May 29, 2011

My name is cholesterol

CHOLESTEROL is a type of fat that is a normal component of most body tissues, and is required for good health. Yet, high levels can increase the risk of developing diseases (eg heart disease).

High cholesterol levels are asymptomatic, and in many cases, the first sign of any problem is a serious health issue. To help reduce the risk of this occuring, cholesterol levels are measured by a simple blood test. Your healthcare professional can organise this for you, along with other measurements of your cardiovascular health, such as blood pressure testing.

Cholesterol is transported through the blood stream in particles known as lipoproteins. The two most important varieties of lipoproteins to be aware of are low-density lipoproteins (LDL) and high-density lipoproteins (HDL).

High levels of LDL-cholesterol can lead to fatty deposits in the artery walls, referred to as atherosclerosis, or “hardening of the arteries”. Atherosclerosis makes the blood vessels narrower and stiffer, and consequently, increases the risk of heart disease and stroke.

This form of cholesterol is sometimes referred to as “bad” cholesterol.

High-density lipoproteins (HDL-cholesterol) help to reduce the risk of heart disease as they have the ability to help remove excess cholesterol from the arteries and other parts of the body. For this reason, they are sometimes referred to as “good” cholesterol.

The narrowing of the arteries associated with high cholesterol levels can sometimes cause symptoms that include chest pain (angina), or leg pain (intermittent claudication), especially with exercise.

High production of cholesterol by the liver may contribute to the development of gallstones, symptoms of which include episodic abdominal and back pain, especially after consumption of fatty foods.

Cholesterol levels in the blood depend on dietary factors and the amount of cholesterol manufactured by the body. High consumption of saturated fat, trans fat and cholesterol in foods may make your total cholesterol and LDL cholesterol levels rise.

Genetics also play a role in some people with high cholesterol. Your genes will partly determine how much cholesterol you naturally produce. Familial hypercholesterolaemia is more likely to be present in people who experience a heart attack at an early age or who have a family member who had a heart attack at an early age.

Being overweight contributes to increased LDL-cholesterol.

Other blood markers that may be associated with high cholesterol levels and are also risk factors for cardiovascular disease include high levels of a compound called homocysteine and high blood levels of triglycerides (fats).

Free radical damage to cholesterol molecules is believed to increase their ability to damage blood vessels.

Remember that cholesterol is not a disease in itself, but an indicator of the risk of developing heart disease. Your healthcare professional will consider your cholesterol level in the context of other risk factors, such as your family history, blood pressure, level of physical activity, and whether you are diabetic or smoke cigarettes.

Measures you can take to help reduce cholesterol levels include:

● To help maintain healthy cholesterol levels, reduce the quantity of cholesterol and saturated and trans fats in your diet. This involves avoiding animal fats (meat and full-fat dairy products) and sources of hidden fat such as pastries and pies.

● At the same time, increase the amount of fish in your diet (but not deep fried fish), and eat more fruit, vegetables and whole grains.

● A diet high in soluble fibre is highly recommended in order to promote the excretion of cholesterol. Good sources include legumes, oats and psyllium.

● Eating moderate amounts of foods that contain monounsaturated fats may support the management of healthy normal cholesterol levels. Important foods to include in your diet include nuts (especially walnuts), seeds and olive oil.

● Garlic and onion have cholesterol-lowering properties and are valuable additions to your diet.

● Limit your alcohol consumption to one to two standard drinks per day, and avoid binge drinking.

● Quit smoking. Cigarette smoking significantly increases the risk of cardiovascular disease and other health problems, and can exacerbate the negative effects of high cholesterol levels.

● Regular aerobic exercise can be of benefit to those with high cholesterol levels. Aim for at least 30 minutes of brisk walking per day. Always seek the advice of your healthcare professional before commencing an exercise programme.

● If you are overweight, talk to your healthcare professional about ways to address this, as being overweight may contribute to raised LDL and triglyceride levels.

There are also certain natural alternatives you can consider:

● Plant sterols (also known as phytosterols) may help reduce LDL-cholesterol levels and assist in improving the LDL:HDL ratio to healthier levels. They work by lowering cholesterol absorption and reabsorption. Take a daily dose of 2-3 grams of plant sterols, as recommended by the National Heart Foundation of Australia. Choose a formula that also supplies a healthy dose of betacarotene, which may become depleted when taking plant sterols.

● Coenzyme Q10 helps maintain heart and artery health and inhibits the oxidation of LDL–cholesterol.

