Renal Physiology PDF

Renal Physiology The kidneys have several functions including the following: Kidneys regulate water and electrolytes balance: Intake of water and many electrolytes usually are governed mainly by a persons`s eating and drinking habits, necessating the kidneys to adjust their excretion rates to match...

Renal Physiology The kidneys have several functions including the following: Kidneys regulate water and electrolytes balance: Intake of water and many electrolytes usually are governed mainly by a persons`s eating and drinking habits, necessating the kidneys to adjust their excretion rates to match precisely intakes of various substances. If intake is less than excretion, the amount of that substance in the body will decrease, and vice versa. Kidneys responsible for excretion of metabolic waste products like urea (from the metabolism of amino acids), creatinine (from muscle creatine), uric acid (from nucleic acid), bilirubin (the end product of Hb breakdown), metabolites of various hormones and foreign chemicals like drugs and toxins. Hormones in the blood are removed in many ways, mostly in the liver, but a number of hormones are removed in parallel by renal processes. A waste is any substance that is useless to the body or present in excess of the body‟s needs. A metabolic waste, more specifically, is a waste substance produced by the body. Thus the food residue in feces, for example, is a waste but not a metabolic waste, since it was not produced by the body and, indeed, never entered the body‟s tissues. Metabolism produces a great quantity of wastes that are lethal to cells if allowed to accumulate. Some of the most toxic examples are small nitrogen-containing compounds called nitrogenous wastes. About 50% of the nitrogenous waste is urea, a by-product of protein catabolism. Proteins are broken down to amino acids, and then the -NH2 group is removed from each amino acid. The -NH2 forms ammonia, which is exceedingly toxic but the liver quickly, converts it to urea. Other nitrogenous wastes in the urine include uric acid and creatinine, produced by the catabolism of nucleic acids and creatine phosphate, respectively. Although less toxic than ammonia and less abundant than urea, these wastes are far from harmless. The level of nitrogenous waste in the blood is typically expressed as blood urea nitrogen (BUN). The urea concentration is normally 7 to 18 mg/dL. An abnormally elevated BUN is called azotemia and may indicate renal insufficiency. Azotemia may progress to uremia, a syndrome of diarrhea, vomiting, dyspnea, and cardiac arrhythmia stemming from the toxic effects of nitrogenous wastes. Convulsions, coma, and death can follow within a few days. Unless a kidney transplant is available, renal failure requires hemodialysis to remove nitrogenous wastes from the blood. Kidneys play essential role in regulation of arterial pressure both in long-term regulation (through excretion of variable amounts of sodium and water) and in short-term regulation (through secretion of vasoactive factors or substances such as renin). Kidneys contribute to acid-base regulation (along with the lungs and body buffers) through excreting acids and by regulating the body buffer stores. Kidneys responsible for regulation of erythrocyte production from the bone marrow by secreting erythropoietin which stimulate the bone marrow to produce erythrocytes.  Kidneys regulate 1, 25- dihydroxy vit D3 production which is essential in regulation of Ca and phosphate. In kidneys, gluconeogenesis can take place. Most gluconeogenesis occurs in the liver, but a substantial fraction occurs in the kidneys, particularly during a prolonged fast. Anatomy and function of the kidney (Figure 1) The kidney consists of: [A] Nephron. [B] Blood vessels. [C] Nerves (A) Nephron: It is a tubular system and it is the basic functional unit of the kidney that capable of forming urine by itself. There are about 1 million nephrons in each kidney in human. Kidneys cannot regenerate new nephrons and their number decrease with aging, each nephron consists of: [A] Bowman`s capsule (figure 1A): It is the invaginated blind end of the tubule that encased the glomerulus (which is a branching capillaries). The pressure in the glomerular capillaries is higher than that in other capillary beds. The membrane of the glomerular capillaries is called the glomerular membrane (figure 2 & 3). The average total area of glomerular capillary endothelium across which filtration occurs (i.e. the glomerular membrane) is about 0.8 m2. In general, this membrane is different from other capillary membranes by having three layers instead of two. These three layers are endothelial layer of the capillary itself, a basement membrane (basal lamina), and a layer of epithelial cells (podocytes). Narrow filtration that slits between these projections are bridged by a membrane protein called nephrin, which also contributes significantly to