Acute kidney injury (AKI) is defined by a sudden decrease in glomerular filtration rate (GFR), occurring within hours to weeks, along with the retention of nitrogenous waste products and renal parenchymal damage. Examples of AKI include acute tubular necrosis, acute interstitial nephritis, and glomerulonephritis. Based on the Kidney Disease: Improving Global Outcomes criteria, AKI is diagnosed by an absolute increase in serum creatinine levels of at least 0.3 mg/dL (26.5 $\mu$mol/L) within 48 hours, or a 50% increase in serum creatinine from baseline within 7 days, or a urine volume of less than 0.5 mL/kg/h for at least 6 hours [1]. Acute kidney injury occurs in a variety of settings, including major surgeries, transplantation, hemorrhage, burns, sepsis, lower limb ischemia/reperfusion, and the administration of nephrotoxic medications [2, 3, 4, 5, 6]. Conversely, chronic kidney disease (CKD) is the gradual loss of nephrons in both number and function. Chronic kidney disease is diagnosed by a persistent abnormality in kidney structure or function such as GFR 60 mL/min/1.73 m${}^2$ or albuminuria $\ge$30 mg per 24 hours for more than 3 months. Arteriolosclerosis, glomerulosclerosis and tubulointerstitial fibrosis are the common pathologic themes of CKD. Important risk factors for developing CKD include hypertension, diabetes, polycystic kidney disease, and sickle cell disease [7, 8, 9]. Chronic kidney disease can eventually result in end-stage kidney disease. Traditionally, AKI and CKD were considered as separate entities. However, newer paradigms recognize continuity between these two diseases, with AKI resulting in CKD and CKD being a recognized risk factor for AKI [7, 9].

Acute kidney injury is associated with poor outcomes. Acute kidney injury is independently associated with both short and long-term morbidity and mortality [6, 10, 11, 12, 13]. For example, a recent study of 1286 COVID-19 patients in Belgium demonstrated that all stages of AKI were associated with increased ICU mortality rates with 9.3% at stage 1, 40.1% at stage 2 and 47.0% at stage 3 compared to 3.6% with no AKI [14]. Furthermore, the incidence of AKI is steadily rising due to an aging population, increased prevalence of CKD, and improved recognition by physicians [15]. In addition to the high human cost, AKI imposes a heavy financial burden on society. In the United States, the in-hospital costs for AKI ranged from $\$$5.4 to $\$$24.0 billion annually [16]. In Queensland, Australia, a study found that the mean total hospital cost in patients with AKI was more than triple that of patients without AKI ($\$$93,042 vs $\$$30,778) [17].

In order to achieve clearance, the human kidney filters approximately 180 liters of blood each day. This filtrate is composed of both harmful metabolites and essential elements for life, such as NaCl, amino acids, and glucose. Approximately 99% of water and ions, and 100% of amino acids and glucose are reabsorbed by the renal tubules through the transcellular and paracellular pathways. The Na${}^{+}$,K${}^{+}$-ATPase is fundamental for the absorptions. In the transcellular pathway, it keeps the intracellular Na${}^{+}$ electrochemical potential lower than the extracellular one, which allows Na${}^{+}$ and Na${}^{+}$-coupled reabsorption [18, 19, 20, 21]. In the paracellular pathway, the Na${}^{+}$,K${}^{+}$-ATPase-dependent ion transport generates the transepithelial voltage favoring certain ion absorption [21]. In aerobic states ATP is generated by mitochondria predominantly through oxidative phosphorylation. To meet the demand of mitochondria for oxygen, the kidney has the largest blood supply (approximately 25% of cardiac output) only next to the heart under a resting state [22]. There is an almost perfect linear relationship between Na${}^{+}$reabsorption and oxygen consumption by the kidney [23]. In addition to supporting aerobic metabolism, oxygen is also needed to generate reactive oxygen species which, at a low level, signal many fundamental cellular activities [24].

