Biochemical functions of liver. Metabolism of porphyrins: metabolism of bile pigments, biochemistry of jaundices. Biotransformation of xenobiotics and endogenous toxins in the liver: microsomal oxidation, cytochrome Ð-450.
Urine formation function of kidney. Physical-chemical properties and chemical composition of normal urine. Pathobiochemistry of kidney.
What are the functions of the liver?
• It is responsible for the
production of bile which is stored in the gallbladder and released when
required for the digestion of fats.
• The liver stores glucose in the form of glycogen which is converted back to glucose again when needed for energy.
• It also plays an important role in the metabolism of protein and fats. It stores the vitamins A, D, K, B12 and folate and synthesizes blood clotting factors.
• Another important role is as a detoxifier, breaking down or transforming substances like ammonia, metabolic waste, drugs, alcohol and chemicals, so that they can be excreted. These may also be referred to as "xenobiotic" chemicals. If we examine the liver under a microscope, we will see rows of liver cells separated by spaces which act like a filter or sieve, through which the blood stream flows. The liver filter is designed to remove toxic matter such as dead cells, microorganisms, chemicals, drugs and particulate debris from the blood stream. The liver filter is called the sinusoidal system, and contains specialized cells known as Kupffer cells which ingest and breakdown toxic matter.
Role of the liver in carbohydrate metabolism.
From intestine glucose pass into the liver, where most part of it undergone the phosphorillation. Glucose-6-phosphate formed in result of this reaction, which catalyzed by two enzymes – hexokinase and glucokinase. When level of glucose in blood of v. porta and in the hepatocytes is normal activity of glucokinase is low. After eating activity of this enzyme increase and blood level of glucose decrease because glucose-6-phosphate cannot pass through membrane.
Fructose and galactose also transformed into glucose-6-phosphate in the liver.
Glucose-6-phosphate is a key product of carbohydrates metabolism. In the liver this substance can metabolized into different ways depend of liver’s and whole organism’s necessity.
1. Synthesis of glicogen. Content in the liver – 70-100g. After eating amount of glicogen in the liver increase up to 150g. After 24 hours of starvation content of glicogen in the liver decreases to zero and glukoneogenesis started.
2. Glucose-6-phosphatase catalize dephosphorillation of glucose-6-phosphate and free glucose formed. This enzyme is present in the liver, kidney and small intestine. This process keep normal level of glucose in the blood.
3. Excess of glucose-6-phosphate, which not used for synthesis of glicogen and forming of free glucose, decomposites in glycolysis for pyruvate and for acetyl-CoA, which are used for fatty acids synthesis.
4. Glucose-6-phosphate decomposites for H2O and CO2, and free energy for hepatocytes formed.
5. Part of glucose-6-phosphate oxidized in pentosophosphate cycle. This way of glucose decomposition supplyes reducted NADPH, which is necessary in fatty acid synthesis, cholesterin synthesis, and also pentosophosphates for nucleic acids. Near 1/3 of glucose in liver used for this pathway, another 2/3 – for glycolisis.
The Hexokinase Reaction:
The ATP-dependent phosphorylation of glucose to form glucose 6-phosphate (G6P)is the first reaction of glycolysis, and is catalyzed by tissue-specific isoenzymes known as hexokinases. The phosphorylation accomplishes two goals: First, the hexokinase reaction converts nonionic glucose into an anion that is trapped in the cell, since cells lack transport systems for phosphorylated sugars. Second, the otherwise biologically inert glucose becomes activated into a labile form capable of being further metabolized.
Four mammalian isozymes of hexokinase are known (Types I - IV), with the Type IV isozyme often referred to as glucokinase. Glucokinase is the form of the enzyme found in hepatocytes. The high Km of glucokinase for glucose means that this enzyme is saturated only at very high concentrations of substrate.
Comparison of the activities of hexokinase and glucokinase. The Km for hexokinase is significantly lower (0.1mM) than that of glucokinase (10mM). This difference ensures that non-hepatic tissues (which contain hexokinase) rapidly and efficiently trap blood glucose within their cells by converting it to glucose-6-phosphate. One major function of the liver is to deliver glucose to the blood and this in ensured by having a glucose phosphorylating enzyme (glucokinase) whose Km for glucose is sufficiently higher that the normal circulating concentration of glucose (5mM).
This feature of hepatic glucokinase allows the liver to buffer blood glucose. After meals, when postprandial blood glucose levels are high, liver glucokinase is significantly active, which causes the liver preferentially to trap and to store circulating glucose. When blood glucose falls to very low levels, tissues such as liver and kidney, which contain glucokinases but are not highly dependent on glucose, do not continue to use the meager glucose supplies that remain available. At the same time, tissues such as the brain, which are critically dependent on glucose, continue to scavenge blood glucose using their low Km hexokinases, and as a consequence their viability is protected. Under various conditions of glucose deficiency, such as long periods between meals, the liver is stimulated to supply the blood with glucose through the pathway of gluconeogenesis. The levels of glucose produced during gluconeogenesis are insufficient to activate glucokinase, allowing the glucose to pass out of hepatocytes and into the blood.
The regulation of hexokinase and glucokinase activities is also different. Hexokinases I, II, and III are allosterically inhibited by product (G6P) accumulation, whereas glucokinases are not. The latter further insures liver accumulation of glucose stores during times of glucose excess, while favoring peripheral glucose utilization when glucose is required to supply energy to peripheral tissues.
Hepatocytes content full set of gluconeogenesis necessary enzymes. So, in liver glucose can be formed from lactate, pyruvate, amino acids, glycerine. Gluconegenesis from lactate takes place during intensive muscular work. Lactate formed from glucose in muscles, transported to the liver, new glucose formed and transported to the muscles (Kori cycle).
Regulation of Blood Glucose Levels
If for no other reason, it is because of the demands of the brain for oxidizable glucose that the human body exquisitely regulates the level of glucose circulating in the blood. This level is maintained in the range of 5mM.
Nearly all carbohydrates ingested in the diet are converted to glucose following transport to the liver. Catabolism of dietary or cellular proteins generates carbon atoms that can be utilized for glucose synthesis via gluconeogenesis. Additionally, other tissues besides the liver that incompletely oxidize glucose (predominantly skeletal muscle and erythrocytes) provide lactate that can be converted to glucose via gluconeogenesis.
Maintenance of blood glucose homeostasis is of paramount importance to the survival of the human organism. The predominant tissue responding to signals that indicate reduced or elevated blood glucose levels is the liver. Indeed, one of the most important functions of the liver is to produce glucose for the circulation. Both elevated and reduced levels of blood glucose trigger hormonal responses to initiate pathways designed to restore glucose homeostasis. Low blood glucose triggers release of glucagon from pancreatic -cells. High blood glucose triggers release of insulin from pancreatic -cells. Additional signals, ACTH and growth hormone, released from the pituitary act to increase blood glucose by inhibiting uptake by extrahepatic tissues. Glucocorticoids also act to increase blood glucose levels by inhibiting glucose uptake. Cortisol, the major glucocorticoid released from the adrenal cortex, is secreted in response to the increase in circulating ACTH. The adrenal medullary hormone, epinephrine, stimulates production of glucose by activating glycogenolysis in response to stressful stimuli.
Glucagon binding to its' receptors on the surface of liver cells triggers an increase in cAMP production leading to an increased rate of glycogenolysis by activating glycogen phosphorylase via the PKA-mediated cascade. This is the same response hepatocytes have to epinephrine release. The resultant increased levels of G6P in hepatocytes is hydrolyzed to free glucose, by glucose-6-phosphatase, which then diffuses to the blood. The glucose enters extrahepatic cells where it is re-phosphorylated by hexokinase. Since muscle and brain cells lack glucose-6-phosphatase, the glucose-6-phosphate product of hexokinase is retained and oxidized by these tissues.
In opposition to the cellular responses to glucagon (and epinephrine on hepatocytes), insulin stimulates extrahepatic uptake of glucose from the blood and inhibits glycogenolysis in extrahepatic cells and conversely stimulates glycogen synthesis. As the glucose enters hepatocytes it binds to and inhibits glycogen phosphorylase activity. The binding of free glucose stimulates the de-phosphorylation of phosphorylase thereby, inactivating it. Why is it that the glucose that enters hepatocytes is not immediately phosphorylated and oxidized? Liver cells contain an isoform of hexokinase called glucokinase. Glucokinase has a much lower affinity for glucose than does hexokinase. Therefore, it is not fully active at the physiological ranges of blood glucose. Additionally, glucokinase is not inhibited by its product G6P, whereas, hexokinase is inhibited by G6P.
One major response of non-hepatic tissues to insulin is
the recruitment, to the cell surface, of glucose transporter complexes. Glucose
transporters comprise a family of five members, GLUT-1 to GLUT-5. GLUT-1 is
ubiquitously distributed in various tissues. GLUT-2 is found primarily in
intestine, kidney and liver. GLUT-3 is also found in the intestine and GLUT-
Hepatocytes, unlike most other cells, are freely permeable to glucose and are, therefore, essentially unaffected by the action of insulin at the level of increased glucose uptake. When blood glucose levels are low the liver does not compete with other tissues for glucose since the extrahepatic uptake of glucose is stimulated in response to insulin. Conversely, when blood glucose levels are high extrahepatic needs are satisfied and the liver takes up glucose for conversion into glycogen for future needs. Under conditions of high blood glucose, liver glucose levels will be high and the activity of glucokinase will be elevated. The G6P produced by glucokinase is rapidly converted to G1P by phosphoglucomutase, where it can then be incorporated into glycogen.
