Lipocalin-2 (LCN2), also known as oncogene 24p3 or neutrophil gelatinase-associated lipocalin (NGAL), is a protein that in humans is encoded by the LCN2 gene. [5] [6] [7] NGAL is involved in innate immunity by sequestering iron and preventing its use by bacteria, thus limiting their growth. [8] It is expressed in neutrophils and in low levels in the kidney, prostate, and epithelia of the respiratory and alimentary tracts. [7] [9] NGAL is used as a biomarker of kidney injury. [10]
The binding of NGAL to bacterial siderophores is important in the innate immune response to bacterial infection. Upon encountering invading bacteria, the toll-like receptors on immune cells stimulate the synthesis and secretion of NGAL. Secreted NGAL then limits bacterial growth by sequestering iron-containing siderophores. [11] [12] [13] Lipocalin-2 binds, next to bacterial siderophores, also to the mammalian siderophore 2,5-dihydroxybenzoic acid (2,5-DHBA). This complex ensures that excess free iron does not accumulate in the cytoplasm. Mammalian cells lacking 2,5-DHBA accumulate abnormal intracellular levels of iron leading to high levels of reactive oxygen species. [14] Lipocalin-2 also functions as a growth factor [12] and participates in synaptic plasticity. [15]
As NGAL is protease resistant and has a low molecular weight, it is excreted and detectable in urine. [16] Injured epithelial cells in the kidney secrete a monomeric form of NGAL, whereas activated neutrophils secrete a dimeric form. It has therefore been hypothesized that classification of NGAL form could improve acute kidney injury (AKI) diagnostics, by distinguishing NGAL of inflammatory origin from that of renal origin. [17] In AKI patients, NGAL levels are however elevated in both blood and urine within two hours of injury [18] and plasma NGAL been shown to be predictive of dialysis need. [19] NGAL has also be associated with chronic kidney disease, contrast induced nephropathy, kidney transplant, [20] and mortality. [19]
Kidney health is most frequently measured by serum creatinine. Serum creatinine is a marker of kidney function, whereas NGAL is a marker of kidney injury. [21] NGAL levels are a more precise and sensitive marker for diagnosing AKI than serum creatinine levels. Therefore, monitoring NGAL levels reduces delayed AKI diagnosis and treatment. [22] Using a more sensitive and specific marker allows for earlier diagnosis, correct responses to AKI, and reduced risk of morbidity and mortality. [23]
The NGAL level measured in an individual is proportional to the severity of the AKI. [23] Individuals positive for NGAL tend to have higher incidence of renal replacement therapy and have higher rates of in-hospital mortality, both in the presence and the absence of serum creatinine. [23] Therefore, an individual may have AKI without the presence of serum creatinine.
The ability to diagnose AKI before acute kidney failure is financially beneficial and favorable for preventative health measures. [24] More than 10% of people in the United States will develop some kind of chronic kidney disease (CKD), with higher incidences for individuals that suffer from obesity, elevated cholesterol, and a family history of CKD. There is no point of return once there is a significant injury to the kidney; therefore, early diagnosis of kidney injury is important for preventing AKI. Using NGAL as a biomarker can lower hospital costs because fewer patients will reach a critical stage in kidney injury. Ultimately, diagnosis of AKI with NGAL can reduce the time a patient stays in a hospital. For example, the early diagnosis of AKI with NGAL as a biomarker can help a patient avoid kidney dialysis.
LCN2 was found to be upregulated in postmortem human brains with Alzheimer's disease. [25] Application of LCN2 to in vitro 3D human astroglia, it reduces neurogenic potential and enhances reactive states. LCN2 activity can be blocked with NGFR signaling. [25]
Renal expression of NGAL increases in the kidneys after injury for a variety of reasons. The level of NGAL in the urine and plasma increases within 2 hours of kidney injury. It is possible to measure NGAL in serum or urine in the range of 25 to 5,000 ng/mL by current laboratory tests. [26] Low levels for NGAL have been considered to be 200 ng/mL, medium levels 400 ng/mL, and high levels 800 ng/mL. [26]
A study on children with pediatric cardiopulmonary bypass operations showed that urinary NGAL concentrations above 50 ng/mL 2 hours after surgery is indicative of serum creatinine levels 50% over basal values. Normally, children tend to have almost undetectable levels of NGAL. [27] Therefore, studies that include children are considered to be “pure.” Adult patients presenting for cardiopulmonary bypass surgery are not considered to be “pure” in NGAL studies because adults often have other disorders such as inflammatory conditions, which can cause slight increases in NGAL.[ citation needed ]
AKI studies investigating the use of NGAL as a biomarker often compare serum creatinine and NGAL production. Unfortunately, serum creatinine production is variable and can reflect hemodynamic variation in the glomerular filtration rate formerly known as prerenal azotemia; therefore, the comparison is not always reliable because creatinine and NGAL measure different components of renal (dys)function. [16] The demonstration that NGAL does not rise in the setting of transient changes in creatinine can help clinicians determine whether changes in creatinine reflect kidney damage or rather only non specific or mild functional changes in kidney function.
