Abstract
Ischemia reperfusion (IR) injury can cause acute kidney injury. It has previously been reported that kidney oxygen consumption (QO2) in relation to glomerular filtration rate (GFR), and thus tubular sodium load, is markedly increased following IR injury, indicating reduced electrolyte transport efficiency. Since proximal tubular sodium reabsorption (TNa) is a major contributor to overall kidney QO2, we investigated whether inhibition of proximal tubular sodium transport through carbonic anhydrase (CA) inhibition would improve renal oxygenation following ischemia reperfusion. Anesthetized adult male Sprague Dawley rats were administered the CA inhibitor acetazolamide (50 mg/kg bolus iv), or volume-matched vehicle, and kidney function, hemodynamics and QO2 were estimated before and after 45 minutes of unilateral complete warm renal ischemia. CA inhibition per se reduced GFR (-20%) and TNa (-22%), while it increased urine flow and urinary sodium excretion (36-fold). Renal blood flow was reduced (-31%) due to increased renal vascular resistance (+37%) without affecting QO2. IR per se resulted in similar decrease in GFR and TNa, independently of CA activity. However, the QO2/TNa ratio following ischemia-reperfusion was profoundly increased in the group receiving CA inhibition, indicating a significant contribution of basal oxygen metabolism to the total kidney QO2 following inhibition of proximal tubular function after IR injury. Ischemia increased urinary excretion of kidney injury molecule-1, an effect that was unaffected by CA. In conclusion, this study demonstrates that CA inhibition further impairs renal oxygenation and does not protect tubular function in the acute phase following IR injury. Furthermore, these results indicate a major role of the proximal tubule in the acute recovery from an ischemic insult.
Highlights
Acute kidney injury (AKI), a sudden decline in renal function, is a common feature in the critically ill patient in the emergency and intensive care setting and is associated with a significant increase in morbidity and mortality [1, 2]
The kidneys receive about 20% of cardiac output under normal physiological conditions, which mainly perfuses the cortex, whereas the renal medulla is functioning on the brink of hypoxia receiving only 10% of total renal blood flow (RBF)
Since proximal tubular reabsorption of Na (TNa) is a major contributor to overall renal QO2 we investigated the impact of reduced proximal TNa, achieved by carbonic anhydrase (CA) inhibition, on kidney function and oxygenation following Ischemia reperfusion (IR) injury to test the hypothesis that proximal tubular function affects the recovery during the acute phase following an ischemic insult to the kidney
Summary
Acute kidney injury (AKI), a sudden decline in renal function, is a common feature in the critically ill patient in the emergency and intensive care setting and is associated with a significant increase in morbidity and mortality [1, 2]. The kidneys receive about 20% of cardiac output under normal physiological conditions, which mainly perfuses the cortex, whereas the renal medulla is functioning on the brink of hypoxia receiving only 10% of total renal blood flow (RBF) This leaves the renal medulla vulnerable due to its high oxygen consumption (QO2) required to maintain steep osmotic gradients essential to the kidneys ability to concentrate the urine [8]. Since proximal TNa is a major contributor to overall renal QO2 we investigated the impact of reduced proximal TNa, achieved by CA inhibition, on kidney function and oxygenation following IR injury to test the hypothesis that proximal tubular function affects the recovery during the acute phase following an ischemic insult to the kidney
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