Diabetes mellitus – general term referring to all states characterized by hyperglycemia.
For the disease characterized by excretion of large amounts of very dilute urine, see diabetes insipidus. For diabetes mellitus in pets, see diabetes in cats and dogs.
Diabetes mellitus (IPA pronunciation: is a metabolic disorder characterized by hyperglycemia (high blood sugar) and other signs, as distinct from a single illness or condition.
The World Health Organization recognizes three main forms of diabetes: type 1, type 2, and gestational diabetes (occurring during pregnancy),[ which have similar signs, symptoms, and consequences, but different causes and population distributions. Ultimately, all forms are due to the beta cells of the pancreas being unable to produce sufficient insulin to prevent hyperglycemia Type 1 is usually due to autoimmune destruction of the pancreatic beta cells which produce insulin. Type 2 is characterized by tissue-wide insulin resistance and varies widely; it sometimes progresses to loss of beta cell function. Gestational diabetes is similar to type 2 diabetes, in that it involves insulin resistance; the hormones of pregnancy cause insulin resistance in those women genetically predisposed to developing this condition.
Types 1 and 2 are incurable chronic conditions, but have been treatable since insulin became medically available in 1921, and are nowadays usually managed with a combination of dietary treatment, tablets (in type 2) and, frequently, insulin supplementation. Gestational diabetes typically resolves with delivery.
Diabetes can cause many complications. Acute complications (hypoglycemia, ketoacidosis or nonketotic hyperosmolar coma) may occur if the disease is not adequately controlled. Serious long-term complications include cardiovascular disease (doubled risk), chronic renal failure (diabetic nephropathy is the main cause of dialysis in developed world adults), retinal damage (which can lead to blindness and is the most significant cause of adult blindness in the non-elderly in the developed world), nerve damage (of several kinds), and microvascular damage, which may cause erectile dysfunction (impotence) and poor healing. Poor healing of wounds, particularly of the feet, can lead to gangrene which can require amputation — the leading cause of non-traumatic amputation in adults in the developed world. Adequate treatment of diabetes, as well as increased emphasis on blood pressure control and lifestyle factors (such as smoking and keeping a healthy body weight), may improve the risk profile of most aforementioned complications.
Role of the liver in lipid metabolism.
In the liver all processes of lipid metabolism take place. Most important of them are following:
1. Lipogenesis (synthesis of fatty acids and lipids). Substrate for this process – acetyl-CoA, formed from glucose and amino acids, which are not used for another purposes. This process is very active when the person eats a lot of carbohydrates. Liver more active than another tissues synthesizes saturated and monounsaturated fatty acids. Fatty acids then used for synthesis of lipids, phospholipids, cholesterol ethers. Glycerol-3-phosphate, which is necessary for lipids synthesis, formed in liver in result of two processes: from free glycerol under influence of glycerolkinase, or in reducing of dioxiacetone phosphate under influence of glycerolphosphate dehydrogenase. Active form of fatty acids interact with glycerol-3-phosphate and phosphatidic acid formed, which used for synthesis of triacylglycerines and glycerophospholipids.
2. Liver play a central role in synthesis of cholesterin, because near 80 % of its amount is synthesized there. Biosynthesis of cholesterin regulated by negative feedback. When the level of cholesterin in the meal increases, synthesis in liver decreases, and back to front. Besides synthesis regulated by insulin and glucagon. Cholesterin used in organism for building cell membranes, synthesis of steroid hormones and vitamin D. Excess of cholesterin leads out in the bile to the intestine. Another part of cholesterin used for bile acids synthesis. This process regulated by reabsorbed bile acids according to negative feedback principles.
3. Liver is a place of ketone bodies synthesis. These substances formed from fatty acids after their oxidation, and from liver transported to another tissues, first of all to the heart, muscles, kidneys and brain. These substances are main source of energy for many tissues of our organism excepting liver in normal conditions (heart) and during starvation (brain).
Transport forms of lipids
Certain lipids associate with specific proteins to form lipoprotein systems in which the specific physical properties of these two classes of biomolecules are blended. In these systems the lipids and proteins are not covalently joined but are held together largely by hydrophobic interactions between the nonpolar portions of the lipid and the protein components.
ransport lipoproteins of blood plasma. The plasma lipoproteins are complexes in which the lipids and proteins occur in a relatively fixed ratio. They carry water-insoluble lipids between various organs via the blood, in a form with a relatively small and constant particle diameter and weight. Human plasma lipoproteins occur in four major classes that differ in density as well as particle size. They are physically distinguished by their relative rates of flotation in high gravitational fields in the ultracentrifuge.
The blood lipoproteins serve to transport water-insoluble triacylglycerols and cholesterol from one tissue to another. The major carriers of triacylglyeerols are chylomicrons and very low density lipoproteins (VLDL).
The triacylglycerols of the chylomicrons and VLDL are digested in capillaries by lipoprotein lipase. The fatty acids that are produced are utilized for energy or converted to triacylglycerols and stored. The glycerol is used for triacylglycerol synthesis or converted to DHAP and oxidized for energy, either directly or after conversion to glucose in the liver. The remnants of the chylomicrons are taken up by liver cells by the process of endocytosis and are degraded by lysosomal enzymes, and the products are reused by the cell.
VLDL is converted to intermediate density lipoproteins (IDL), which is degraded by the liver or converted in blood capillaries to low density lipoproteins LDL by further digestion of triacylglycerols. LDL is taken up by various tissues and provides cholesterol, which the tissue utilize
High density lipoproteins (HDL) which is synthesized by the liver, transfers apoproteins to ehylomicrons and VLDL.
HDL picks up cholesterol from cell membranes or from other lipoproteins. Cholesterol is converted to cholesterol esters by the lecithin:cholesterol acyltransferase (LCAT) reaction. The cholesterol esters may be transferred to other lipoproteins or carried by HDL to the liver, where they are hydrolyzed to free cholesterol, which is used for synthesis of VLDL or converted to bile salts.
Composition of the blood lipoproteins
The major components of lipoproteins are triacylglycerols, cholesterol, cholesterol esters, phospholipids, and proteins. Purified proteins (apoproteins) are designated A, B, C, and E.
Chylomicrons are the least dense of the blood lipoproteins because they have the most triacylglycerol and the least protein.
VLDL is more dense than chylomicrons but still has a high content of triacylglycerol.
IDL, which is derived from VLDL, is more dense than chylomicrons but still has a high content of triacylglycerol.
LDL has less triacylglycerol and more protein and, therefore, is more dense than the IDL from which it is derived. LDL has the highest content of cholesterol and its esters.
HDL is the most dense lipoprotein. It has the lowest triacylglycerol and the highest protein content.
Metabolism of Chylomicrons
Chylomicrons are synthesized in intestinal epithelial cells. Their triacylglycerols are derived from dietary lipid, and their major apoprotein is apo B-48.Chylomicrons travel through the lymph into the blood. In peripheral tissues, particularly adipose and muscle, the triacylglyerols are digested by lipoprotein lipase.The chylomicron remnants interact with receptors on liver cells and are taken+ up by endocytosis. The contents are degraded by lysosomal enzymes, and the products (amino acids, fatty acids, glycerol, and cholesterol) are released into the cytosol and reutilized.
Metabolism of VLDL
VLDL is synthesized in the liver, particularly after a high-carbohydrate meal. It is formed from triacylglycerols that are package with cholesterol, apoproteins (particularly apo B-100), and phospholipids and it is released into the blood.
In peripheral tissues, particularly adipose and muscle, VLDL triacylglycerols are digested by lipoprotein lipase, and VLDL is converted to IDL.
IDL returns to the liver, is taken up by endocytosis, and is degraded by lysosomal enzymes.
IDL may also be further degraded by lipoprotein lipase, forming LDL.
LDL reacts with receptors on various cells, is taken up by endocytosis and is digested by lysosomal enzymes.
Cholesterol, released from cholesterol esters by a lysosomal esterase, can be used for the synthesis of cell memmbranes or bile salts in the liver or steroid hormones in endocrine tissue.
Metabolism of HDL.
HDL is synthesized by the liver and released into the blood as disk-shaped particles. The major protein of HDL is apo A.
HDL cholesterol, obtained from cell membranes or from other lipoproteins, is converted to cholesterol esters. As cholesterol esters accumulate in the core of the lipoprotein, HDL particles become spheroids.
HDL particles are taken up by the liver by endocytosis and hydrolyzed by lysosomal enzymes. Cholesterol, released from cholesterol esters may be packaged by the liver in VLDL and released into the blood or converted to bile salts and secreted into the bile.
However, there is also considerable awareness that abnormal levels of certain lipids, particularly cholesterol (in hypercholesterolemia) and, more recently, trans fatty acids, are risk factors for heart disease and other diseases. We need fats in our bodies and in our diet. Animals in general use fat for energy storage because fat stores 9 KCal/g of energy. Plants, which don’t move around, can afford to store food for energy in a less compact but more easily accessible form, so they use starch (a carbohydrate, NOT A LIPID) for energy storage. Carbohydrates and proteins store only 4 KCal/g of energy, so fat stores over twice as much energy/gram as other sources of energy.
We need fats in our bodies and in our diet. Animals in general use fat for energy storage because fat stores 9 KCal/g of energy. Plants, which don’t move around, can afford to store food for energy in a less compact but more easily accessible form, so they use starch (a carbohydrate, NOT A LIPID) for energy storage. Carbohydrates and proteins store only 4 KCal/g of energy, so fat stores over twice as much energy/gram as fat. By the way, this is also related to the idea behind some of the high-carbohydrate weight loss diets.
