What causes hyperlipidemia in nephrotic syndrome?
Hyperlipidemia is common in patients with the nephrotic syndrome. The main cause is probably increased hepatic lipogenesis, a non-specific reaction to falling oncotic pressure secondary to hypoalbuminemia.
Is dyslipidaemia a risk factor for nephrotic syndrome?
Nephrotic syndrome is a highly prevalent disease that is associated with high morbidity despite notable advances in its treatment. Many of the complications of nephrotic syndrome, including the increased risk of atherosclerosis and thromboembolism, can be linked to dysregulated lipid metabolism and dyslipidaemia.
What is the prognosis of hyperlipidaemia in nephrotic syndrome?
Prolonged hyperlipidaemia in nephrotic syndrome is a major risk factor for multiple disease complications, including accelerated atherosclerosis, myocardial infarction, stroke, chronic kidney disease and thrombosis
Can hypercholesterolemia cause glomerulosclerosis in nephrotic syndrome?
Experiments suggest that hypercholesterolemia may cause glomerulosclerosis, a common complication of the nephrotic syndrome. The hypercholesterolemia of the nephrotic syndrome can now be treated effectively with HMG coenzyme A reductase inhibitors. Cardiovascular Diseases / etiology
Why proteinuria causes hyperlipidemia?
Abstract. Hyperlipidemia in the nephrotic syndrome is the result of abnormalities in both synthesis and catabolism of lipids and lipoproteins. The etiology of nephrotic hyperlipidemia has not been established, but both abnormal glomerular permeability to plasma proteins and reduced serum oncotic pressure may contribute ...
Is hyperlipidemia a symptom of nephrotic syndrome?
Nephrotic syndrome is a set of symptoms characterized by proteinuria, hypoalbuminemia, hyperlipidemia, and edema. There are also several other symptoms that are reported by patients that result from these primary changes in the blood and urine.
Why does nephrotic syndrome cause high cholesterol?
Nephrotic syndrome results in marked elevation of serum total cholesterol and LDL cholesterol. This is due to a combination of increased production1 and impaired catabolism/clearance of LDL3 and apoB-100.
Can nephrotic syndrome cause high cholesterol?
Patients with the nephrotic syndrome frequently have marked elevations in the plasma levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides, and lipoprotein(a) [1,2].
What is a hallmark of the diagnosis of nephrotic syndrome?
The hallmark of idiopathic nephrotic syndrome (INS) is massive proteinuria, leading to decreased circulating albumin levels. The initiating event that produces proteinuria remains unknown.
What are the complications of nephrotic syndrome?
Possible complications of nephrotic syndrome include:Blood clots. ... High blood cholesterol and elevated blood triglycerides. ... Poor nutrition. ... High blood pressure. ... Acute kidney injury. ... Chronic kidney disease. ... Infections.
What hyperlipidemia means?
Hyperlipidemia means your blood has too many lipids (or fats), such as cholesterol and triglycerides. One type of hyperlipidemia, hypercholesterolemia, means you have too much non-HDL cholesterol and LDL (bad) cholesterol in your blood. This condition increases fatty deposits in arteries and the risk of blockages.
What is the definition for hyperlipidemia?
Hyperlipidemia (high cholesterol) is an excess of lipids or fats in your blood. This can increase your risk of heart attack and stroke because blood can't flow through your arteries easily.
Why is hyperlipidemia common in nephrotic patients?
The main cause is probably increased hepatic lipogenesis, a non-specific reaction to falling oncotic pressure secondary to hypoalbuminemia. Cardiovascular morbidity and mortality are increased in patients with the nephrotic syndrome, with the exception of patients with minimal change ...
Can hypercholesterolemia cause glomerulosclerosis?
Experiments suggest that hypercholesterolemia may cause glomerulosclerosis, a common complication of the nephrotic syndrome. The hypercholesterolemia of the nephrotic syndrome can now be treated effectively with HMG coenzyme A reductase inhibitors.
Does nephrotic syndrome cause increased mortality?
Cardiovascular morbidity and mortality are increased in patients with the nephrotic syndrome, with the exception of patients with minimal change disease. It is not clear whether this is caused by the hypercholesterolemia or secondary to uremia or medical treatment.
What is nephrotic syndrome?
Nephrotic syndrome is one of the most common kidney diseases in children and adults, and is characterized by massive proteinuria, oedema and hypoalbuminaemia1. The annual incidence and prevalence of nephrotic syndrome in children are 2–7 new cases and 16 cases per 100,000 children, respectively, and in adults the yearly incidence is three new cases per 100,000 adults 2–5. It is difficult to establish the prevalence of nephrotic syndrome in adults, as it usually results from an underlying disease. Although the majority of children and adults respond to initial treatment with glucocorticoids by entering into clinical remission, a substantial proportion of patients (~20% of children and 50% of adults) either present with or subsequently develop clinical steroid resistance during the course of their disease6,7. Failure to enter clinical remission greatly increases a patient’s risk of various complications. These complications may result from persistence of the nephrotic state and/or from exposure to the relatively toxic alternative therapies that are used to induce remission.