● Omega-3 fatty acids EPA and DHA from fish oil, may help decrease fat in the blood (triglycerides) in healthy people. Omega-3s also help to maintain the flexibility of the blood vessels, help maintain healthy heart rates, and help maintain healthy blood pressure.

● Antioxidant nutrients such as vitamin C and vitamin E help reduce the oxidation of LDL-cholesterol. Antioxidants are often taken with folic acid and the vitamins B6 and B12. Low intake of these B-group vitamins is a common cause of elevated plasma homocysteine.

● If you’re overweight, achieving a healthy body weight may aid the management of healthy cholesterol levels.

Your cholesterol level is only one aspect of your cardiovascular health profile and should be addressed in conjunction with other risk factors. Talk to your healthcare professional for more information.

May 12, 2011

Regulation of Kidney Function

One of the most important aspects of the mammalian kidney is its ability to adjust both the volume and osmolarity of urine, depending on the animal′s water and salt balance and the rate of urea production. In situations of high salt intake and low water availability, a mammal can excrete urea and salt with minimal water loss in small volumes of hyperosmotic urine. But if salt is scarce and fluid intake is high, the kidney can get rid of the excess water with little salt loss by producing large volumes of hypoosmotic urine (as dilute as 70 mosm/L, compared to about 300 mosm/L for human blood). This versatility in osmoregulatory function is managed with a combination of nervous and hormonal controls.

One hormone that is important in regulating water balance is antidiuretic hormone (ADH).

ADH is produced in the hypothalamus of the brain and is stored in and released from the posterior pituitary gland, which is positioned just below the hypothalamus. Osmoreceptor cells in the hypothalamus monitor the osmolarity of blood; when it rises above a set point of 300 mosm/L (perhaps due to water loss from sweating or to ingestion of salty food), more ADH is released into the bloodstream and reaches the kidney. The main targets of ADH are the distal tubules and collecting ducts of the kidney, where the hormone increases the permeability of the epithelium to water. This amplifies water reabsorption, which reduces urine volume and helps prevent further increase of blood osmolarity above the set point. By negative feedback, the subsiding osmolarity of the blood reduces the activity of osmoreceptor cells in the hypothalamus, and less ADH is then secreted. But only the gain of additional water in food and drink can bring osmolarity all the way back down to 300 mosm/L.

Conversely, if a large intake of water has reduced blood osmolarity below the set point, very little ADH is released. This decreases the permeability of the distal tubules and collecting ducts, so water reabsorption is reduced, resulting in increased discharge of dilute urine. (Increased urination is called diuresis, and it is because ADH opposes this state that it is called anti diuretic hormone.) Alcohol can disturb water balance by inhibiting the release of ADH, causing excessive urinary water loss and dehydration (which may cause some of the symptoms of a hangover). Normally, blood osmolarity, ADH release, and water reabsorption in the kidney are all linked in a feedback loop that contributes to homeostasis.

A second regulatory mechanism involves a specialised tissue called the juxtaglomerular apparatus (JGA), located near the afferent arteriole that supplies blood to the glomerulus. When blood pressure or blood volume in the afferent arteriole drops (for instance, as a result of reduced salt intake or loss of blood), the enzyme renin initiates chemical reactions that convert a plasma protein called angiotensinogen to a peptide called angiotensin II. Functioning as a hormone, angiotensin II raises blood pressure by constricting arterioles, decreasing blood flow to many capillaries, including those of the kidney. Angiotensin II also stimulates the proximal tubules of the nephrons to reabsorb more NaCl and water. This reduces the amount of salt and water excreted in the urine and consequently raises blood volume and pressure. Another effect of angiotensin II is stimulation of the adrenal glands to release a hormone called aldosterone. This hormone acts on the nephrons′ distal tubules, making them reabsorb more sodium (Na+) and water and increasing blood volume and pressure. In summary, the renin–angiotensin–aldosterone system (RAAS) is part of a complex feedback circuit that functions in homeostasis. A drop in blood pressure and blood volume triggers renin release from the JGA. In turn, the rise in blood pressure and volume resulting from the various actions of angiotensin II and aldosterone reduce the release of renin.

The functions of ADH and the RAAS may seem to be redundant, but this is not the case. Both increase water reabsorption, but they counter different osmoregulatory problems. The release of ADH is a response to an increase in the osmolarity of the blood, as when the body is dehydrated from excessive water loss or inadequate intake of water. However, a situation that causes an excessive loss of both salt and body fluids—an injury, for example, or severe diarrhea—will reduce blood volume without increasing osmolarity. This will not induce a change in ADH release, but the RAAS will respond to the fall in blood volume and pressure by increasing water and Na+ reabsorption. ADH and the RAAS are partners in homeostasis; ADH alone would lower blood Na+ concentration by stimulating water reabsorption in the kidney, but the RAAS helps maintain balance by stimulating Na+ reabsorption.