The human body burns carbohydrates and fats for fuel in a given proportion to each other. The theory behind these diets is that if they supply carbohydrates but not fats, then it is hoped that the fat needed to balance with the sugar will be taken from the dieter’s body stores. Fat is also is used in our bodies to a) cushion vital organs like the kidneys and b) serve as insulation, especially just beneath the skin.
Role of the liver in protein metabolism.
Liver has full set of enzymes, which are necessary for amino acids metabolism. Amino acids from food used in the liver for following pathways:
1. Protein synthesis.
2. Decomposition for the final products.
3. Transformation to the carbohydrates and lipids.
4. Interaction between amino acids.
5. Transformation to the different substances with amino group.
6. Release to the blood and transport to another organs and tissues.
The high speed of protein synthesis and decomposition is typical for the liver. Hepatocytes catch different protein from blood (from hemolysated RBC, denaturated plasma proteins, protein and peptide hormones) and decomposite them to the free amino acids which used for new synthesis. When organism does not get necessary quantity of amino acids from food, liver synthesizes only high necessary proteins (enzymes, receptors).
Liver syntesizes 100 % of albumines, 90 % of α1-globulines, 75 % of α2-globulines, 50 % of β-globulines, blood clotting factors, fibrinogen, protein part of blood lipoproteins, such enzyme as cholinesterase. The speed of these processes is enough high, for example, liver synthesizes 12-16g of albumines per day.
Amino acids, which are not used for protein synthesis, transformed to another substances. Oxidative decomposition of amino acids is main source of energy for liver in normal conditions.
Liver can synthesize non-essential amino acids.
Liver synthesizes purine and pyrimidine nucleotides, hem, creatin, nicotinic acid, cholin, carnitin, polyamines.
The decomposition of hemoglobin in tissues, bile pigments formation.
a life span of about 120 days the erythrocytes die. The dead erythrocytes are
taken up by the phagocytes of the reticuloendothelial system of the body. About
1. The protein (globin) part is utilized partly as such or along with other body proteins.
2. The iron is stored in the reticuloendothelial cells and is reused for the synthesis of Hb and other iron containing substances of the body.
3. The porphyrin part is converted to bile pigment, i.e. bilirubin which is excreted in bile.
The several stages, which are involved in the formation of bile pigment from Hb and the farther fate of this pigment, are given below:
1. Hemoglobin dissociates into heme and globin.
2. Heme in the presence of the enzyme, heme oxygenase, loses one molecule of CO and one atom of iron in Fe3+ form producing biliverdin. In this reaction, the porphyrin ring is cleaved by oxidation of the alpha methenyl bridge between pyrrole rings. The enzyme needs NADPH+H+ and O2.
Biliverdin which is green in color is the first bile pigment to be produced; it is reduced to the yellow-colored bilirubin, the main bile pigment, by the enzyme biliverdin reductase requiring NADPH+H+.
Bilirubin is non-polar, lipid soluble but water insoluble. Bilirubin is a very toxic compound. For example, it is known to inhibit RNA and protein synthesis and carbohydrate metabolism in brain. Mitochondria appear to be especially sensitive to its effect. Bilirubin formed in reticuloendothelial cells then is associated with plasma protein albumin to protect cells from the toxic effects. As this bilirubin is in complex with plasma proteins, therefore it cannot pass into the glomerular filtrate in the kidney; thus it does not appear in urine, even when its level in the blood plasma is very high. However, being lipid soluble, it readily gets deposited in lipid-rich tissues specially the brain.
This bilirubin is called indirect bilirubin or free bilirubin or unconjugated bilirubin.
The detoxication of indirect bilirubin takes place in the membranes of endoplasmatic reticulum of hepatocytes. Here bilirubin interact with UDP-glucuronic acid and is converted to the water soluble form -bilirubin mono- and diglucoronids. Another name of bilirubin mono- and diglucoronids is conjugated bilirubin or direct bilirubin or bound bilirubin. This reaction is catalized by UDP-glucoroniltransferase.
Conjugated bilirubin is water soluble and is excreted by hepatocytes to the bile. Conjugated (bound) bilirubin undergoes degradation in the intestine through the action of intestinal microorganisms. Bilirubin is reduced and, mesobilirubin is formed. Then mesobilirubin is reduced again and mesobilinogen is formed. The reduction of mesobilinogen results in the formation of stercobilinogen (in a colon). Stercobilinogen is oxidized and the chief pigment (brown color) of feces stercobilin is formed. A part of mesobilinogen is reabsorbed by the mucous of intestine and via the vessels of vena porta system enter liver. In hepatocytes mesobilinogen is splitted to pyrol compounds which are excreted from the organism with bile. If the liver has undergone degeneration mesobilinogen enter the blood and is excreted by the kidneys. This mesobilinogen in urine is called urobilin, or true urobilin. Thus, true urobilin can be detected in urine only in liver parenchyma disease.
Another bile pigment that can be reabsorbed in intestine is stercobolinogen. Stercobolinogen is partially reabsorbed in the lower part of colon into the haemorroidal veins. From the blood stercobolinogen pass via the kidneys into the urine where it is oxidized to stercobilin. Another name of urine stercobilin is false urobilin.
As mentioned above, the conversion of bilirubin to mesobilirubin occurs under the influence of intestinal bacteria. These bacteria are killed or modified when broad-spectrum antibiotics are administered. The gut is sterile in the newborn babies. Under these circumstances, bilirubin is not-converted to urobilinogen, and the feces are colored yellow due to bilirubin. The feces may even become green because some bilirubin is reconverted to green-colored biliverdin by oxidation.
The total bilirubin content in the blood serum is 1,7-20,5 micromol/l, indirect (unconjugated) bilirubin content is 1,7-17,1 micromol/l and direct (conjugated) bilirubin content is 0,86-4,3 micromol/l.
Differentiation between unconjugated and conjugated bilirubin. Direct and indirect bilirubin.
Diazo reagent which is a mixture of sulfanilic acid, HCI and NaN02 is added to the serum. The conjugated bilirubin gives a reddish violet color with it and the maximum color intensity is obtained within 30 seconds; this is called direct test.
The unconjugated bilirubin does not give the direct test; however, it gives indirect test in which alcohol or caffeine is also added which sets free the bilirubin frum its complex with plasma proteins. Due to this difference in the type of diazo reaction given by these two forms of bilirubin, the term direct and indirect forms of bilirubin are also used to describe conjugated and unconjugated forms of bilirubin.
Some other differences between these two forms of bilirubin are given below:
Soluble in lipid, insoluble in water
Soluble in water, insoluble in lipid
2. Excretion in urine
3. Deposition in hram
4. Plasma level is increased in jaundice
Hepatic and posthepatic
The mechanism of jaundice development, their biochemical characteristic.
Jaundice or icterus is the orange-yellow discoloration of body tissues which is best seen in the skin and conjunctivae; it is caused by the presence of an excess of bilirubin in the blood plasma and tissue fluids. Depending upon the cause of an increased plasma bilirubin level, jaundice can be classified as
2) hepatic and
Pre-hepafic jaundice. This type of jaundice is due to a raised plasma level of unconjugated bilirubin. It is due to an excessive breakdown of red cells which leads to an increased production of uncongugated bilirubin; it is also called haemolytic jaundice. As the liver is not able to excrete into the bile all the bilirubin reaching it, the plasma bilirubin level rises and jaundice results. This type of jaundice was in the past called acholuric jaundice because the unconjugated bilirubin, being bound to plasma proteins, is not excreted in the urine despite its high level in the plasma; the urine is also without bile salts. Prehepatic jaundice is also seen in neonates (physiological jaundice) especially in the premature ones because the enzyme UDP-glucuronyl transferase is deficient. Moreover relatively more bilirubin is produced in-the neonates because of excessive breakdown of red blood cells.
Hepatic jaundice.This is typically seen in viral hepatitis. Several viruses are responsible for viral hepatitis and include hepatitis A, B, C and D viruses. The liver cells are damaged: inflammation produces obstruction of bile canaliculi due to swelling around them. This cholestasis causes the bile to regurgitate into the blood through bile canaliculi. The blood contains abnormally raised amount both of conjugated and unconjugated bilirubin and bile salts which are excreted in the urine.
Post hepatic jaundice. This results when there is extrahepatic cholestasis due to an obstruction in the biliary passages outside the liver. In this way, the bile cannot reach the small intestine and therefore the biliary passages outside as well as inside the liver are distended with bile. This leads to damage to the liver and bile regurgitates into the blood. The conjugated bilirubin and the bile salt levels of the blood are thus greatly raised and both of these are excreted in the urine. Liver function tests will vary according to the degree of obstruction, i.e complete or incomplete. If the obstruction is complete, the stools become pale or clay-colored and the urine does not have any stercobilin. The absorption of fat and fat soluble vitamins also suffers due to a lack of bile salts. Excess of bile salts in the plasma produces severe pruritus (itching).
Hemolytic jaundice is characterized by
1. Increase mainly of unconjugated bilirubin in the blood serum.
2. Increased excretion of urobilinogen with urine.
3. Dark brown colour of feces due to high content of stercobilinogen.
Hepatic jaundice is characterized by
1.Increased levels of conjugated and unconjugated bilirubin in serum.
2.Dark coloured urine due to the excessive excretion of bilirubin and urobilinogen.
3.Pale, clay coloured stools due to the absence of stercobilinogen.