Despite diverse etiologies, the majority of AKI sub types share common pathophysiologic mechanisms, including microvascular dysfunction and inflammation [3]. Microvascular dysfunction leads to hypoxia. Hypoxia is a state where oxygen supply cannot meet oxygen demand, which has a profound impact on kidney function (Fig. 1). Artificially induced hypoxia by increasing oxygen consumption with triiodothyronine without other compounding factors induces kidney injury in rats [25]. Similarly, treating rats with normobaric hyperoxia per se helps renal recovery from warm ischemia-induced injury [26]. Hypoxia compromises mitochondrial aerobic metabolism by diminishing nicotinamide adenine dinucleotide hydrogen (NADH) supply and electron transport [27]. Hypoxia leads to the accumulation of non-esterified fatty acids, which contributes to activation of pro-inflammatory pathways and produces reactive oxygen species, resulting in apoptosis and necrosis [28, 29]. Furthermore, inflammation directly inhibits mitochondrial respiration. As a result, the ability of mitochondria to generate ATP is compromised and the cellular ATP levels are reduced in AKI [30]. Therefore, AKI has been broadly characterized as a state of tubular ATP depletion [31].

Fig. 1.

A common mechanism for acute kidney injury.

To make matters worse, the efficiency of the kidney in using oxygen to reabsorb Na${}^{+}$ is reduced in AKI. Redfors et al. [32] measured renal blood flow, oxygen extraction, Na${}^{+}$ filtration and excretion in 12 patients with AKI and 37 patients without AKI in a cardiothoracic intensive care unit. They found that renal blood flow was reduced by 40% and renal Na${}^{+}$ reabsorption was reduced by 59% in subjects with AKI. However, renal oxygen extraction was increased by 68% in patients with AKI compared to those without AKI. This resulted in an approximately 2.4-fold increase in the amount of oxygen required to absorb the same amount of Na${}^{+}$ [32]. Similar results were also found for sepsis-induced AKI in humans, rats, and mice [30, 33, 34]. A potential reason for this decrease in efficiency is the loss of epithelial polarization and tight junction integrity, which cause back leak and make Na${}^{+}$ transport less efficient [32, 34, 35, 36]. This has been observed in the mouse kidney after ischemia/reperfusion- and endotoxemia-induced injury [37, 38]. Inhibition of nitric oxide synthase more than doubles renal oxygen extraction/Na${}^{+}$ reabsorption in dogs and rats [39, 40]. It is also possible that AKI damages endothelial cells and inhibits endothelial nitric oxide synthase, leading to inefficient use of oxygen for Na${}^{+}$ reabsorption [32, 34, 35, 36]. Regardless of the cause, if more ATP is consumed for reabsorption of Na${}^{+}$, less ATP will be left for maintenance of cell integrity, resulting in cellular injury.

To restore the balance between oxygen supply and demand, many studies have examined increasing oxygen supply. Examples include fluid resuscitation, vasoconstrictors and removing the underlying cause of AKI (e.g., antibiotics and nephrotoxic medications). These approaches have been reviewed previously [41, 42, 43]. While these approaches unarguably improve patient outcomes, they are clearly insufficient. In most tissues, increasing blood flow will increase tissue oxygenation, however, the kidney is an exception to this rule. The variation in plasma Na${}^{+}$ concentrations is minimal in both healthy and disease states. Therefore, the delivery of Na${}^{+}$ into tubules is directly correlated to GFR. An increase of renal blood flow increases GFR, resulting in increased Na${}^{+}$ delivery and subsequent Na${}^{+}$ reabsorption and oxygen consumption [35, 36]. For example, infusion of a vasodilator atrial natriuretic peptide (ANP) to postoperative patients with normal renal function increases GFR by 15%, Na${}^{+}$ reabsorption by 9%, and oxygen consumption by 25% [44]. Although direct evidence is lacking, since approaches that increase renal blood flow inherently raise oxygen demand, it is unlikely that these treatments alone will be able to restore the supply-demand balance [35, 36].

