Kidney ischemia is a disease with a high morbidity and mortality rate. Blood vessels shrink and undergo apoptosis which results in poor blood flow in the kidneys. More complications happen when failure of the kidney functions result in toxicity in various parts of the body which may cause septic shock, hypovolemia, and a need for surgery. What causes kidney ischemia is not entirely known, but several pathophysiology relating to this disease have been elucidated. Possible causes of kidney ischemia include the activation of IL-17C and hypoxia due to surgery or transplant. Several signs and symptoms include injury to the microvascular endothelium, apoptosis of kidney cells due to overstress in the endoplasmic reticulum, dysfunctions of the mitochondria, autophagy, inflammation of the kidneys, and maladaptive repair.
Kidney ischemia can be diagnosed by checking the levels of several biomarkers such as clusterin and cystatin C. While the duration of ischemia was used as a biomarker, it was found that it has significant flaws in predicting renal function outcomes. More emerging treatments are in the clinical trials such as Bendavia in targeting mitochondrial dysfunction and using Mesenchymal Stem Cell Therapy. Several receptors agonists and antagonists have shown promise in animal studies; however, they have not been proven clinically yet.
Causes 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. This accumulation of phospholipids lead to an increase aggregation of ubiquitin in the kidney cells. When this happens, autophagy becomes exaggerated and results in malfunction of the mitochondria and inflammation of the tissue.
Atherosclerosis A common cause of ischemic renal disease is atherosclerosis. 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. This accounts for 60-97% of renal arterial lesions, which could lead to the occlusion of the renal artery and ischemic atrophy of the kidneys.
Genetics Several genetic pathways that lead to apoptosis of kidney cells have been implicated in mice models and in-vitro assays. These are proapoptotic genes that can be categorized in two: extrinsic and intrinsic pathways. The extrinsic pathway are directly induced upon renal ischemic injury, while intrinsic pathways are dependent on mitochondrial signaling pathways. Moreover, several genes have been implicated as risk factors in the development of ischemic injury.
Extrinsic Pathway Activation of pro-caspase 8 initiates apoptosis via signaling from cell-surface death receptors such as Fas proteins and their ligands FADD and DAXX. This series of signaling cascade generally regulates programmed cell-death or apoptosis. Upregulation of Fas and FADD protein has occurred in mice models after a 24h period of ischemic injury. This is also shown in cell-based assays wherein tubule cells are monitored after ischemic-like injury. This shows that the Fas-pathway may play a role in the pathogenesis of the apoptosis of tubule cells during the early ischemic-reperfusion period. The role of DAXX is still unclear; however, DAXX mediates both Fas-dependent and TGF-beta-induced apoptosis and renal induction of TGF-beta is well documented in renal ischemia studies.
Intrinsic Pathway Activation of pro-caspase 9 is dependent on mitochondrial signaling pathways which are regulated by the Bcl-2 family of proteins. Activation of Bcl-2 proteins such as Bax and Bak triggers a signaling cascade that results in the release of cytochrome c into the cytosol. This then activates pro-caspase 9 and results in apoptosis of the cells.
Genetic Risk Factors Polymorphisms in genes have been shown to increase or decrease risk of renal ischemic injury. Genes such as Apolipoprotein E (APO E), which controls cholesterol metabolism, NADPH Oxidase which regulates oxidative stress, Angiotensin-converting enzyme (ACE) for vasomotor regulation, HSP72 which helps in tolerance of ischemic injury, Interleukin cytokines which is an inflammation modulator, and VEGF which regulates angiogenesis or the formation of blood vessels have all been shown to have significant effects in acute kidney 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.
NADPH Oxidase NADPH Oxidase regulates oxidative stress by conjugating with reactive oxygen species in cells. Polymorphisms in NADPH Oxidase p22phox and with the T allele has been shown to have a greater risk of dialysis and mortality.
Angiotensin-converting Enzyme Angiotensin-converting enzyme regulates vasomotor movement by controlling blood pressure going through the kidneys. Similarly to the APO-E polymorphism, patients with the D-allele for ACE has an increased risk of acute kidney injury after coronary artery bypass grafting, as well.
HSP72 In infant studies, it was shown that HSP72 gene with the G allele gave an increased risk for acute kidney injury.
Interleukin Researchers have found that IL-17C is activated in kidney injury. In hypoxia-induced studies of mice, an upregulation of the synthesis of IL-17C was evident upon oxygen loss in the kidney. Moreover, Knockout variants of the IL-17C decreased the inflammation caused by activation of IL-17C.Using antibodies and siRNA against IL-17C also provided the same results. 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.
Mitochondrial Dysfunction In acute kidney ischemia, the proximal tubules are vulnerable to mitochondrial dysfunction because they rely on aerobic metabolism and they are in a more oxidized state as compared to the distal tubules. When mitochondrial dysfunction happens, cellular respiration is disrupted. This leads to the mitochondria releasing pro-apoptotic proteins such as cytochrome c and end up in the death of kidney cells.
Autophagy During ischemic stress, the cross-talk between the mitochondria and the UPR is activated. This results in autophagy by which proteins, organelles, and cytoplasmic components are recycled and degraded by the lysosomes. The process of autophagy helps in removing unnecessary components of the cells to maintain more important functions. In this case, autophagy is induced in kidneys in response to hypoxia to protect against further kidney injury.
Inflammation The renal inflammatory process involves events that lead to injury or death of renal cells. 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.
Maladaptive Repair When an injury is severe, the adaptive responses that are activated to restore normal cell and tissue homeostasis become maladaptive. This leads to cell and tissue malfunction. This could lead to chronic kidney disease progression.
Physical Symptoms
Kidney features can be clinically suggestive of renal ischemia. Because renal failure can be correlated to hypertension, both of these situations have been observed. 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.
Renovascular hypertension Renovascular hypertension or renal artery stenosis is characterized as an increase in blood pressure through the arteries to the kidneys. This is due to an abnormal narrowing of the arteries.
Acute Renal Failure caused by the treatment of hypertension In patients with hypertension, treatment of the disease using Angiotensin-converting enzyme inhibitors (ACEIs) are sometimes necessary. The glomerular filtration rate (GFR) in patients is regulated by vasoconstriction of the efferent arteriole. When ACEI is taken by the patient, this vasoconstrictor effect of the efferent arteriole is blocked. This then leads to a decrease in GFR and leads to acute renal failure. Studies have shown that 6-38% of patients with renal vascular disease or hypertension will develop acute renal ischemia through acute renal failure.
Progressive Azotemia (with Renovascular Hypertension, refractory or severe hypertension, or atherosclerotic diseases)