4.Increased activities of alanine and aspartate transaminases.
Obstructive (post hepatic ) jaundice is characterized by
1.Increased concentration mainly of conjugated bilirubin in serum.
2.Dark coloured urine due to elevated excretion of bilirubin and clay coloured feces due to absence of stercobilinogen.
Role of the liver in detoxification processes.
A xenobiotics is a compound that is foreign to the body. The principal classes of xenobiotics of medical relevance are drugs, chemical cancerogens, and various compounds that have found their way into our environment by one route or another (insecticides, herbicides, pesticides, food additions, cosmetics, domestic chemical substances). Most of these compounds are subject to metabolism (chemical alteration) in the human body, with the liver being the main organ involved; occasionally a xenobiotics may be excreted unchanged.
Some internal substances also have toxic properties (for example, bilirubin, free ammonia, bioactive amines, products of amino acids decay in the intestine). Moreover, all hormones and mediatores must be inactivated.
Reactions of detoxification take place in the liver. Big molecules like bilirubin excreted with the bile to intestine and leaded out with feces. Small molecules go to the blood and excreted via kidney with urine.
The metabolism of xenobiotics has 2 phases:
In phase 1, the major reaction involved is hydroxylation, catalyzed by members of a class of enzymes referred to as monooxygenases or cytochrome P-450 species. These enzymes can also catalyze deamination, dehalogenation, desulfuration, epoxidation, peroxidation and reduction reaction. Hydrolysis reactions and non-P-450-catalyzed reactions also occur in phase 2.
In phase 2, the hydroxylated or other compounds produced in phase 1 are converted by specific enzymes to various polar metabolites by conjugation with glucuronic acid, sulfate, acetate, glutathione, or certain amino acids, or by methylation.
The overall purpose of metabolism of xenobiotics is to increase their water solubility (polarity) and thus facilitate their excretion from the body via kidney.Very hydrophobic xenobiotics would persist in adipose tissue almost indefinitely if they were not converted to more polar forms.
In certain cases, phase 1 metabolic reaction convert xenobiotics from inactive to biologically active compounds. In these instances, the original xenobiotics are referred to as prodrugs or procarcinogens. In other cases, additional phase 1 reactions convert the active compounds to less active or inactive forms prior to conjugation. In yet other cases, it is the conjugation reactions themselves that convert the active product of phase 1 to less active or inactive species, which are subsequently excreted in the urine or bile. In a very few cases, conjugation may actually increase the biologic activity of a xenobiotics.
Hydroxylation is the chief reaction involved in phase 1. The responsible enzymes are called monooxygenases or cytochrome P-450 species. The reaction catalyzed by a monooxygenase is:
RH above can represent a very widee variety of drugs, carcinogens, pollutants, and certain endogenous compounds, such as steroids and a number of other lipids. Cytochrome P-450 is considered the most versatile biocatalyst known. The importance of this enzyme is due to the fact that approximately 50 % of the drugs that patients ingest are metabolized by species of cytochrome P-450. The following are important points concerning cytochrome P-450 species:
1. Like hemoglobin, they are hemoproteins.
2. They are present in highest amount in the membranes of the endoplasmic reticulum (ER) (microsomal fraction) of liver, where they can make up approximately 20 % of the total protein. Thay are also in other tissues. In the adrenal, they are found in mitochondria as well as in the ER; the various hydroxylases present in that organ play an important role in cholesterol and steroid biosynthesis.
3. There are at least 6 closely related species of cytochrome P-450 present in liver ER, each with wide and somewhat overlapping substrate specificities, that act on a wide variety of drugs, carcinogens, and other xenobiotics in addition to endogenous compounds such as certain steroids.
4. NADPH, not NADP, is involved in the reaction mechanism of cytochrome P-450. The enzyme that uses NADPH to yield the reduced cytochrome P-450 is called NADPH-cytochrome P-450 reductase.
5. Lipids are also components of the cytochrome P-450 system. The preferred lipid is phosphatidylcholine, which is the major lipid found in membranes of the ER.
6. Most species of cytochrome P-450 are inducible. For instance, the administration of phenobarbital or of many other drugs causes a hypertrophy of the smooth ER and a 3- to 4-fold increase in the amount of cytochrome P-450 within 4-5 days. Induction of this enzyme has important clinical implications, since it is a biochemical mechanism of drug interaction.
7. One species of cytochrome P-450 has its characteristic absorption peak not at 450 nm but at 448 nm. It is often called cytochrome-448.This species appears to be relatively specific for the metabolism of polycyclic aromatic hydrocarbons (PAHs) and related molecules; for this reason it is called aromatic hydrocarbon hydroxylase (AHH). This enzyme is important in the metabolism of PAHs and in carcinogenesis produced by this agents.
8. Recent findings have shown that individual species of cytochrome P-450 frequently exist in polymorphic forms, some of which exhibit low catalytic activity. These observation are one important explanation for the variations in drug responses noted among many patients.
In phase 1 reactions, xenobiotics are generally converted to more polar, hydroxylated derivates. In phase 2 reactions, these derivates are conjugated with molecules such as glucuronic acid, sulfate, or glutatione. This renders them even more water-soluble, and they are eventually excreted in the urine or bile.
There are at least 5 types of phase 2 reactions:
1. Glucuronidation. UDP-glucuronic acid is the glucuronyl donor, and a variety of glucuronyl transferases, present in both the ER and cytosol, are the catalysts. Molecules such as bilirubin, thyroxin, 2-acetylaminofluorene (a carcinogen), aniline, benzoic acid, meprobromate (a tranquilizer), phenol, crezol, indol and skatol, and many steroids are excreted as glucuronides. The glucuronide may be attached to oxygen, nitrogen, or sulfur groups of substrates. Glucuronidation is probably the most frequent conjugation reaction.
Glucuronidation, the combining of glucuronic acid with toxins, requires the enzyme UDP-glucuronyl transferase (UDPGT). Many of the commonly prescribed drugs are detoxified through this pathway. It also helps to detoxify aspirin, menthol, vanillin (synthetic vanilla), food additives such as benzoates, and some hormones. Glucuronidation appears to work well, except for those with Gilbert's syndrome--a relatively common syndrome characterized by a chronically elevated serum bilirubin level (1.2-3.0 mg/dl). Previously considered rare, this disorder is now known to affect as much as 5% of the general population. The condition is usually without serious symptoms, although some patients do complain about loss of appetite, malaise, and fatigue (typical symptoms of impaired liver function). The main way this condition is recognized is by a slight yellowish tinge to the skin and white of the eye due to inadequate metabolism of bilirubin, a breakdown product of hemoglobin. The activity of UDPGT is increased by foods rich in the monoterpene limonene (citris peel, dill weed oil, and caraway oil). Methionine, administered as SAM, has been shown to be quite beneficial in treating Gilbert's syndrome.
2. Sulfation. Some alcohols, arylamines, and phenols are sulfated. The sulfate donor in these and other biologic sulfation reactions is adenosine 3´-phosphate-5´-phosphosulfate (PAPS); this compound is called active sulfate.
Sulfation is the conjugation of toxins with sulfur-containing compounds. The sulfation system is important for detoxifying several drugs, food additives, and, especially, toxins from intestinal bacteria and the environment. In addition to environmental toxins, sulfation is also used to detoxify some normal body chemicals and is the main pathway for the elimination of steroid and thyroid hormones. Since sulfation is also the primary route for the elimination of neurotransmitters, dysfunction in this system may contribute to the development of some nervous system disorders.
Many factors influence the activity of sulfate conjugation. For example, a diet low in methionine and cysteine has been shown to reduce sulfation. Sulfation is also reduced by excessive levels of molybdenum or vitamin B6 (over about 100 mg/day). In some cases, sulfation can be increased by supplemental sulfate, extra amounts of sulfur-containing foods in the diet, and the amino acids taurine and glutathione.
Sulfoxidation is the process by which the sulfur-containing molecules in drugs and foods are metabolized. It is also the process by which the body eliminates the sulfite food additives used to preserve many foods and drugs. Various sulfites are widely used in potato salad (as a preservative), salad bars (to keep the vegetables looking fresh), dried fruits (sulfites keep dried apricots orange), and some drugs. Normally, the enzyme sulfite oxidase metabolizes sulfites to safer sulfates, which are then excreted in the urine. Those with a poorly functioning sulfoxidation system, however, have an increased ratio of sulfite to sulfate in their urine. The strong odor in the urine after eating asparagus is an interesting phenomenon because, while it is unheard of in China, 100% of the French have been estimated to experience such an odor (about 50% of adults in the U.S. notice this effect). This example is an excellent example of genetic variability in liver detoxification function. Those with a poorly functioning sulfoxidation detoxification pathway are more sensitive to sulfur-containing drugs and foods containing sulfur or sulfite additives. This is especially important for asthmatics, which can react to these additives with life-threatening attacks. Molybdenum helps asthmatics with an elevated ratio of sulfites to sulfates in their urine because sulfite oxidase is dependent upon this trace mineral.
3. Conjugation with Glutathione. Glutathione (γ-glutamylcysteinylglycine) is a tripeptide consisting of glutamic acid, cysteine, and glycine. Glutathione is commonly abbreviated to GSH; the SH indicates the sulfhydryl group of its cysteine and is the business part of the molecule. A number of potentially toxic electrophilic xenobiotics (such as certain carcinogens) are conjugated to the nucleophilic GSH. The enzymes catalyzing these reactions are called glutathione S-transferases and are present in high amounts in liver cytosol and in lower amounts in other tissues. glutathione conjugates are subjected to further metabolism before excretion. The glutamyl and glycinyl groups belonging to glutathione are removed by specific enzymes, and an acetyl group (donated by acetyl-CoA) is added to the amino group of the remaining cystenyl moiety. The resulting compound is a mercapturic acid, a conjugate of L-acetylcysteine, which is then excreted in the urine.