Still another hormone, a peptide called atrial natriuretic factor (ANF), opposes the RAAS. The walls of the atria of the heart release ANF in response to an increase in blood volume and pressure. ANF inhibits the release of renin from the JGA, inhibits NaCl reabsorption by the collecting ducts, and reduces aldosterone release from the adrenal glands. These actions lower blood volume and pressure. Thus, ADH, the RAAS, and ANF provide an elaborate system of checks and balances that regulate the kidney′s ability to control the osmolarity, salt concentration, volume, and pressure of blood. The precise regulatory role of ANF is an area of active research.

May 3, 2011

Mammalian Kidney

The excretory system of mammals centres on the kidneys, which are also the principal site of water balance and salt regulation. Mammals have a pair of kidneys. Each kidney, bean–shaped and about 10 cm long in humans, is supplied with blood by a renal artery and drained by a renal vein.

Blood flow through the kidneys is voluminous. In humans, the kidneys account for less than 1% of body weight, but they receive about 20% of resting cardiac output. Urine exits each kidney through a duct called the ureter, and both ureters drain into a common urinary bladder. During urination, urine is expelled from the urinary bladder through a tube called the urethra, which empties to the outside near the vagina in females or through the penis in males. Sphincter muscles near the junction of the urethra and the bladder, which are under nervous system control, regulate urination.

The mammalian kidney has two distinct regions, an outer renal cortex and an inner renal medulla. Packing both regions are microscopic excretory tubules and their associated blood vessels. The nephron—the functional unit of the vertebrate kidney—consists of a single long tubule and a ball of capillaries called the glomerulus. The blind end of the tubule forms a cup–shaped swelling, called Bowman′s capsule, which surrounds the glomerulus. Each human kidney contains about a million nephrons, with a total tubule length of 80 km.

Filtration of the Blood
Filtration occurs as blood pressure forces fluid from the blood in the glomerulus into the lumen of Bowman′s capsule. The porous capillaries, along with specialised cells of the capsule called podocytes, are permeable to water and small solutes but not to blood cells or large molecules such as plasma proteins. Filtration of small molecules is nonselective, and the filtrate in Bowman′s capsule contains salts, glucose, amino acids, and vitamins; nitrogenous wastes such as urea; and other small molecules—a mixture that mirrors the concentrations of these substances in blood plasma.

Pathway of the Filtrate
From Bowman′s capsule, the filtrate passes through three regions of the nephron: the proximal tubule; the loop of Henle, a hairpin turn with a descending limb and an ascending limb; and the distal tubule. The distal tubule empties into a collecting duct, which receives processed filtrate from many nephrons. This filtrate flows from the many collecting ducts of the kidney into the renal pelvis, which is drained by the ureter.

In the human kidney, approximately 80% of the nephrons, the cortical nephrons, have reduced loops of Henle and are almost entirely confined to the renal cortex. The other 20%, the juxtamedullary nephrons, have well–developed loops that extend deeply into the renal medulla. Only mammals and birds have juxtamedullary nephrons; the nephrons of other vertebrates lack loops of Henle. It is the juxtamedullary nephrons that enable mammals to produce urine that is hyperosmotic to body fluids, an adaptation that is extremely important for water conservation.

The nephron and the collecting duct are lined by a transport epithelium that processes the filtrate to form the urine. One of this epithelium′s most important tasks is reabsorption of solutes and water. Between 1,100 and 2,000 L of blood flows through a pair of human kidneys each day, a volume about 275 times the total volume of blood in the body. From this enormous traffic of blood, the nephrons and collecting ducts process about 180 L of initial filtrate, equivalent to two or three times the body weight of an average person. Of this, nearly all of the sugar, vitamins, and other organic nutrients and about 99% of the water are reabsorbed into the blood, leaving only about 1.5 L of urine to be voided.

Blood Vessels Associated with the Nephrons
Each nephron is supplied with blood by an afferent arteriole, a branch of the renal artery that subdivides into the capillaries of the glomerulus. The capillaries converge as they leave the glomerulus, forming an efferent arteriole. This vessel subdivides again, forming the peritubular capillaries, which surround the proximal and distal tubules. More capillaries extend downward and form the vasa recta, the capillaries that serve the loop of Henle. The vasa recta also form a loop, with descending and ascending vessels conveying blood in opposite directions.