the filtration barrier. Fixed negative charges are present in the basement membrane and the filtration slits, and account for electrical repulsion of negatively charged macromolecules by the filtration barrier. Substances with a molecular weight of about 10 kDa are freely filtered; as molecular weight increases from 10 kDa to 70 kDa, there is a roughly linear decline in the amount of solute filtered. Albumin, with a molecular weight of 70 kDa, is almost large enough to be filtered. It is essential that albumin is not lost in the urine because the plasma albumin concentration is the largest contributor to plasma oncotic pressure. The electrical charge on a macromolecule also determines its filterability. There is less filtration of negatively charged macromolecules compared to neutral molecules of the same size. At a physiologic extracellular fluid pH of 7.4, proteins carry net negative charges, which reduce their filtration. What is not filtered? Cells, of course, are too large to be filtered. Importantly, proteins are NOT filtered, but are retained in the plasma. Also, small molecular weight substances that are bound to proteins will not be filtered. It is the structure of the filtration membrane that prevents proteins from being filtered. Another type of cells is also present between the basal lamina and the endothelium called mesangial cells, which are contractile cells and play a role in the regulation of glomerular filtration besides other functions. Yet, despite the number of layers, the permeability of the glomerular membrane is from 100-500 times as great as that of the usual capillary. The tremendous permeability of the glomerular membrane is caused by the presence of thousands of small holes which are called fenestrae in the endothelial cells, by the presence of large spaces in the basement membrane, and by incontinuity of the cells that form the epithelial layer which are finger-like projections that forms slits between themselves called slit-pores. [B] The Tubule: Throughout its course, the tubule is made up of a single layer of epithelial cells resting on a basement membrane. (Note: All epithelial cell layers rest on a basement membrane). The structural and immunocytochemical characteristics of these epithelial cells vary from segment to segment of the tubule. A common feature is the presence of tight junctions between adjacent cells that physically link them together. Proximal tubules: It includes proximal convoluted tubule and proximal straight tubule. They lie in the renal cortex along with the glomerulus. The epithelial cells of the proximal tubule are highly metabolic cells, with large number of mitochondria to support extremely rapid active transport processes and they are interdigitated with one another and are united by apical tight junction but contain lateral intercellular space. It contains a brush border due to the presence of microvilli. Reabsorption in the proximal tubule (figure 4) is essentially isotonic; i.e. the osmolality of fluid in all parts of the proximal tubule is approximately to that of plasma. The proximal tubule resorbs from the filtered material 65% of Na+, K+, Cl-, HCO3- and H2O, and nearly all glucose, lactate and amino acids and a proportional amount of water. The mechanism for glucose and amino acid reabsorption involves co-transport with Na+ across the proximal tubule apical membrane. In addition, the proximal tubule also resorbs urea, phosphate, Mg, sulfate, lactate, acetoacetate ions, vitamins and lipid-soluble substances. Approximately 99% of the water filtered by the glomerulus is also resorbed by the whole renal tubule segments; and about 65% of the filtered water is resorbed by the proximal tubule. Carbonic anhydrase is found in the cytoplasm (soluble) and brush border membranes (membrane-bound enzyme) of renal proximal tubular cells. Both have been assigned roles for the secretion of hydrogen ions into the tubular fluid and hence also for the reabsorption of bicarbonate. In addition, the proximal tubule epithelium also secretes H+, organic acids, bases, and certain drugs, such as penicillin into the tubule fluid. The proximal tubule is the site of glomerulotubular balance as we will see later. The transporter that is responsible for H+ secretion in the proximal tubules is the Na– H exchanger. This is an example of secondary active transport, Na+ is moved from the inside of the cell to the interstitium by Na-K ATPase on the basolateral membrane, which keeps intracellular Na+ low, thus establishing the drive for Na to enter the cell, via the Na–H exchanger, from the tubular lumen. The Na–H exchanger secretes H+ into the lumen in exchange for Na. Proteins are absorbed through the brush border of the proximal tubule by the process of pinocytosis. Although the amount of Na in the tubular fluid decreases markedly along the proximal tubule, the concentration of Na and the total osmolarity remains relatively constant (isotonic) because water permeability of the proximal tubules is so great that water reabsorption proportional to Na reabsorption. The proximal tubule is also the site for secretion of organic acids and bases (bile salts, oxalate, urate, Catecholamines), drugs, and toxins. Reabsorption of HCO3- occurs primarily in the proximal tubule indirectly through the absorption of CO2 from proximal tubular fluid.. Loops of Henle: The nephrons with their glomeruli located in the outer portion of the renal cortex have short loops of Henle (cortical nephrons, 70%), where as those with glomeruli in the juxtamedullary region of the cortex (juxtamedullary nephrons, 30%) have long loop extending down into medullary pyramids. The juxtamedullary nephrons are important for urine concentration. They also reabsorb a higher proportion of glomerular filtrate than cortical nephrons and are said to be “salt-conserving.” In states where effective circulating blood volume is reduced, a higher proportion of renal blood flow (RBF) is directed to the juxtamedullary nephrons, helping to conserve extracellular fluid volume. Loops of Henle include: The thin descending segment, the thin ascending segment, and the thick ascending segment. The thin descending segment of the loop of Henle: The epithelia cells of it are very thin with no brush border and very few mitochondria. They are highly permeable to water but nearly impermeable to sodium and most other ions. The thin ascending segment of the loop of Henle: The epithelia cells of the ascending thin segment, on the other hand, are far less permeable to water but more permeable to urea and NaCl than is the descending portion. Because the ascending thin limb is impermeable to water, no water reabsorption is taking place in this area of the nephron. The thick ascending segment of the loop of Henle (figure 5): The epithelial cells of the ascending thick segment are similar to those of the proximal tubules except that they have a rudimentary brush border and much tighter tight junction. The cells adapted for strong active transport of Na, K, and Cl ions. On the other hand, the thick segment is almost entirely impermeable to both water and urea. Therefore, no water reabsorption is taking place in this area of the nephron. Therefore, this segment is called the diluting segment. Basic mechanism for active transport of sodium through the tubular epithelial cell is as follow:  The sodium-potassium pump transports sodium from the interior of the cell across the basolateral membrane, creating a low intracellular sodium concentration and a negative intracellular electrical potential (figure 5, step 1). The low intracellular sodium concentration and the negative electrical potential cause sodium ions to diffuse from the tubular lumen into the cell through the brush border through Na-K-2Cl co-transporter that transports Na+, K+ and 2Cl- from the lumen into the cell (figure 5, step 2). The transport of K+ creates excess of K+ within the cell (figure 5, step 3). This results in back leak of K+ OUT of the cell back into the lumen (and back to the interstitial fluid through K+-Cl- co-transport If there is an associated hypokalemia) (figure 5, step 4). This back leak creates electrical driving force in the tubular fluid (figure 5, step 4) which enhances the reabsorption of cations Mg++ and Ca++ via paracellular pathway (figure 5, step 5). Na-K-2CL co-transporter can be inhibited by drugs called loop diuretics such as frusemide, ethacrynic acid, and bumetanide. This thick ascending segment ascends all the way back to the same glomerulus from which the tubule originated and passes tightly through the angle between the afferent and efferent arterioles. The cells of this portion of the thick ascending segment which are in complete attachment with the epithelial cells of the afferent and efferent arterioles are called Macula densa (figure 6). The specialized smooth muscle cells of the afferent arterioles that come in contact with the macula densa are called juxtaglomerular cells (JG cells) which contain renin granules. Macula densa and JG cells plus few granulated cells between them are collectively known as juxtaglomerular complex or apparatus which has a dense adrenergic neural innervation. About 27% of filtered loads of Na, Cl, and K (and other ions such as Ca, HCO3-, Mg) are reabsorbed in the loop of Henle mainly in the thick ascending limb. Because the thick segment of the ascending loop of Henle is impermeable to water, most of the water delivered to this segment remains in the tubule, despite the reabsorption of large amounts of solute. Thus, the tubular fluid in the ascending limb becomes very dilute as it flows toward the distal tubule (hypotonic). Distal convoluted tubule: They lie in the renal cortex. The „early‟ or „proximal‟ part of the distal tubule is functionally similar to the thick ascending limb of the loop of Henle. The distal tubule (also called the diluting