Maintaining a balance between the supply and demand of oxygen is vital for
proper organ function. Most types of acute kidney injury (AKI) are characterized
by hypoxia, a state where the supply of oxygen cannot match the demand for normal
cellular activities. Hypoxia results from hypo perfusion and impaired
microcirculation in the kidney. It inhibits mitochondrial oxidative
phosphorylation, resulting in a decrease in production of adenosine triphosphate (ATP), which is essential
to power tubular transport activities, especially reabsorption of Na, and
other vital cellular activities. To ameliorate AKI, the majority of studies have
focused on increasing renal oxygen delivery by restoring renal blood flow and
altering intra-renal hemodynamics. However, to date these approaches remain
inadequate. In addition to augmenting oxygen supply, increasing renal blood flow
also increases glomerular filtration rate, leading to increased solute deliver
and workload for the renal tubules, causing an increase in oxygen consumption.
The relationship between Na reabsorption and oxygen expenditure in the
kidney is linear. Experimental models have demonstrated that inhibition of
Na reabsorption can alleviate AKI. Since the proximal tubules reabsorb
approximately 65% of filtered Na, consuming the largest portion of oxygen,
many studies focus on examining the effects of inhibiting Na reabsorption
in this segment. Potential therapeutics that have been examined include
acetazolamide, dopamine and its analog, inhibitors of the renin-angiotensin II
system, atrial natriuretic peptide, and empagliflozin. The effectiveness of
inhibition of Na reabsorption in the thick ascending limb of the Loop of
Henle by furosemide has been also examined. While these approaches produced
impressive results in animal models, their clinical benefits remain mixed. This
review summarizes the progress in this area and argues that the combination of
increasing oxygen supply with decreasing oxygen consumption or different
approaches to reducing oxygen demand will be more efficacious.