Lipocalin-2 (NGAL) is typically assessed for clinical or research purposes using ELISA or immunoturbidimetric assays.
Lipocalin-2 (NGAL) was approved by the US FDA (Dec 7, 2023) to detect injury leading to worsening renal function. NGAL was approved previously in Japan (2017) and Europe to detect kidney damage in patients.
Nephrology is a specialty for both adult internal medicine and pediatric medicine that concerns the study of the kidneys, specifically normal kidney function and kidney disease, the preservation of kidney health, and the treatment of kidney disease, from diet and medication to renal replacement therapy. The word "renal" is an adjective meaning "relating to the kidneys", and its roots are French or late Latin. Whereas according to some opinions, "renal" and "nephro" should be replaced with "kidney" in scientific writings such as "kidney medicine" or "kidney replacement therapy", other experts have advocated preserving the use of renal and nephro as appropriate including in "nephrology" and "renal replacement therapy", respectively.
Azotemia is a medical condition characterized by abnormally high levels of nitrogen-containing compounds in the blood. It is largely related to insufficient or dysfunctional filtering of blood by the kidneys. It can lead to uremia and acute kidney injury if not controlled.
Creatinine is a breakdown product of creatine phosphate from muscle and protein metabolism. It is released at a constant rate by the body.
Rhabdomyolysis is a condition in which damaged skeletal muscle breaks down rapidly, often due to high intensity exercise over a short period of time. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some of the muscle breakdown products, such as the protein myoglobin, are harmful to the kidneys and can cause acute kidney injury.
Kidney failure, also known as end-stage renal disease (ESRD), is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as either acute kidney failure, which develops rapidly and may resolve; and chronic kidney failure, which develops slowly and can often be irreversible. Symptoms may include leg swelling, feeling tired, vomiting, loss of appetite, and confusion. Complications of acute and chronic failure include uremia, hyperkalemia, and volume overload. Complications of chronic failure also include heart disease, high blood pressure, and anaemia.
Acute kidney injury (AKI), previously called acute renal failure (ARF), is a sudden decrease in kidney function that develops within 7 days, as shown by an increase in serum creatinine or a decrease in urine output, or both.
Nephrotoxicity is toxicity in the kidneys. It is a poisonous effect of some substances, both toxic chemicals and medications, on kidney function. There are various forms, and some drugs may affect kidney function in more than one way. Nephrotoxins are substances displaying nephrotoxicity.
Acute tubular necrosis (ATN) is a medical condition involving the death of tubular epithelial cells that form the renal tubules of the kidneys. Because necrosis is often not present, the term acute tubular injury (ATI) is preferred by pathologists over the older name acute tubular necrosis (ATN). ATN presents with acute kidney injury (AKI) and is one of the most common causes of AKI. Common causes of ATN include low blood pressure and use of nephrotoxic drugs. The presence of "muddy brown casts" of epithelial cells found in the urine during urinalysis is pathognomonic for ATN. Management relies on aggressive treatment of the factors that precipitated ATN. Because the tubular cells continually replace themselves, the overall prognosis for ATN is quite good if the underlying cause is corrected, and recovery is likely within 7 to 21 days.
Protein toxicity is the effect of the buildup of protein metabolic waste compounds, like urea, uric acid, ammonia, and creatinine. Protein toxicity has many causes, including urea cycle disorders, genetic mutations, excessive protein intake, and insufficient kidney function, such as chronic kidney disease and acute kidney injury. Symptoms of protein toxicity include unexplained vomiting and loss of appetite. Untreated protein toxicity can lead to serious complications such as seizures, encephalopathy, further kidney damage, and even death.
Interstitial nephritis, also known as tubulointerstitial nephritis, is inflammation of the area of the kidney known as the renal interstitium, which consists of a collection of cells, extracellular matrix, and fluid surrounding the renal tubules. It is also known as intestinal nephritis because the clinical picture may include mesenteric lymphadenitis in some cases of acute pyelonephritis. More specifically, in case of recurrent urinary tract infection, secondary infection can spread to adjacent intestine. In addition to providing a scaffolding support for the tubular architecture, the interstitium has been shown to participate in the fluid and electrolyte exchange as well as endocrine functions of the kidney.
Contrast-induced nephropathy (CIN) is a purported form of kidney damage in which there has been recent exposure to medical imaging contrast material without another clear cause for the acute kidney injury.