Although the excretory tubules and their surrounding capillaries are closely associated, they do not exchange materials directly. The tubules and capillaries are immersed in interstitial fluid, through which various substances diffuse between the plasma within capillaries and the filtrate within the nephron tubule. This exchange is facilitated by the relative direction of blood flow and filtrate flow in the nephrons.

Secretion and reabsorption in the proximal tubule substantially alter the volume and composition of filtrate. For example, the cells of the transport epithelium help maintain a relatively constant pH in body fluids by the controlled secretion of H+. The cells also synthesise and secrete ammonia, which neutralises the acid and keeps the filtrate from becoming too acidic. The more acidic the filtrate, the more ammonia the cells produce and secrete, and the urine of a mammal usually contains some ammonia from this source (even though most nitrogenous waste is excreted as urea). The proximal tubules also reabsorb about 90% of the important buffer bicarbonate (HCO3−). Drugs and other poisons that have been processed in the liver pass from the peritubular capillaries into the interstitial fluid, and then are secreted across the epithelium of the proximal tubule into the nephron′s lumen. Conversely, valuable nutrients, including glucose, amino acids, and potassium (K+), are actively or passively transported from the filtrate to the interstitial fluid and then are moved into the peritubular capillaries.

One of the most important functions of the proximal tubule is reabsorption of most of the NaCl (salt) and water from the huge initial filtrate volume. Salt in the filtrate diffuses into the cells of the transport epithelium, and the membranes of the cells actively transport Na+ into the interstitial fluid. This transfer of positive charge is balanced by the passive transport of Cl− out of the tubule. As salt moves from the filtrate to the interstitial fluid, water follows by osmosis. The exterior side of the epithelium has a much smaller surface area than the side facing the lumen, minimizing leakage of salt and water back into the tubule. Instead, the salt and water now diffuse from the interstitial fluid into the peritubular capillaries.

Reabsorption of water continues as the filtrate moves into the descending limb of the loop of Henle. Here the transport epithelium is freely permeable to water but not very permeable to salt and other small solutes. For water to move out of the tubule by osmosis, the interstitial fluid bathing the tubule must be hyperosmotic to the filtrate. The osmolarity of the interstitial fluid does in fact become progressively greater from the outer cortex to the inner medulla of the kidney. Thus, filtrate moving downward from the cortex to the medulla within the descending limb of the loop of Henle continues to lose water to interstitial fluid of greater and greater osmolarity, which increases the solute concentration of the filtrate.

The filtrate reaches the tip of the loop, deep in the renal medulla in the case of juxtamedullary nephrons, then moves back to the cortex within the ascending limb. In contrast to the descending limb, the transport epithelium of the ascending limb is permeable to salt but not to water. The ascending limb has two specialized regions: a thin segment near the loop tip and a thick segment adjacent to the distal tubule. As filtrate ascends in the thin segment, NaCl, which became concentrated in the descending limb, diffuses out of the permeable tubule into the interstitial fluid. This movement increases the osmolarity of the interstitial fluid in the medulla. The exodus of salt from the filtrate continues in the thick segment of the ascending limb, but here the epithelium actively transports NaCl into the interstitial fluid. By losing salt without giving up water, the filtrate is progressively diluted as it moves up to the cortex in the ascending limb of the loop.

The distal tubule plays a key role in regulating the K+ and NaCl concentration of body fluids by varying the amount of the K+ that is secreted into the filtrate and the amount of NaCl reabsorbed from the filtrate. Like the proximal tubule, the distal tubule also contributes to pH regulation by the controlled secretion of H+ and reabsorption of bicarbonate (HCO3−).

The collecting duct carries the filtrate through the medulla to the renal pelvis. By actively reabsorbing NaCl, the transport epithelium of the collecting duct plays a large role in determining how much salt is actually excreted in the urine. Though its degree of permeability is under hormonal control, the epithelium is permeable to water. However, it is not permeable to salt or, in the renal cortex, to urea. Thus, as the collecting duct traverses the gradient of osmolarity in the kidney, the filtrate becomes increasingly concentrated as it loses more and more water by osmosis to the hyperosmotic interstitial fluid. In the inner medulla, the duct becomes permeable to urea. Because of the high urea concentration in the filtrate at this point, some urea diffuses out of the duct and into the interstitial fluid. Along with NaCl, this urea contributes to the high osmolarity of the interstitial fluid in the medulla. This high osmolarity enables the mammalian kidney to conserve water by excreting urine that is hyperosmotic to the general body fluids.