Glutathione is also an important antioxidant. This combination of detoxification and free radical protection, results in glutathione being one of the most important anticarcinogens and antioxidants in our cells, which means that a deficiency is cause of serious liver dysfunction and damage. Exposure to high levels of toxins depletes glutathione faster than it can be produced or absorbed from the diet. This results in increased susceptibility to toxin-induced diseases, such as cancer, especially if phase I detoxification system is highly active. Disease states due to glutathione deficiency are not uncommon.
A deficiency can be induced either by diseases that increase the need for glutathione, deficiencies of the nutrients needed for synthesis, or diseases that inhibit its formation. Smoking increases the rate of utilization of glutathione, both in the detoxification of nicotine and in the neutralization of free radicals produced by the toxins in the smoke. Glutathione is available through two routes: diet and synthesis. Dietary glutathione (found in fresh fruits and vegetables, cooked fish, and meat) is absorbed well by the intestines and does not appear to be affected by the digestive processes. Dietary glutathione in foods appears to be efficiently absorbed into the blood. However, the same may not be true for glutathione supplements.
In healthy individuals, a daily dosage of 500 mg of vitamin C may be sufficient to elevate and maintain good tissue glutathione levels. In one double-blind study, the average red blood cell glutathione concentration rose nearly 50% with 500 mg/day of vitamin C. Increasing the dosage to 2,000 mg only raised red blood cell (RBC) glutathione levels by another 5%. Vitamin C raises glutathione by increasing its rate of synthesis. In addition, to vitamin C, other compounds which can help increase glutathione synthesis include N-acetylcysteine (NAC), glycine, and methionine. In an effort to increase antioxidant status in individuals with impaired glutathione synthesis, a variety of antioxidants have been used. Of these agents, only microhydrin, vitamin C and NAC have been able to offer some possible benefit.
Over the past 5-10 years, the use of NAC and glutathione products as antioxidants has become increasingly popular among nutritionally oriented physicians and the public. While supplementing the diet with high doses of NAC may be beneficial in cases of extreme oxidative stress (e.g. AIDS, cancer patients going through chemotherapy, or drug overdose), it may be an unwise practice in healthy individuals.
4. Acetylation. These reactions is represented by X + Acetyl-CoA → Acetyl-X + CoA, where X represents a xenobiotic. These reactions are catalyzed by acetyltransferases present in the cytosol of various tissues, particularly liver. The different aromatic amines, aromatic amino acids, such drug as isoniazid, used in the treatment of tuberculosis, and sulfanylamides are subjects to acetylation. Polymorphic types of acetyltransferases exist, resulting in individuals who are classified as slow or fast acetylators, and influence the rate of clearance of drugs such as isoniazid from blood. Slow acetylators are more subject to certain toxic effects of isoniazid because the drug persists longer in these individuals.
Conjugation of toxins with acetyl-CoA is the primary method by which the body eliminates sulfa drugs. This system appears to be especially sensitive to genetic variation, with those having a poor acetylation system being far more susceptible to sulfa drugs and other antibiotics. While not much is known about how to directly improve the activity of this system, it is known that acetylation is dependent on thiamine, pantothenic acid, and vitamin C.
5. Methylation. A few xenobiotics (amines, phenol, tio-substances, inorganic compounds of sulphur, selen, mercury, arsenic) are subject to methylation by methyltransferases, employing S-adenosylmethionine as methyl donor. Also catecholamines and nicotinic acid amid (active form of vitamin PP) are inactivated due to methylation.
Very important way of detoxification is ureogenes (urea synthesis). Free ammonia, which formed due to metabolism of amino acids, amides and amines, removed from organism in shape of urea.
Methylation involves conjugating methyl groups to toxins. Most of the methyl groups used for detoxification come from S-adenosylmethionine (SAM). SAM is synthesized from the amino acid methionine, a process which requires the nutrients choline, vitamin B12, and folic acid. SAM is able to inactivate estrogens (through methylation), supporting the use of methionine in conditions of estrogen excess, such as PMS. Its effects in preventing estrogen-induced cholestasis (stagnation of bile in the gall bladder) have been demonstrated in pregnant women and those on oral contraceptives. In addition to its role in promoting estrogen excretion, methionine has been shown to increase the membrane fluidity that is typically decreased by estrogens, thereby restoring several factors that promote bile flow. Methionine also promotes the flow of lipids to and from the liver in humans. Methionine is a major source of numerous sulfur-containing compounds, including the amino acids cysteine and taurine.
Kidney – the couple organ, which is responsible for excriting of final products of metabolism and for homeostasis. They regulate water and mineral metabolism, acid-base balance, excriting of nitrogenous slags, osmotic pressure. Also they regulate arterial pressure and erhythropoesis.
Kidney functions in organism:
a) excretion of final metabolic products;
b) maintaining of acid-base balance;
c) water-salts balance regulation;
d) endocrine function.(The kidneys secrete a variety of hormones, including erythropoietin, and the enzyme renin. Erythropoietin is released in response to hypoxia (low levels of oxygen at tissue level) in the renal circulation. It stimulates erythropoiesis (production of red blood cells) in the bone marrow. Calcitriol, the activated form of vitamin D, promotes intestinal absorption of calcium and the renalreabsorption of phosphate. Part of the renin-angiotensin-aldosterone system, renin is an enzyme involved in the regulation of aldosterone levels.)
The kidney participates in whole-body homeostasis, regulating acid-base balance, electrolyte concentrations, extracellular fluid volume, and regulation of blood pressure. The kidney accomplishes these homeostatic functions both independently and in concert with other organs, particularly those of the endocrine system. Various endocrine hormones coordinate these endocrine functions; these include renin, angiotensin II, aldosterone, antidiuretic hormone, and atrial natriuretic peptide, among others.
the kidney's functions are accomplished by relatively simple mechanisms of
filtration, reabsorption, and secretion, which take place in the nephron.
Filtration, which takes place at therenal
corpuscle, is the process by which cells and large proteins
are filtered from the blood to make an ultrafiltrate that eventually becomes
urine. The kidney generates
Physical and chemical characteristics and components of urine:
a) volume, physical and chemical properties of urine;
b) inorganic components of urine;
c) organic components of urine.
Key words and phrases:
Nephron – is the structural and functional unit of kidney.
Urine – fluid with different organic and inorganic compouds, which must be excreted (excess of water, final products of nitrogen metabolism, xenobiotics, products of protein’s decay, hormones, vitamins and their derivates). Most of them present in urine in a bigger amount than in blood plasma. So, urine formation – is not passive process (filtration and diffusion only).
In basis of urine formation lay 3 processes: filtration, reabsorbtion and secretion.
Water and low weight molecules go to the urine with help of following powers:
blood hydrostatic pressure in glomerulas (near
Hydrostatic pressure depends from correlation between opening of a. afference and a. efference.
urine formed in result of filtration (about
For evaluate of filtration used clearance (clearance for some substance – it is a amount of blood plasma in ml, which is cleaned from this substance after 1 minute passing through kidney).
Drugs which stimulate blood circulation in kidney (theophyllin), also stimulate filtration. Inflammatory processes of renal tissue (nephritis) reduce filtration, and azotaemia occurred (accumulation of urea, uric acid, creatinin, and other metabolic final products).
Lenght of renal tubules is about
All substances can be divided into 3 group:
1. Actively reabsorbed substances.
2. Substances, which are reabsorbed in a little amount.
3. Non-reabsorbed substances.
To the first group belong Na+, Cl-, Mg2+, Ca2+, H2O, glucose and other monosaccharides, amino acids, inorganic phosphates, hydrocarbonates, low-weight proteins, etc.
Na+ reabsorbed by active transport to the epitelium cell, then – into the extracellular matrix. Cl- and HCO3- following Na+ according to the electroneutrality principle, water – according to the osmotic gradient. From extracellular matrix substances go to the blood vessels. Mg2+ and Ca2+ are reabsorbed with help of special transport ATPases. Glucose and amino acids use the energy of Na+ gradient and special carriers. Proteins are reabsorbed by endocytosis.
Urea and uric acid are little reabsorbable substances.
Creatinin, mannitol, inulin and some other substances are non-reabsorbable.
Henle’s loop play important role in the reabsobtion process. Its descendent and ascendent parts create anti-stream system, which has big capacity for urine concentration and dilution. Fluid which passes from proximal part of renal tubule to the descendent part of Henle’s loop, where concentration of osmotic active substances higher than in kidney cortex. This concentration is due to activity of thick ascendent part of Henle’s loop, which is non-penetrated for water and which cells transport Na+ and Cl- into the interstitium. Wall of descendent part is penetrated for water and here water pass into the interstitium by osmotic gradient but osmotic active substances stay in the tubule. Ascendent part continue to reabsorb salt hypertonically, even in the absence of aldosteron, so that fluid entering the distal tubule still has a much lower osmolality than does interstitial fluid.
