define acute kidney injury. however, it is insensitive, nonspecific. also, it is a fairly late marker of damage, highly dependent on diet, skeletal muscle function, and kidney stability. clusterin - clusterin is a protein ubiquitously expressed in different cell lines. secreted clusterin is involved in lipid transport. the cells release clusterin as a response to cell stress. this is due to clusterin being able to protect the cell by reducing oxidative stress and by binding to misfolded proteins. cystatin c - cystatin c is produced in kidney cells and is used as a biomarker. the level of cystatin c is used to determine whether the kidney is functioning well or not since it is removed from the kidney through glomerular filtration. therefore, a high amount of cystatin c in the blood is a determinant of kidney injury. egf - lower levels of egf mrna and proteins in the kidneys are indicative of injury after kidney ischemia and reperfusion. kim-1 - also known as kidney injury model 1 is a protein that is highly expressed upon kidney injury. therefore, higher levels of kim-1 signifies that there is an injury with proximal tubes due to ischemia. il-6 - interleukin-6 expression is a response to ischemia and reperfusion injury linked to renal dysfunction. this is also highly expressed when a transplant of the kidney is rejected. endothelin-1 - endothelin-1 is a vasoconstrictor and can be detected in the urine. more specifically, urinary endothelin-1 levels are used as an acute marker in cold ischemic reperfusion and injury. ngal - neutrophil gelatinase-associated lipocalin 2 is expressed in neutrophils and in low levels in the kidney, prostate, and epithelia of the respiratory and alimentary tracts. (source). ngal is used as a biomarker for kidney injury. this is because a high ngal excretion can be correlated to ischemic insult. ngal is secreted at high levels in the blood and urine within two hours of injury. ima - ischemic modified albumin. ima can be used as an early biomarker for ischemic injury. moreover, the amount of ima in the blood is proportional to the duration of ischemic injury and necrosis factor, as such it can be used as a biomarker to determine how long the injury has been. timp-2 and igfbp7. in the distal tubular regions, there is an elevation of the expression of timp2 and igfbp7 and this is linked to early tubular damage in ischemic injury and reperfusion, as well as acute kidney injury. duplex doppler sonography sonography example duplex doppler sonography(dds) is an imaging test for evaluating blood flow in the kidney or the renal system. b-mode ultrasonography is combined with doppler ultrasonography, to locate and assess the renal artery and the velocity of blood flowing through it. this test is useful even in the presence of azotemia and for patients with hypertension, it is not necessary to relieve the administration of aceis. by assessing the velocity of blood flow, the doctors can measure whether the kidney is receiving enough blood and nutrients to function normally. magnetic resonance angiography similar to dds, magnetic resonance angiography(mra) also images blood vessels. mra uses magnetic resonance and unlike a traditional angiogram, this does not require inserting a catheter. this test can be used to evaluate stenosis and occlusions in the kidney. this test can also be used to determine aneurysms in the brain. more clinical uses of mra is used to check blood vessels in different parts of the body, such as the thorax, lower limbs, and the heart. plasma renin activity plasma renin activity is also known as renin assay. this assay measures the activity of renin, also known as angiotensinogenase, which plays a role in blood pressure regulation and urine output. this is considered a non-invasive test and patients who are taking aceis should opt to take it. this is because it is useful in detecting renovascular hypertension, one of the symptoms of kidney ischemia, with sensitivity going to 90%. however, renal failure may diminish the accuracy of this test. renography after administration of acei renography uses radioisotopes in diagnosing renovascular disease. this test compares normal function of kidney versus stenotic kidney by measuring the amount of the radionucleotides going to the kidney and being excreted by it. two radionuclides are used in renography: tc99m-mag3 (mercaptoacetyltriglycine) and tc99m-dtpa (diethylenetriaminepentacetate). in this test, the radionucleotides are injected intravenously to the system. the compound then progresses through the renal system and is tracked with a gamma camera. the camera then takes images at intervals and a measurement of the radioactivity is taken. by performing this scan, doctors can differentiate between kidney ischemia and intrinsic renal disease by checking the amount of time for the radioactivity to peak and decline. renovascular hypertension is very sensitive to this imaging, with a specificity of 95% and sensitivity of 96%. treatments traditional treatments