segment) has almost the same characteristics as the thick segment of ascending limb of the loop of Henle. It reabsorbs Na ions and other ions but is almost entirely impermeable to both water and urea (figure 7). Thiazide diuretics block the Na-Cl co-transporter of the distal tubule. Unlike loop diuretics, which cause urinary loss of Ca2+ by inhibiting Ca2+ reabsorption in the thick ascending limb, thiazides reduce urinary calcium loss by increasing Ca2+ reabsorption in the distal tubule. In the “late” distal tubule and collecting duct there are two main cell types in this region: Principal cells (figure 8) and Intercalated cells (figure 9). The principal cells respond to aldosterone and ADH. The principal cells are the most abundant cells and are associated with NaCl reabsorption and K+ excretion. The activity of this mechanism is regulated by the adrenal cortical hormone, aldosterone (figure 8). It works (through a nuclear receptor to induce the formation of one or more proteins) by increasing the number of membrane Na+ and K+ channels to increase Na+ and K+ fluxes at the apical (luminal) cell membrane and by increase the activity of the Na+/K+-ATPase at the basal side of cell membrane depicted in the figure 8: The increase of the expression of basolateral Na+/K+-ATPase (figure 8, step 1) generates a low intracellular [Na]i concentration, high intracellular [K]i concentration. The low intracellular [Na]i concentration favors Na+ reabsorption passively via apical Na channels (due to concentration gradient) (figure 8, step 2). The influx of Na+ from tubular fluid to intracellular fluid creates luminal electronegativity. Luminal electronegativity enhances K+ excretion passively by principal cell (due to electrochemical gradient) through apical K channels. The magnitude of this passive secretion is determined by the chemical and electrical driving forces on K+ across the luminal membrane. Maneuvers that increase the intracellular K+ concentration or decrease the luminal K+ concentration or increase intraluminal negativity will increase K+ secretion by increasing the electrochemical driving force. Maneuvers that decrease the intracellular K+ concentration (as occurs only on a low-K+ diet), or increase the luminal K+ concentration or decrease intraluminal negativity will decrease K+ secretion by decreasing the electrochemical driving force. The body cannot get rid of excess K+ in the absence of aldosterone- stimulated secretion of K+ into the cortical collecting ducts. Indeed, when both adrenal glands are removed from an experimental animal, the hyperkalemia (high blood K+) that results can produce fatal cardiac arrhythmias. Abnormally low plasma K+ concentrations (hypokalemia), as might result from excessive aldosterone secretion or from diuretic drugs, can produce arrhythmias as well as muscle weakness. Figure 10 summarized the factors affect distal tubular K+ secretion. Diuretics that increase flow rate through the distal tubule (e.g., thiazide diuretics, loop diuretics) cause dilution of the luminal K+ concentration. Consequently, diuretics increase the driving force for K+ secretion. Also, as a result of increased K+ secretion, these diuretics cause hypokalemia. Luminal anions such as excess anions (e.g., HCO3–) in the lumen cause an increase in K+ secretion by increasing the negativity of the lumen, which favors K+ secretion. Figure 10 summarizes the factors that affect distal K+ secretion. In addition, the principal cells permeability to water is governed by a hypothalamic hormone, antidiuretic hormone (ADH). It is otherwise impermeable to water but becomes permeable in the presence of ADH. The intercalated cells (figure 9) come in two different varieties: Alpha- intercalated cells (which secrete Acid) and Beta-intercalated cells (which secrete Base). The intercalated cells are involved with acid-base balance. In the distal tubules and collecting ducts, there is no Na–H exchanger (as in proximal tubule); and H+ secretion is relatively independent of Na+ in the tubular lumen. In this part of the tubule, most H+ is secreted by an ATP-driven proton pump. Aldosterone acts on this pump to increase distal H+ secretion. The late distal tubule is impermeable to urea so that urea does not get reabsorbed. Thus this segment ensures that all urea that reaches it remains in the tubular fluid and is passed on further for excretion in the urine. But the fate of other substances, notably water, sodium, potassium and hydrogen ions is determined by the homeostatic requirements of the body. Collecting tubules and ducts: About eight distal tubules coalesce to form the collecting tubule which turns once again away from the cortex and passes downward into medulla where it becomes the collecting ducts. This is functionally identical to the late distal tubule. The cortical collecting duct has two distinct cell types. The principal cells are the most abundant cells and are associated with