The kidney is responsible for maintaining a balance of the following substances:
All are reabsorbed nearly completely.
reabsorption (50%) via passive transport
reabsorption in medullary collecting ducts
reabsorption (65%, isosmotic)
reabsorption (25%, thick ascending, Na-K-2Cl symporter)
reabsorption (5%, sodium-chloride symporter)
reabsorption (thin ascending, thick ascending, Na-K-2Cl symporter)
reabsorption (sodium-chloride symporter)
absorbed osmotically along with solutes
reabsorption (regulated by ADH, via arginine vasopressin receptor 2)
reabsorption (80–90%) 
reabsorption (thick ascending) 
Uses vacuolar H+ATPase
secretion (intercalated cells)
Varies upon dietary needs.
reabsorption (20%, thick ascending, Na-K-2Cl symporter)
reabsorption (thick ascending) via passive transport
Calcium and magnesium compete, and an excess of one can lead to excretion of the other.
reabsorption (thick ascending)
Excreted as titratable acid.
The body is very sensitive to its pH. Outside the range of pH that is compatible with life, proteins are denatured and digested, enzymes lose their ability to function, and the body is unable to sustain itself. The kidneys maintain acid-base homeostasis by regulating the pH of the blood plasma. Gains and losses of acid and base must be balanced. Acids are divided into "volatile acids" and "nonvolatile acids". See also titratable acid.
The major homeostatic control point for maintaining this stable balance is renal excretion. The kidney is directed to excrete or retain sodium via the action of aldosterone, antidiuretic hormone(ADH, or vasopressin), atrial natriuretic peptide (ANP), and other hormones. Abnormal ranges of the fractional excretion of sodium can imply acute tubular necrosis or glomerular dysfunction.
Some substances (K+, ammonia and other) are secreted into urine in the distal part of tubules. K+ is changed to Na+ by the activity of Na+-K+ATPase.
The renin–angiotensin system (RAS) or the renin–angiotensin–aldosterone system (RAAS) is a hormone system that regulates blood pressure and water (fluid) balance. When blood volume is low, juxtaglomerular cells in the kidneys secrete renin directly into circulation. Plasma renin then carries out the conversion of angiotensinogen released by the liver to angiotensin I.
Angiotensin I is subsequently converted to angiotensin II by the enzyme angiotensin converting enzyme found in the lungs. Angiotensin II is a potent vaso-active peptide that causes blood vessels to constrict, resulting in increased blood pressure. Angiotensin II also stimulates the secretion of the hormone aldosterone from the adrenal cortex. Aldosterone causes the tubules of the kidneys to increase the reabsorption of sodium and water into the blood. This increases the volume of fluid in the body, which also increases blood pressure.
If the renin–angiotensin–aldosterone system is abnormally active, blood pressure will be too high. There are many drugs that interrupt different steps in this system to lower blood pressure. These drugs are one of the main ways to control high blood pressure (hypertension), heart failure,kidney failure, and harmful effects of diabetes.
The system can be activated when there is a loss of blood volume or a drop in blood pressure (such as in hemorrhage). This loss of pressure is interpreted by baroreceptors in the carotid sinus. In alternative fashion, a decrease in the filtrate NaCl concentration and/or decreased filtrate flow rate will stimulate the macula densa to signal the juxtaglomerular cells to release renin.
· If the perfusion of the juxtaglomerular apparatus in the kidney's macula densa decreases, then the juxtaglomerular cells (granular cells, modified pericytes in the glomerular capillary) release the enzyme renin.
· Angiotensin I is then converted to angiotensin II by angiotensin-converting enzyme (ACE), which is thought to be found mainly in lung capillaries. One study in 1992 found ACE in all blood vessel endothelial cells.
· Angiotensin II is the major bioactive product of the renin-angiotensin system, binding to receptors on intraglomerular mesangial cells, causing these cells to contract along with the blood vessels surrounding them and causing the release of aldosterone from the zona glomerulosa in the adrenal cortex. Angiotensin II acts as an endocrine, autocrine/paracrine, and intracrinehormone.
· In the kidneys, it constricts glomerular arterioles, having a greater effect on efferent arterioles than afferent. As with most other capillary beds in the body, the constriction of afferent arterioles increases the arteriolar resistance, raising systemic arterial blood pressure and decreasing the blood flow. However, the kidneys must continue to filter enough blood despite this drop in blood flow, necessitating mechanisms to keep glomerular blood pressure up. To do this, angiotensin II constricts efferent arterioles, which forces blood to build up in the glomerulus, increasing glomerular pressure. The glomerular filtration rate(GFR) is thus maintained, and blood filtration can continue despite lowered overall kidney blood flow. Because the filtration fraction has increased, there is less plasma fluid in the downstream peritubular capillaries. This in turn leads to a decreased hydrostatic pressure and increased oncotic pressure (due to unfiltered plasma proteins) in the peritubular capillaries. The effect of decreased hydrostatic pressure and increased oncotic pressure in the peritubular capillaries will facilitate increased reabsorption of tubular fluid.
· Angiotensin II decreases medullary blood flow through the vasa recta. This decreases the washout of NaCl and urea in the kidney medullary space. Thus, higher concentrations of NaCl and urea in the medulla facilitate increased absorption of tubular fluid. Furthermore, increased reabsorption of fluid into the medulla will increase passive reabsorption of sodium along the thick ascending limb of the loop of Henle.
· Angiotensin II stimulates Na+/H+ exchangers located on the apical membranes (faces the tubular lumen) of cells in the proximal tubule and thick ascending limb of the loop of Henle in addition to Na+ channels in the collecting ducts. This will ultimately lead to increased sodium reabsorption
· Angiotensin II stimulates the hypertrophy of renal tubule cells, leading to further sodium reabsorption.
· In the adrenal cortex, it acts to cause the release of aldosterone. Aldosterone acts on the tubules (e.g., the distal convoluted tubules and the cortical collecting ducts) in the kidneys, causing them to reabsorb more sodium and water from the urine. This increases blood volume and, therefore, increases blood pressure. In exchange for the reabsorbing of sodium to blood, potassiumis secreted into the tubules, becomes part of urine and is excreted.
· Release of anti-diuretic hormone (ADH), also called vasopressin – ADH is made in the hypothalamus and released from the posterior pituitary gland. As its name suggests, it also exhibits vaso-constrictive properties, but its main course of action is to stimulate reabsorption of water in the kidneys. ADH also acts on the central nervous system to increase an individual's appetite for salt, and to stimulate the sensation of thirst.
These effects directly act in concert to increase blood pressure.
Locally expressed renin-angiotensin systems have been found in a number of tissues, including the kidneys, adrenal glands, the heart, vasculature and nervous system, and have a variety of functions, including local cardiovascular regulation, in association or independently of the systemic renin-angiotensin system, as well as non-cardiovascular functions. Outside the kidneys, renin is predominantly picked up from the circulation but may be secreted locally in some tissues; its precursor prorenin is highly expressed in tissues and more than half of circulating prorenin is of extrarenal origin, but its physiological role besides serving as precursor to renin is still unclear.Outside the liver, angiotensinogen is picked up from the circulation or expressed locally in some tissues; with renin they form angiotensin I, and locally expressed angiotensin converting enzyme, chymase or other enzymes can transform it into angiotensin II. This process can be intracellular or interstitial.
In the adrenal glands, it is likely involved in the paracrine regulation of aldosterone secretion, in the heart and vasculature, it may be involved in remodeling or vascular tone, and in the brain where it is largely independent of the circulatory RAS, it may be involved in local blood pressure regulation. In addition, both the central and peripheral nervous systems can use angiotensin for sympathetic neurotransmision. Other places of expression include the reproductive system, the skin and digestive organs. Medications aimed at the systemic system may affect the expression of those local systems, beneficially or adversely.[
Peculiarities of biochemical processes in kidney.
have a very high level of metabolic processes. They use about 10 % of all O2,
which used in organism. During 24 hours through kidney pass 700-
Metabolism of proteins also present in kidney in high level. Especially, glutamine deaminase is very active and a lot of free ammonia formed. In kidney take place the first reaction of creatin synthesis.
Kidney have plenty of different enzymes: LDG (1, 2, 3, 5), AsAT, AlAT. Specific for kidney is alanine amino peptidase, 3rd isoform.
Utilization of glucose in cortex and medulla is differ one from another. Dominative type of glycolysis in cortex is aerobic way and CO2 formed in result. In medulla dominative type is anaerobic and glucose converted to lactate.
Two sources contribute to the renal ammonia: blood ammonia (is about one-third of excreted ammonia), and ammonia formed in the kidney. The predominant source for ammonia production within the kidney is glutamine, the most abundant amino acid in plasma, but a small amount may originate from the metabolism of other amino acids such as asparagine, alanine, and histidine. Ammonia is secreted into the tubular lumen throughout the entire length of the nephron. Secretion occurs both during normal acid-base balance and in chronic acidosis.Metabolic acidosis is accompanied by an adaptive increase in renal ammonia production with a corresponding increase in urinary ammonium excretion.
Kidney cortex like liver appear to be unique in that it possess the enzymatic potential for both glucose synthesis from noncarbohydrate precursors (gluconeogenesis) and glucose degradation via the glycolytic pathway. Gluconeogenesis is important when the dietary supply of glucose does not satisfy the metabolic demands. Under these conditions, glucose is required by the central nervous system, the red blood cells, and possibly other tissues which cannot obtain all their energy requirements from fatty acids or ketone body oxidation. Also, gluconeogenesis may be important in the removal of excessive quantities of glucose precursors from the blood (lactate acid after severe exercise for example). Although the biosynthetic pathways are similar, there are several important differences in the factors which regulate gluconeogenesis in the two organs. 1) The liver utilizes predominately pyruvate, lactate and alanine. The kidney cortex utilizes pyruvate, lactate, citrate, α-ketoglutarate, glycine and glutamine. 2) Hydrogen ion activity has little effect upon hepatic gluconeogenesis, but it has marked effects upon renal gluconeogenesis. Thus, when intracellular fluid pH is reduced (metabolic acidosis, respiratory acidosis or potassium depletion), the rates of gluconeogenesis in slices of renal cortex are markedly increased. The ability of the kidney to convert certain organic acids to glucose, a neutral substance, is an example of a nonexcretory mechanism in the kidney for pH regulation.