How does dyslipidaemia affect the kidney?
The direct effects of dyslipidaemia on decreased kidney function are referred to as ‘lipid nephrotoxicity’, although the role of altered lipid metabolism in the molecular pathophysiology of nephrotic syndrome is not well understood. During dyslipidaemia, triglyceride-rich lipoproteins, such as very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) as well as oxidized LDL, are taken up by mesangial cells, leading to the production of cytotoxic agents, cytokines and reactive oxygen species, which further damage the glomerular epithelial and endothelial cells, resulting in sclerosis. Furthermore, levels of free fatty acids are increased in patients with nephrotic syndrome, which have been reported to have toxic effects in the kidney, especially in glomeruli and podocytes, but also in the tubulointerstitium. Free fatty acids bound to albumin cause podocyte damage by enhancing macropinocytosis and activating G protein-coupled receptor (GPCR) signalling, leading to disruption of the podocyte actin cytoskeleton and podocyte morphology. In addition, these albumin bound free fatty acids cause loss of podocyte viability and increased production of several cytokines. Moreover, free cholesterol-mediated injury is another pathway of cellular injury in podocytes, and involves the ATP binding cassette sub family A member 1 (ABCA1) cholesterol transporter. Furthermore, the role of free fatty acids, and saturated fatty acids in particular, is well documented in causing damage to proximal tubule cells and tubulointerstitial injury.
What are the consequences of dyslipidaemia?
2; TABLE 2). Dyslipidaemia can result in acceleration of atherosclerosis, as well as an increased risk of myocardial infarction or cerebrovascular accident (stroke). Furthermore, dyslipidaemia in nephrotic syndrome might have a causative role in the established increased risk of thrombosis associated with this disease. Dyslipidaemia is one of the dominant risk factors associated with atherothrombotic disorders. Atherosclerosis is usually accompanied by hyperreactive platelets that increase the risk of thrombosis, which is further exacerbated by dyslipidaemia82. Furthermore, the products of LDL oxidation enhance platelet activation and thrombus formation83. Dyslipidaemia during nephrotic syndrome is also clearly associated with an increased risk of nephrotoxicity, which can manifest as progressive kidney disease33,82. This progressive kidney disease might result from the development of glomerulosclerosis, owing to podocyte injury and/or mesangial cell proliferation, as well as from proximal tubular cell injury (FIG. 3).
What is the role of VLDL in fatty acid delivery?
1). On arrival in peripheral tissues , removal of fatty acids from VLDL by lipoprotein lipase (LPL) results in the formation of IDL, which is then cleared from the circulation by LDL receptor-related protein 1 (LRP1)-mediated endocytosis by hepatocytes. In addition to LRP1, the LDL receptor, liver proteoglycans and plasminogen receptor contribute to catabolism of lipoprotein(a) and hepatic uptake of ApoB and ApoA26,27. Furthermore, differences in the affinity of ApoE proteins for the receptors responsible for lipoprotein clearance owing to different APOEgenotypes affects lipoprotein(a) catabolism, possibly owing to competition between lipoprotein(a) and ApoE for the same receptors28. The levels of both IDL and VLDL are increased in patients with nephrotic syndrome, primarily owing to defective LPL activity and decreased hepatic lipase activity21. For decades, the dogma was that LPL, which contains positively charged heparin-binding domains, binds to negatively charged heparin sulfate proteoglycans in the glycocalyx coating of blood vessels29,30. However, it is now established that the binding of LPL to heparan sulfate proteoglycans on endothelial cells occurs via endothelium-derived glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1)31. Interestingly, GPIHBP1 is downregulated in patients with nephrotic syndrome32. Furthermore, the loss of LPL activators in patients with nephrotic syndrome is associated with increased glomerular basement membrane permeability, resulting in hyperlipidaemia33. In addition to downregulation of LPL activity, nephrotic syndrome is also characterized by downregulation of hepatic lipase activity, which contributes to decreased clearance of IDL and hypertriglyceridaemia. Furthermore, upregulation of ANGPTL4 levels in nephrotic syndrome, which is driven primarily by circulating free fatty acids34, may inactivate LPL by converting active LPL dimers into inactive monomers35or by acting as a reversible noncompetitive inhibitor of LPL36. The reduced plasma clearance of VLDL in nephrotic syndrome may be linked to suppression of VLDL receptor expression, as was described in a rat model of nephrotic syndrome37. Fatty acid metabolism is also altered in nephrotic syndrome, as there is increased expression of key enzymes involved in fatty acid biosynthesis, including acetyl-CoA carboxylase and fatty acid synthase, and downregulation of fatty acid catabolism in the liver38. Triglyceride-rich, ApoB-containing lipoproteins, such as VLDL, may have atherogenic properties and increase the risk of coronary events independently of LDL39. The levels of ApoC-II and ApoC-III are elevated in patients with nephrotic syndrome40, although they return to normal within 4 weeks after normalization of the levels of urinary protein, suggesting that the elevated ApoC-II and ApoC-III levels are unlikely to contribute to the development of nephrotic syndrome41. However, the finding that ApoC-II may contribute to a new form of amyloidosis that primarily affects the kidney in humans is once more challenging the cause and effect relationship between ApoC-II and nephrotic syndrome42. A potential role for ApoA-V in nephrotic syndrome should also be investigated further, as the level of ApoA-V is higher in patients with diabetes and proteinuria than in patients with diabetes without proteinuria43.
