Reducing Oxygen Demand to Alleviate Acute Kidney Injury

Abstract

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.

Keywords: Na⁺ reabsorption; Na⁺-H⁺ exchanger 3; Na⁺-dependent glucose transporter 2; hypoxia; mitochondria; oxygenation.