Regulation of urine formation.
Na-uretic hormone (produced in heart) decrease reabsorbtion of Na+, and quantity of urine increased.
Aldosteron and some other hormones (vasopressin, renin, angiotensin II) increase Na-reabsorbtion and decrease quantity of urine.
Role of kidney in acid-base balance regulation.
The kidneys have two important roles in the maintaining of the acid-base balance: to reabsorb bicarbonate from and to excrete hydrogen ions into urine. 4500 mmol of bicarbonate are filtered into the primary filtrate of urine daily, but only 2 mmol of it are finally excreted. 70-80% of bicarbonate is reabsorbed in the first part of proximal tubule, 10-20% in the loop of Henle and 5-10% in the distal tubule and collecting ducts. (Jalanko & Holmberg 1998)
Carbonic anhydrase plays an important role in the reabsorption in the proximal tubule. Disturbance in the reabsorption of bicarbonate in the proximal tubule leads to metabolic acidosis, hyperchloremia and alkalotic urine. This disease is named as "type II renal tubular acidosis" (N25.8). (Jalanko & Holmberg 1998)
Renal tubules actively secrete hydrogen ions. Most of this takes place in the distal part of the nephron, but active transport of hydrogen ions occurs in the proximal tubule, too. The H-ATPase of the apical cell membrane secretes hydrogen ions into urine. For each hydrogen ion secreted, one bicarbonate molecule is transported to the interstitial fluid, from there it diffuses into the bloodstream. Fifty mmol of hydrogen ions are normally excreted daily. (Jalanko & Holmberg 1998)
If the hydrogen ions are not properly secreted into the collecting ducts, the result is metabolic acidosis, hypokalemia, hypocalcemia, nephrocalcinosis and an alkalotic urine. This disease is called "type I renal tubular acidosis" (N25.8). (Jalanko & Holmberg 1998)
hydrogen ion gradient, against which the transport mechanism can secrete H+ ions,
corresponds to a urine pH of
The source of the hydrogen ions secreted by the tubular cells is not completely certain. It is probably produced by dissociation of H2CO3. The acid-secreting cells contain carbonic anhydrase, which facilitates the rapid formation of H2CO3 from CO2 and water. The renal acid secretion is mainly regulated by the changes in the intracellular pCO2, potassium concentration, carbonic anhydrase activity and adrenocortical hormone concentration. (Ganong 1991)
Kidney have some mechanisms for maintaining acid-base balance. Na+ reabsorbtion and H+ secretion play very important role.
1. Primary urine has a lot of Na2HPO4 (in dissociated form). When Na+ reabsorbed, H+ secreted into urine and NaH2PO4 formed.
2. Formation of hydrocarbonates. Inside renal cells carboanhydrase forms from CO2 and H2O H2CO3, which dissociated to H+ and HCO3-. H+ excreted from cell into urine (antiport with Na+) and leaded with urine. Na+ connect with HCO3-, NaHCO3 formed and go to the blood, thereupon acidity decreased.
3. Formation of free ammonia. NH3 used for formation of NH4+ (H+ ion associted), and different acid metabolites excreted as ammonia salts.
Physical and chemical characteristics of urine.
Urine amount (diures) in healthy people is 1000-2000 ml per day. Day-time diures is in 3-4 times more than night-time.
Normal colour of urine is yellow (like hay or amber), what is due to presence of urochrom (derivate of urobilin or urobilinogen). Some another colour substances are uroerythrin (derivate of melanine), uroporphyrines, rybophlavine and other. Colour depends from urine concentration.
Urine varies in appearance, depending principally upon a body's level of hydration, as well as other factors. Normal urine is a transparent solution ranging from colorless to amber but is usually a pale yellow. In the urine of a healthy individual the color comes primarily from the presence of urobilin. Urobilin in turn is a final waste product resulting from the breakdown of heme from hemoglobin during the destruction of aging blood cells.
Colorless urine indicates over-hydration, generally preferable to dehydration (though it can remove essential salts from the body). Colorless urine in drug tests can suggest an attempt to avoid detection of illicit drugs in the bloodstream through over-hydration.
· Dark yellow urine is often indicative of dehydration.
· Yellowing/light orange may be caused by removal of excess B vitamins from the bloodstream.
· Bloody urine is termed hematuria, a symptom of a wide variety of medical conditions
· Black or dark-colored urine is referred to as melanuria and may be caused by a melanoma.
· Pinkish urine can result from the consumption of beets.
· Greenish urine can result from the consumption of asparagus.
· Blue urine can be caused by the ingestion of methylene blue, e.g. in medications
· Blue urine stains can be caused by blue diaper syndrome
Urine is transparent. This characteristic depends from amount of different salts (oxalates, urates, phosphates), amount of present epitelium cells and leucocytes.
Density of urine depends from concentration of soluble
substances. Borders of variation are from 1002 to 1035 g/l. Near 60-
The pH of urine can vary between 4.6 and 8, with neutral (7) being norm. In persons with hyperuricosuria, acidic urine can contribute to the formation of stones of uric acid in the kidneys, ureters, or bladder. Urine pH can be monitored by a physician or at home.
A diet high in citrus, vegetables, or dairy can increase urine pH (more basic). Some drugs also can increase urine pH, including acetazolamide, potassium citrate, and sodium bicarbonate.
A diet high in meat can decrease urine pH (more acidic). Cranberries, popularly thought to decrease the pH of urine, have actually been shown not to acidify urine. Drugs that can decrease urine pH include ammonium chloride, chlorothiazide diuretics, and methenamine mandelate.
In normal conditions urine has acid or weak acid reaction (pH=5,3-6,8). This depends from presence of NaH2PO4 and KH2PO4.
Fresh urine has a specific smell, which is due to presence of flying acids. But a lot of microorganisms, which are present in urine, split urea and free ammonia formed.
Exhaustive detailed description of the composition of human urine can be found in NASA Contractor Report No. NASA CR-1802, D. F. Putnam, July 1971. That report provided detailed chemical analyses for inorganic and organic constituents, methods of analysis, chemical and physical properties and its behavior during concentrative processes such as evaporation, distillation and other physiochemical operations. Urine is an aqueous solution of greater than 95% water, with the remaining constituents, in order of decreasing concentration urea 9.3 g/L, chloride 1.87 g/L, sodium 1.17 g/L, potassium 0.750 g/L, creatinine 0.670 g/L and other dissolved ions, inorganic and organic compounds.
Urine is sterile until it reaches the urethra, where epithelial cells lining the urethra are colonized by facultatively anaerobic Gram negative rods and cocci. Subsequent to elimination from the body, urine can acquire strong odors due to bacterial action, and in particular the release of ammonia from the breakdown of urea.
Some diseases alter the quantity and consistency of urine, such as diabetes introducing sugar. Consuming beets can result in beeturia (pink/red urine containing betanin) for some 10–14% of the popu Urine is a liquid produced by the kidneys to remove waste products from the bloodstream. Human urine is yellowish in color and variable in chemical composition, but here is a list of its primary components.
Human urine consists primarily of water, with organic solutes including urea, creatinine, uric acid, and trace amounts of enzymes, carbohydrates, hormones, fatty acids, pigments, and mucins, and inorganic ions such as sodium (Na+), potassium (K+), chloride (Cl-), magnesium (Mg2+), calcium (Ca2+), ammonium (NH4+), sulfates (SO42-), and phosphates (e.g., PO43-). A representative chemical composition would be:
urea 9.3 g/l
chloride 1.87 g/l
sodium 1.17 g/l
potassium 0.750 g/l
creatinine 0.670 g/l
Organic compounds of urine.
Proteins. Healthy people excretes 30 mg of proteins per day. As a rule these are low weight proteins.
This is main part of organic compounds in urine. Urea nitrogen is about 80-90 %
of all urine nitrogen. 20-
Uric acid. Approximately 0,6-1,0 g of uric acid is excreted per day in form of different salts (urates), mainly in form of sodium salt. Its amount depends from food.
and creatin. Near 1-
acids. Per day healthy person excretes 2-
substances. Hypuric acid (benzoyl glycine) is excreted in
(potassium salt of indoxylsulfuric acid). Per day
excrition of indican is about 10-
Organic acids. Formic, acetic, butyric, β-oxybutyric, acetoacetic and some other organic acids are present in urine in a little amount.
Vitamines. Almost all vitamines can be excreted via kidney, especially, water-soluble. Approximately 20-30 mg of vit C, 0.1-0.3 mg of vit B1, 0.5-0.8 mg of vit B2 and some products of vitamine’s metabolism. These data can be used for evaluating of supplying our organism by vitamines.
Hormones and their derivates are always present in urine. Their amount depends
from functional state of endocrinal glands and liver. There is a very wide used
test – determination of 17-ketosteroids in urine. For healthy man this index is
Urobilin. Present in a little amount, gives to urine yellow colour.
Bilirubin. In normal conditions present in so little amount that cannot be found by routine methods of investigations.
Glucose. In normal conditions present in so little amount that cannot be found by routine methods of investigations.