What are the three pathways that are responsible for the generation and transport of lipids in the body?
Lipoproteins are the major carriers of lipids in the blood and they participate in three major pathways that are responsible for the generation and transport of lipids within the body (TABLE 1) — namely, the exogenous pathway , the endogenous pathway and the reverse cholesterol transport pathway (FIG. 1). Lipid and lipoprotein metabolism is altered in nephrotic syndrome, with or without chronic kidney disease (CKD)17(FIG. 2). The extent of altered lipid metabolism in nephrotic syndrome correlates with the magnitude of proteinuria. In particular, the plasma concentrations of cholesterol, triglycerides and apolipoprotein B (ApoB)-containing lipoproteins (including very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and lipoprotein(a)) are all elevated in nephrotic syndrome. The concentration of high-density lipoprotein (HDL) cholesterol17and the content of ApoA-I and ApoA-II apolipoproteins18are very similar in healthy individuals and in patients with nephrotic syndrome. However, the efficiency of HDL particles in causing cholesterol efflux from peripheral tissues has yet to be studied in nephrotic syndrome, but is of interest as cholesterol efflux has been shown to be impaired in patients with diabetic nephropathy19. In fact, not only the total amount, but also the composition and function of lipoproteins are markedly altered in patients with nephrotic syndrome, with substantial increases in the levels of ApoA-I, ApoA-IV, ApoB, ApoC and ApoE, as well as in the ratio of ApoC-III to ApoC-II18. These changes in serum lipids and lipoproteins in patients with nephrotic syndrome are primarily a result of their impaired clearance and, to a lesser extent, their altered biosynthesis. In fact, although nephrotic syndrome can affect LDL synthesis20, the levels of most ApoB-containing lipoproteins are altered owing to decreased clearance21. Albumin metabolism was originally thought to be linked to hyperlipidaemia in nephrotic syndrome; however, the link between hepatic lipogenesis and albumin synthesis has been challenged by data from elegant studies suggesting that proteinuria, and not albumin synthesis, is linked to hyperlipidaemia in nephrotic rats22. The composition of lipoproteins can also be affected in nephrotic syndrome associated with CKD, because the activity of enzymes such as lecithin-cholesterol acyltransferase (LCAT) is reduced, whereas enzymes such as plasma cholesteryl ester transfer protein (CETP) are activated, resulting in the production of immature HDL23.
What are the complications of nephrotic syndrome?
Major complications include infections, acute kidney injury (AKI) and thromboembolisms9–12. A 2015 study found that AKI occurred in ~58% of 336 children admitted to hospital for nephrotic syndrome and in ~50% of 615 hospitalized children with nephrotic syndrome12. After infections and AKI, thromboembolism is also considered to be the most common, major complication of nephrotic syndrome13–16. Children with nephrotic syndrome develop thromboembolism at a rate of 2.8%, whereas adults have a much higher rate of 26.7%. Thromboembolism is particularly prevalent in patients with membranous nephropathy, affecting as many as 37% of adults and 25% of children14. Thromboembolism in patients with nephrotic syndrome is thought to be due to increased urinary loss of antithrombotic factors and increased hepatic production of prothrombotic factors13,14,16.
What are the two major forms of lipids in the body?
The major forms of lipoproteins are chylomicrons, very low-density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and high density lipoprotein (HDL), and they differ in their size, density, composition and functions (detailed in TABLE 1). In the exogenous pathway, dietary lipids, which consist mainly of triglycerides (95%) and some phospholipids, free fatty acids and cholesterol, are packaged into chylomicrons by intestinal mucosal cells. These chylomicrons enter the lymphatic system and then the circulation, where triglycerides are released as free fatty acids by lipoprotein lipase (LPL) activity on the capillary endothelium. These free fatty acids are taken up by the muscle, adipose and other peripheral tissues, whereas the remnants of chylomicrons are cleared by the liver. In the endogenous pathway, the liver produces VLDL, which interacts with LPL in the circulation to form IDL, with the release of triglyceride and free fatty acids. IDL is rapidly removed by the liver via the interaction of its apolipoprotein E component with LDL receptor (LDLR). Furthermore, IDL forms LDL upon removal of triglyceride by hepatic lipase. LDL, which is very high in cholesterol content, is in turn removed from the circulation by binding to LDLR in the liver and in extrahepatic tissues. HDL is an anti-atherogenic lipoprotein or ‘good cholesterol’, as it captures the cholesterol from peripheral tissues or other lipoproteins and transports it back to liver by the third pathway, which is termed reverse cholesterol transport.