Phosphate nephropathy or nephrocalcinosis is an adverse renal condition that arises with a formation of phosphate crystals within the kidney's tubules. This renal insufficiency is associated with the use of oral sodium phosphate (OSP) such as C.B. Fleet's Phospho soda and Salix's Visocol, for bowel cleansing prior to a colonoscopy.
The lipocalins are a family of proteins which transport small hydrophobic molecules such as steroids, bilins, retinoids, and lipids, and most lipocalins are also able to bind to complexed iron as well as heme. They share limited regions of sequence homology and a common tertiary structure architecture. This is an eight stranded antiparallel beta barrel with a repeated + 1 topology enclosing an internal ligand binding site.
Rapidly progressive glomerulonephritis (RPGN) is a syndrome of the kidney that is characterized by a rapid loss of kidney function, with glomerular crescent formation seen in at least 50% or 75% of glomeruli seen on kidney biopsies. If left untreated, it rapidly progresses into acute kidney failure and death within months. In 50% of cases, RPGN is associated with an underlying disease such as Goodpasture syndrome, systemic lupus erythematosus or granulomatosis with polyangiitis; the remaining cases are idiopathic. Regardless of the underlying cause, RPGN involves severe injury to the kidneys' glomeruli, with many of the glomeruli containing characteristic glomerular crescents.
Cystatin C or cystatin 3, a protein encoded by the CST3 gene, is mainly used as a biomarker of kidney function. Recently, it has been studied for its role in predicting new-onset or deteriorating cardiovascular disease. It also seems to play a role in brain disorders involving amyloid, such as Alzheimer's disease. In humans, all cells with a nucleus produce cystatin C as a chain of 120 amino acids. It is found in virtually all tissues and body fluids. It is a potent inhibitor of lysosomal proteinases and probably one of the most important extracellular inhibitors of cysteine proteases. Cystatin C belongs to the type 2 cystatin gene family.
Cardiorenal syndrome (CRS) is an umbrella term used in the medical field that defines disorders of the heart and kidneys whereby "acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other". When one of these organs fails, the other may subsequently fail. The heart and the kidneys are involved in maintaining hemodynamic stability and organ perfusion through an intricate network. Patients who have renal failure first may be hard to determine if heart failure is concurrent. These two organs communicate with one another through a variety of pathways in an interdependent relationship. In a 2004 report from the National Heart, Lung and Blood Institute, CRS was defined as a condition where treatment of congestive heart failure is limited by decline in kidney function. This definition has since been challenged repeatedly but there still remains little consensus over a universally accepted definition for CRS. At a consensus conference of the Acute Dialysis Quality Initiative (ADQI), the CRS was classified into five subtypes primarily based upon the organ that initiated the insult as well as the acuity of disease.
Onconephrology is a specialty in nephrology that deals with the study of kidney diseases in cancer patients. A nephrologist who takes care of patients with cancer and kidney disease is called an onconephrologist. This branch of nephrology encompasses nephrotoxicity associated with existing and novel chemotherapeutics, kidney disease as it pertains to stem cell transplant, paraneoplastic kidney disorders, paraproteinemias, electrolyte disorders associated with cancer, and more as discussed below.
Renal angina is a clinical methodology to risk stratify patients for the development of persistent and severe acute kidney injury (AKI). The composite of risk factors and early signs of injury for AKI, renal angina is used as a clinical adjunct to help optimize the use of novel AKI biomarker testing. The term angina from Latin and from the Greek ankhone ("strangling") are utilized in the context of AKI to denote the development of injury and the choking off of kidney function. Unlike angina pectoris, commonly caused due to ischemia of the heart muscle secondary to coronary artery occlusion or vasospasm, renal angina carries no obvious physical symptomatology. Renal angina was derived as a conceptual framework to identify evolving AKI. Like acute coronary syndrome which precedes or is a sign of a heart attack, renal angina is used as a herald sign for a kidney attack. Detection of renal angina is performed by calculating the renal angina index.
Siderocalin(Scn), lipocalin-2, NGAL, 24p3 is a mammalian lipocalin-type protein that can prevent iron acquisition by pathogenic bacteria by binding siderophores, which are iron-binding chelators made by microorganisms. Iron serves as a key nutrient in host-pathogen interactions, and pathogens can acquire iron from the host organism via synthesis and release siderophores such as enterobactin. Siderocalin is a part of the mammalian defence mechanism and acts as an antibacterial agent. Crystallographic studies of Scn demonstrated that it includes a calyx, a ligand-binding domain that is lined with polar cationic groups. Central to the siderophore/siderocalin recognition mechanism are hybrid electrostatic/cation-pi interactions. To evade the host defences, pathogens evolved to produce structurally varied siderophores that would not be recognized by siderocalin, allowing the bacteria to acquire iron.
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.
PDB gallery | |
|---|---|
|