Galactose. Present in the newborn’s urine, when digestion of milk or transformation of glalactose into glucose in the liver are violated.
Fructose. It is present in urine very seldom, after eating a lot of fruits, berries and honey. In all other cases it indicates about liver’s disorders, diabetes mellitus.
Pentoses. Pentoses are excreted after eating a lot of fruits, fruit juices, in case of diabetes mellitus and steroid diabetes, some intoxications.
Ketone bodies. In normal conditions urine contains 20-50 mg of ketone bodies and this amount cannot be found by routine methods of clinical investigations.
Porphyrines. Urine of healthy people contains a few I type porphyrines (up to 300 mkg per day).
Inorganic compounds of urine.
Urine of healthy people contains 15-
Per day near 8-
Twenty-four hours urine contains 2-
Different drugs can change excretion of Na and K. For example, salicylates and cortikosteroids keep Na and amplify excretion of K.
Twenty-four hours urine contains 0.1-
Content of magnesium in urine is 0.03-
Iron. Amount of iron in urine is about 1 mg per day.
Phosphorus. In urine are present one-substituted phosphates of potassium and sodium. Their amount depends from blood pH. In case of acidosis two-substituted phosphates (Na2HPO4) react with H+ and one-substituted phosphates (NaH2PO4) formed. In case of alkalosis one-substituted phosphates react with bases and two-substituted phosphates formed. So, in both cases amount of phosphates in urine increases.
Amount of sulfur in twenty-four hours urine is 2-
Ammonia. Ammonia is excreted in ammonium sulfates and couple substances. Ammonium salts make up 3-6 % of all nitrogen in urine. Their amount depends from character of food and blood pH.
Urine analysis infers valuable information in a variety of ailments. Physical characteristics of urine have been used as diagnostic and prognostic tool from the time immemorial by the health physicians. We know that the major functions of kidneys are:
· Removal of water not needed by the body fluids, the amount depending on the balance between glomerular filtrate and he degree of tubular reabsorption;
· The excretion of certain substances normally present in the plasma when their concentration rises above a certain level;
· The selective reabsorption of substances such as glucose which are of value to the body;
· The excretion of useless substances; and
· Regulation of acid base balance.
Disordered renal function may lead to a change in the volume of the urine excreted per day along with remarkable changes in its physical and chemical properties and microscopic contents. Urine analysis is the very first investigation of diagnostic importance not only in renal disorders but also in other diseases like diabetes, liver disease, jaundice etc. In diagnostic pathology the extent of abnormalities could only be understood in comparison with the reference values obtained from similar investigations in normal individuals. Hence, it is important to have an understanding of normal parameters of physical and chemical characteristics of urine.
Characteristics of normal urine:
· Quantity: The quantity averages 1500 to 2000 ml in an adult man daily. It may vary with the amount of fluid taken. In fact it is linked with the protein metabolism; higher is the protein intake higher will be the urinary output since the urea produced from the protein needs to be flushed out from the body. Higher is the urea production in the body, the higher is the volume of urine to excrete it.
· Color: The color should be clear pale amber without any deposits. However, a light flocculent cloud of mucus may sometimes be seen floating in the normal urine.
· Specific gravity: It varies from 1.010 to 1.025. Specific gravity is determined with urinometer.
· Odor: The odor is aromatic.
· Reaction: The reaction of normal urine is slightly acidic with an average pH of 6.0.
of normal urine: Urine is mainly composed of water, urea
and sodium chloride. I an adult taking about
· Water: Near about 96%
· Solids: About 4% (urea 2% and other metabolic products 2%. Other metabolic products include: uric acid, creatinine, electrolytes or salts such as sodium chloride, potassium chloride and bicarbonate).
Urea is one of
the end products of protein metabolism. It is prepared from the deaminated
amino-acid in the liver and reach the kidneys through blood
circulation (The normal blood urea level is 20-40 mg/dl). About
Uric Acid: The normal
level of uric acid in blood is 2 to 6 mg/dl and about 1.5 to
§ Creatinine: Creatinine is the metabolic waste of creatin in muscle. Purine bodies, oxalates, phosphates, sulphates and urates are the other metabolic products.
§ Electrolytes or salts such as sodium chloride and potassium chloride are also excreted in the urine to maintain the normal level in blood. These are the salts which are the part of our daily diet and are always taken in excess and need to be excreted to maintain normal physiological balance.
Proteinuria may be a sign of renal (kidney) damage. Since serum proteins are readily reabsorbed from urine, the presence of excess protein indicates either an insufficiency of absorption or impaired filtration. Diabetics may suffer from damaged nephrons and develop proteinuria. The most common cause of proteinuria is diabetes, and in any person with proteinuria and diabetes, the etiology of the underlying proteinuria should be separated into two categories: diabetic proteinuria versus the field.
Conditions with proteinuria as a sign
Proteinuria may be a feature of the following conditions:
· Nephrotic syndromes (i.e. intrinsic renal failure)
· Toxic lesions of kidneys
· Collagen vascular diseases (e.g. systemic lupus erythematosus)
· Strenuous exercise
· Benign orthostatic (postural) proteinuria
· Focal segmental glomerulosclerosis (FSGS)
· IgA nephropathy (i.e. Berger's disease)
· Rheumatoid arthritis
· A urinary tract infection which has spread to the kidney(s)
· Malignancies (e.g., lymphoma, other cancers)
There are three main mechanisms to cause proteinuria:
· Due to disease in glomerulus
· Because of increased quantity of proteins in serum (overflow proteinuria)
Proteinuria can also be caused by certain biological agents, such as bevacizumab (Avastin) used in cancer treatment, or
by excessive fluid intake (drinking in excess of
Glucosuria is the excretion of glucose into the urine. Ordinarily, urine contains no glucose because the kidneys are able to reclaim all of the filtered glucose back into the bloodstream. Glycosuria is nearly always caused by elevated blood glucose levels, most commonly due to untreated diabetes mellitus. Rarely, glycosuria is due to an intrinsic problem with glucose reabsorption within the kidneys themselves, a condition termed renal glycosuria. Glycosuria leads to excessive water loss into the urine with resultant dehydration, a process called osmotic diuresis.
Glycosuria refers to sugar in the urine. Less than 0.1% of glucose normally filtered by the glomeruli appears in the urine, and less than 130 mg should appear in the urine over a 24-hour period. Glucose is present in glomerular filtrate but is reabsorbed by the kidney's proximal tubule. If the blood glucose level exceeds the capacity of the tubules to reabsorb all the glucose present in the glomerular filtrate, the renal threshold is reached and glucose spills into the urine. A finding of glycosuria indicates that the person is hyperglycemic or has a lowered renal threshold for glucose. The renal threshold for glucose is approximately 160 to 190mg/dl of blood; glucose does not appear in the urine until the blood glucose rises above this level.
Occasionally, glycosuria may be a normal finding, such as after eating a heavy meal or during times of emotional stress. Some individuals have a benign condition in which they have a lower than usual renal threshold for glucose, but have normal blood glucose levels. In pregnancy, the renal threshold for glucose may be lowered so that small amounts of glycosuria may be present. Patients on hyperalimentation may have glycosuria if the carbohydrate solution is being infused faster than the pancreas can produce insulin. The most common reason for glycosuria is diabetes mellitus. Urine glucose tests are used to screen for diabetes, to confirm a diagnosis of diabetes, or to monitor diabetic control.
Renal glycosuria, also known as renal glucosuria, is a rare condition in which the simple sugar glucose is excreted in the urine despite normal or low blood glucose levels. With normal kidney (renal) function, glucose is excreted in the urine only when there are abnormally elevated levels of glucose in the blood. However, in those with renal glycosuria, glucose is abnormally elevated in the urine due to improper functioning of the renal tubules, which are primary components of nephrons, the filtering units of the kidneys.
Hematuria, or haematuria, is the presence of red blood cells (erythrocytes) in the urine. It may be idiopathic and/or benign, or it can be a sign that there is a kidney stone or a tumor in the urinary tract (kidneys, ureters, urinary bladder, prostate, and urethra), ranging from trivial to lethal. If white blood cells are found in addition to red blood cells, then it is a signal of urinary tract infection.
Red discoloration of the urine can have various causes:
o Macroscopic hematuria (or "frank" or "gross") hematuria
· Other pigments
Acute hematuria due to trauma.
Often, the diagnosis is made on the basis of the medical history and some blood tests—especially in young people in whom the risk of malignancy is negligible and the symptoms are generally self-limiting.
If combined with pain, it may be loin pain hematuria syndrome.
The most common causes of hematuria are:
· Benign prostatic hyperplasia, in older men, especially those over 50
Other, less common causes of hematuria include:
· IgA nephropathy ("Berger's disease") - occurs during viral infections in predisposed patients
· Trauma (e.g., a blow to the kidneys)
· Kidney diseases
· Prostate infection or inflammation (prostatitis)
Rare causes include:
· Sickle cell trait can precipitate large amounts of red blood cell discharge, but only a small number of individuals endure this problem
· Arteriovenous malformation of the kidney (rare, but may impress like renal cell carcinoma on scans as both are highly vascular)
· Fibrinoid necrosis of the Glomeruli (as a result of malignant hypertension)
· Allergy may rarely cause episodic gross hematuria in children
· Ureteral Pelvic Junction Obstruction (UPJ) is a rare condition beginning from birth in which the ureter is blocked between the kidney and bladder. This condition may cause blood in the urine 
· March hematuria secondary to repetitive impacts on the body, usually the feet
· Athletic nephritis secondary to strenuous exercise