Kidney ischemia

Little is known as to what causes ischemic injury in the kidneys; however, several physical insults are stated to be activated during injury. Physical stress such as infarction, surgery and transplant may produce kidney ischemia. Dietary habits and genetics could cause ischemic injury, as well. Diseases such as sepsis can cause kidney ischemia too. Infarction or Physical Injury Infarction is defined as the blockage of blood flow in tissues or organs, which may cause necrosis or death of a group of cells in the tissue. In studies of mice models, clamping of the kidney may result in kidney ischemia. Renal Surgery and Transplant Renal surgery and coronary artery bypass grafting can produce renal ischemia and reperfusion injury. This could lead to an acute kidney injury. Moreover, renal ischemia can cause the delay of graft function after renal transplant and can cause rejection of the transplant. Dietary Habits In studies of mice models, a high-fat diet can induce greater injury to the kidney with renal ischemia-reperfusion as compared to mice with normal diet. This is because in a high-fat diet model, accumulation of phospholipids resulted in enlarged lysosomes within proximal tubular cells. Atherosclerosis is a specific type of arteriosclerosis. Arteriosclerosis is defined as the thickening or stiffening or both of the blood vessels; more specifically, atherosclerosis refers to the buildup of cholesterol and fats in the artery walls. Because the blood vessels carry oxygen and nutrients throughout the body, having atherosclerosis restrict blood flow and consequently prevent necessary nutrients to reach the kidneys. Moreover, several genes have been implicated as risk factors in the development of ischemic injury. Apolipoprotein E Apolipoprotein E are proteins that metabolize fats in the body. In studies of patients undergoing coronary artery bypass grafting, carriers of APO-E e4 allele was found to have a decreased risk of acute kidney injury compared to non-carriers of the allele. Also, studies of IL-60174GG showed that carriers of this polymorphism have a higher creatinine levels in the blood; however, carriers of the G-allele of IL-10 have a decreased risk of death after organ failure. VEGF Unlike with HSP72 polymorphism, infant studies show that VEGF with a homozygous A allele resulted in reduced risk for acute kidney injury. ==Pathophysiology==

Several pathophysiological conditions that change when the kidney is undergoing ischemic injuries are listed below. This includes changes in the vasculature, endoplasmic reticulum stress, disfunction of the mitochondria, autophagy of cells, inflammation, and incorrect or maladaptive repair. Vasculature Normal functions of the kidney require a high amount of oxygen, as such the oxygen supply to the kidney is well regulated. Production of adenosine triphosphate and nitric oxide requires a high concentration of oxygen. These compounds, as well as some reactive oxygen species, are required for the kidney to function properly. With an injury, cellular respiration is compromised. This leads to an imbalance of the supply of oxygen and the products of cellular respiration. When that happens, the kidney undergoes oxidative stress and injury to the microvascular endothelium promotes the recruitment of leukocytes and platelets. This leads to changes in perfusion and oxygen delivery. Endoplasmic Reticulum Stress Misfolded and unfolded proteins accumulate in the endoplasmic reticulum. This triggers the unfolded protein response (UPR). The unfolded protein response is an adaptive mechanism to restore cell and tissue homeostasis. If the stress is too severe, the maladaptive response is activated and the C/EBP Homologous Protein pathway (CHOP) is induced. This leads to apoptosis. When the kidneys undergo inflammatory responses, it produces mediators such as bradykinin, histamine, and pro-inflammatory cytokines such as interleukin-1 and tumor necrosis factor-a. In mice models, studies wherein removal of these mediators from plasma were observed and has shown beneficial to mice. In general, kidney sizes differ in patients with acute kidney ischemia. Hypertension, acute renal failure, progressive azotemia, and acute pulmonary edema are also signs of a developing ischemic injury for hypertensive patients. Kidney size differences In normal patients, the length of the two kidneys only differ by less than 1.5  cm; however, hypertensive patients tend to have an asymmetric kidney size. This strongly suggests ischemic renal disease. This is due to an abnormal narrowing of the arteries. Patients with poorly-controlled hypertension and renal insufficiency usually also have recurrent acute pulmonary edema. While patients may have other risk factors for having pulmonary edema, volume-dependent renovascular hypertension appears to be the dominant factor. == Diagnosis and Screening ==

Screening of Biomarkers is one way to diagnose a patient if their kidney is functioning normally. Biomarkers • Creatinine - Serum creatinine is a standard biomarker to 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. • 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. Imaging Tests Duplex Doppler Sonography 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. 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. Functional Tests 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%. 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. 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. Emerging Treatments 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. 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 ==References==