsis, angiotensin II was

FUROSEMIDE

The loop diuretic furosemide is used commonly in intensive care units to correct oliguria and positive fluid balance in patients with septic AKI.9 Furosemide induces potent diuretic and natriuretic effects not only by inhibiting the sodium-potassium-two-chloride (NaKCC2) cotransporter in the thick ascending limb of Henle's loop, but also by inhibiting the NaKCC2 within the macula densa, and thus blocking the TGF mechanism.82 A reduction in active sodium reabsorption within the medullary tubular

ESTIMATING RENAL MEDULLARY TISSUE OXYGEN TENSION BY MEASURING BLADDER URINARY OXYGEN TENSION

The results presented earlier indicate that measurement of renal medullary Po2 would be useful for monitoring the onset and degree of AKI. However, it is not clinically feasible to directly monitor renal medullary tissue Po2 in critically ill patients with septic AKI. Nevertheless, given the common occurrence of renal medullary hypoxia in multiple forms of AKI,5,6,8 it would be extremely useful to develop a noninvasive technique to estimate medullary tissue Po2. Our research group recently

CONCLUSIONS

In experimental hyperdynamic septic AKI there is an uncoupling of the renal macrocirculation and microcirculation, so despite preserved whole-organ blood flow and oxygen delivery, localized tissue ischemia and hypoxia can occur. The renal medulla appears to be particularly susceptible to developing hypoxia during the early stages of sepsis. An early onset of renal medullary hypoxia in sepsis may initiate a downward spiral of oxidative stress, inflammation, mitochondrial dysfunction, and tubular

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    Financial support: The studies referred to from the Clive N. May laboratory were funded by National Health and Medical Research Council of Australia grants 454615, 1009280, 1050672, and 1122455. Also supported by a Future Leader Postdoctoral Fellowship from the National Heart Foundation of Australia (101853 to Yugeesh R. Lankadeva).

    Conflict of interest statement: none.

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