Reducing oxygen demand is another way to maintain the supply-demand balance of oxygen when supply is low. Western painted turtles (Chrysemys picta) can survive under water with little oxygen for as long as 30 hours. They tolerate anoxia in part by reducing Na${}^{+}$ channels and metabolism in the hepatocytes and brain (channel arrest), therefore, reducing oxygen consumption [45, 46]. A similar defensive mechanism may occur in AKI. In one study, mitochondrial oxygen consumption in the proximal tubules is reduced 4 hours after septic AKI despite increased mitochondrial content and biogenesis [30]. This reduction in oxygen consumption is most likely due to reduced demand for ATP synthesis [30]. The Na${}^{+}$-H${}^{+}$ exchanger 3 (NHE3) reabsorbs approximate 65% of Na${}^{+}$ in the proximal tubules [47]. The NHE3-dependent pathway is one of the large oxygen consumers in the renal cortex, if not the largest. Acute kidney injury induced by ischemia/reperfusion, injection of lipopolysaccharides or mercury chloride decreases mRNA and protein levels of NHE3 in murine models [48, 49, 50, 51]. In human AKI, there is a loss of the brush border in the proximal tubules where NHE3 is localized [52]. This down-regulation of NHE3 has been interpreted as a defense mechanism against AKI [53]. The hypoxia-inducible factor (HIF) pathway, a key mediator of cellular adaptation in low oxygen tension states, may be another defense mechanism. Epithelial Na${}^{+}$ channels (ENaC) in the distal nephron participates in Na${}^{+}$ reabsorption. HIF-1$\alpha$ activation by hypoxia reduces expression of the $\gamma$-subunit of ENaC in mice and activity of ENaC in cultured principal cells [54]. Despite marked reduction in renal reabsorption and function, structural injury such as necrosis appears to be relatively mild in AKI [30, 55, 56, 57]. These observations have led to the hypothesis that early organ dysfunction is a defense mechanism that preserves energy to reduce cell injury and death [53].

How can reducing tubular cell injury and death help preserve and/or delay deterioration of GFR? The renal tubular cells are the primary site of injury in AKI. When the tubular cells undergo necrosis or apoptosis, they detach from the supporting basement membrane and obstruct the tubular lumen, causing back leakage of fluid with resultant decreased clearance. Even a sub-lethal injury can disrupt tight junctions, causing a loss of epithelial integrity and back leakage of fluid. The fluid back leakage further diminishes already impaired glomerular filtration induced by hypoperfusion of the kidney, eventually contributing to the filtration failure [58, 59, 60, 61]. Therefore, reducing oxygen demand through inhibition of Na${}^{+}$ transport in the renal epithelial cells may prevent injury and maintain clearance.

The present review summarizes progress in balancing supply and demand to prevent or treat AKI in patients (Table 1, Ref. [62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87]) and animal models. Acute kidney injury is also associated with oxidative stress, which in turn increases oxygen consumption resulting in kidney tissue hypoxia [88, 89]. While various antioxidants have been shown to improve renal oxygenation and ameliorate AKI, reviewing the effect of antioxidants is beyond the scope of this article [90, 91, 92, 93].

Na${}^{+}$-K${}^{+}$-2Cl${}^{-}$ cotransporter (NKCC2) is located in the apical membrane of the epithelial cells in the thick ascending limb of the loop of Henle. It facilitates approximately 20–25% of the reuptake of filtered NaCl. Therefore, oxygen consumption by this segment of nephron is second only to the proximal tubule. Furosemide, a diuretic that inhibits NKCC2, was shown to improve renal oxygenation in patients [44, 198] and reduces ischemia/reperfusion-induced AKI in animal models [199, 200]. However, furosemide has had disappointing results in clinical studies (Table 1). A meta- analysis of 2084 patients in 9 studies found that furosemide combined with intravenous fluids had no significant impact on the incidence of contrast-induced AKI in patients after coronary intervention, but could reduce major adverse cardiovascular events and mortality [201]. Combination of infusing furosemide with dopamine or ANP in patients with AKI after cardiac surgery decreased the need for dialysis and improved dialysis-free survival rates in two studies [82, 83]. However, a systemic review and meta-analysis of randomized clinical trials found that the quantity and quality of evidence for using furosemide to treat AKI in adult post-operative patients were very low with no firm evidence for benefit or harm [202]. Abraham et al. [203] also found that furosemide infusion in early-onset AKI did not reduce the progression to a higher stage of AKI in critically ill children.