our knowledge of renal ischemia comes from animal studies. based on these studies, kidney transplants and retrospective partial nephrectomy series indicate the risk of renal function impairment the longer the ischemic injury persists. however, based on historical studies, the use of the duration of the ischemia as a dichotomous marker has been found to have significant flaws in predicting renal function outcomes. the duration of kidney ischemia does not affect kidney function either in the short term or long term. ischemic preconditioning in patients who get a kidney transplant or a coronary artery bypass, ischemic preconditioning is given. in ischemic preconditioning, the kidney is given a tolerable amount of ischemia. this preconditions the kidney to tolerate subsequent ischemia-induced injuries. this reduces cell lysis and apoptosis of kidney cells and improves the overall renal function of the kidneys post-ischemia as compared to not having the preconditioning. furosemide to promote post-perfusion diuresis a vial of furosemide taken intravenously or intramuscularly furosemide is a common diuretic and is used for the prevention or to reverse acute kidney injury. a diuretic is a substance that promotes excretion of water from the body. when the kidneys undergo ischemia, it leads to reperfusion or a return of blood supply to the organs. as such, using diuretics has helped in getting rid of excess water in the kidneys after reperfusion. taking furosemide as a tablet, as a liquid solution, or via injection is used as a preventative measure or as treatment of kidney ischemia has shown to reduce the severity of renal failure, reduce apoptosis induced by ischemia, and speed the recovery of renal function. this as also lead to the reduction of the need of surgical renal replacement in some patients. fenoldopam mesylate fenoldopam is used postoperatively in treating acute kidney injury, if used before kidney damage. similar to furosemide, this can be taken orally or intravenously; however, bioavailability, or the amount of the drug that reaches the blood circulation, is reduced if taken orally. fenoldopam is used as a vasodilator and can increase blood flow to the kidneys, as well as renin secretion. thus, it can be used to regulate the blood pressure in the arteries and reduce injury due to ischemia. bendavia bendavia is currently in clinical studies targeting mitochondrial dysfunction. it is protective in rat models of kidney ischemia when it was administered before the injury. bendavia binds to cardiolipin on the inner mitochondrial membrane and this inhibits cytochrome c peroxidase activity. this protects respiration during the early reperfusion and accelerates the recovery of atp. in the animal models, it was found that tubular cell death and dysfunction were reduced. therapeutic gases: co, no, and h2s this figure shows how carbon monoxide, nitric oxide, and hydrogen sulfide help in attenuating kidney ischemia by reducing inflammation, tissue injury, hypoxia, apoptosis of cells, and vasoconstriction. this was drawn using biorender.com carbon monoxide (co) helps in stabilizing hif, which helps in regulating autophagy and hypoxic response. through this, inflammation and tissue injury are stabilized. nitric oxide (no) is a byproduct of the metabolism of arginine to citrulline by no synthase. this gas is available in all cells, and inhalation of no has been found to be therapeutically active. this reduces pulmonary vasoconstriction and lessens apoptosis during renal ischemia. hydrogen sulfide (h2s) is also an endogenous product of metabolic activity in cells. this is a byproduct of the metabolism of cysteine by cystathionine-b-synthase. like with no, inhalation of h2s has been found to be therapeutic and has been shown to stabilize hypothermia and stabilize cardiovascular hemodynamics which protects from ischemic injury. mesenchymal stem cell mesenchymal stem cells (mscs) are multipotent mature stem cells that are capable of differentiating into different types of cells. this is a promising line of therapy as regenerative medicine has shown benefits in the restoration of the kidneys. mscs have anti-inflammatory properties and has been applied in animal and human patients. because of their regenerative capabilities, the kidney can benefit from it by transdifferentiation into kidney cells. moreover, they can give anti-inflammatory and immuno-modulatory properties and therefore protecting the kidney as well as repairing it from ischemic injury. outcome ischemic kidney injury might result in fibrosis, irreversible renal dysfunction, and a need for renal replacement therapy. acute kidney ischemia is associated with high mortality. chronic ischemic kidney disease (cikd) usually involves loss of renal parenchyma or reduction of gfr caused by gradual vascular obstruction. clinically, the term “ischemic renal disease” most often describes cikd, which contributes to 6–27% of end-stage kidney disease, particularly among patients older than 50 years