Na${}^{+}$,K${}^{+}$-ATPase is localized to the basolateral membrane of the entire renal tubules, from the proximal tubules to the inner medullary collecting ducts. The basolaterally located Na${}^{+}$,K${}^{+}$-ATPase is the only pathway to pump out intracellular Na${}^{+}$ that enters the renal epithelial cells from the apical NHE3, Sglt2, NKCC2 and other Na${}^{+}$-dependent transporters. Inhibition of the apical Na${}^{+}$ entry will reduce the availability of Na${}^{+}$ to Na${}^{+}$,K${}^{+}$-ATPase, thus reducing the activity of the enzyme and oxygen expenditure, whereas stimulation of apical Na${}^{+}$ entry does the opposite. Dopamine inhibits Na${}^{+}$,K${}^{+}$-ATPase activity [204, 205]. Dopamine stimulates cAMP-dependent inhibitory phosphorylation $\alpha$-subunit of the enzyme [206]. The renal dopaminergic system and ANP acted synergistically to produce a potent inhibition of Na${}^{+}$,K${}^{+}$-ATPase [123]. Dopamine and hypoxia induces endocytosis of Na${}^{+}$,K${}^{+}$-ATPase through protein kinase C-dependent phosphorylation of the $\alpha$-subunit [207]. Angiotensin II stimulates Na${}^{+}$,K${}^{+}$-ATPase activity [208], whereas angiotensin 1-7 does the opposite [209]. However, it remains unknown whether these hormones directly regulate Na${}^{+}$,K${}^{+}$-ATPase or indirectly regulate the pump by affecting Na${}^{+}$ entry from the apical membrane [210].

The pathophysiology of AKI is complex, involving hypoperfusion, impaired microcirculation, hypoxia, oxidative stress, abnormal coagulation, and inflammation. There is no single approach that can address all aspects of this complicated pathophysiology. Further, addressing one aspect may exacerbate other aspects, even within the concept of reducing oxygen demand. For example, although furosemide reduces oxygen consumption by inhibiting NKCC2 in the thick ascending limb of the Loop of Henle, it also activates the renin-angiotensin-aldosterone system. Combining different treatments that increase oxygen supply and decrease oxygen consumption or different approaches to reduce oxygen consumption may be a better approach. A good example is the synergistic effect observed with using fenoldopam in combination with furosemide in treatment of AKI in critically ill surgical patients [68].

ACEIs, angiotensin converting enzyme inhibitors; AKI, acute kidney injury; ANP, atrial natriuretic peptide; ARBs, angiotensin receptor blockers; CKD, chronic kidney disease; NHE3, Na${}^{+}$-H${}^{+}$ exchanger 3; NKCC2, Na${}^{+}$-K${}^{+}$-2Cl${}^{-}$ cotransporter; Scr, serum creatinine concentration; Sglt2, Na${}^{+}$-dependent glucose transporter 2.

The content and views expressed in this article are the sole responsibility of the author and do not necessarily reflect the views or policies of the Uniformed Services University or Department of Defense of USA. Mention of trade names, commercial products, or organizations does not imply endorsement by the Uniformed Services University or Department of Defense of USA.

XZ conceived ideas, searched for references, drafted, edited and approved the manuscript.

Not applicable.

The author would like to thank Lieutenant Colonel Ian J. Stewart for his help with editing this manuscript.

This work was supported in part by the United States of America Department of Defense grants W81XWH-22-2-0068 and MED-83-12715.

The author declares no conflict of interest.