NaCl and water reabsorption; the intercalated cells are involved with acid-base balance. The medullary collecting duct is the last portion of the nephron. It retains two of the important characteristics of the cortical collecting duct, i.e. water permeability sensitive to ADH, and capacity to secrete hydrogen ions if necessary. It is the final site for urine processing, and reabsorb less than 10% of the filtered water and Na. It plays an extremely important role in determining the final urine output of water and solutes. Its permeability to water is under the control of ADH similar to the cortical collecting duct. It is permeable to urea (unlike the cortical collecting duct) which is increased in the presence of ADH. It is capable of secreting H ions against concentration gradient. Figure 11 summarizes the absorption and excretion ions and water across various parts of nephron. In summary: The three important roles that the collecting tubule system plays in the formation of urine are: 1. Final concentration of Na+ and water in the urine. 2. Collecting tubule system is the site where mineralocorticoids play the important role in urine formation; 3. Collecting tubule system is the most important site for K+ secretion by the kidney. Blood vessels: The renal fraction of the total cardiac output is about 21% (vary from 12-30%). In resting adult, the blood flow in renal cortex is about 98% of the total renal blood flow while in medulla is only 2% of the total renal blood flow. This is why the O2 consumption of cortex is much higher than that of medulla. Arterial system of the kidney is technically a Portal System (figure 12), fferent of the peritubular capillary network lies in the renal cortex alongside the proximal, distal, and collecting tubules. In the juxtamedullary glomeruli, long efferent arterioles extend from the glomeruli down into the outer medulla and then divide into specialized long and straight capillary loops called vasa recta (figures 12 and 12A) extended downward into the medulla to lay side by side with the lower parts of thin segments of juxtaglomerular loops of Henle all the way to the renal papillae. Then, like the loop of Henle, they also loop back toward the cortex and empty into the cortical veins. This specialized network of capillaries in the medulla plays an essential role in the formation of concentrated urine. The shape and the arrangement of the loop of the vasa recta capillaries allows the blood to run parallel to and opposite to the flow of the fluid in the loop of Henle (figure 12A) Renal Blood Flow and Oxygen Consumption: On a per-gram-weight basis, the kidneys normally consume oxygen at twice the rate of the brain but have almost seven times the blood flow of the brain. Thus, the oxygen delivered to the kidneys far exceeds their metabolic needs, and the arterial-venous extraction of oxygen is relatively low compared with that of most other tissues. A large fraction of the oxygen consumed by the kidneys is related to the high rate of active sodium reabsorption by the renal tubules. If renal blood flow and GFR are reduced and less sodium is filtered, less sodium is reabsorbed and less oxygen is consumed. Therefore, renal oxygen consumption varies in proportion to renal tubular sodium reabsorption, which in turn is closely related to GFR and the rate of sodium filtered. If glomerular filtration completely ceases, renal sodium reabsorption also ceases and oxygen consumption decreases to about one-fourth normal. This residual oxygen consumption reflects the basic metabolic needs of the renal cells [C] Nerve supply: There is no significant parasympathetic innervation. The kidney has a rich adrenergic sympathetic nerve (figure 13) supply distributed to the: [A] Vascular smooth muscle to cause vasoconstriction, which leads to a decrease in renal blood flow (RBF). [B] Juxtaglomerular cells to cause renin secretion and consequently angiotensin II formation. At low concentrations, angiotensin II preferentially constricts efferent arterioles, thereby increasing the GFR. In addition, this constriction in efferent arterioles 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 further increase in 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-converting enzyme (ACE) inhibitors dilate efferent arterioles and produce a decrease in GFR; these drugs reduce hyperfiltration and the occurrence of diabetic nephropathy in diabetes mellitus. Vasodilation of renal arterioles, which leads to an increase in RBF, is produced by prostaglandins E2 and I2, bradykinin, nitric oxide, and dopamine. [C] Tubular cells to stimulate Na and water reabsorption. Glomerular function: Glomerular filtration rate (GFR): It is the fluid that filtrate through the glomerulus into Bowman`s capsule each minute in all nephrons of both kidneys which is about 125 ml/min or 180 L/day in males (10% lower in female). The high GFR of the glomerular membrane is due to very high permeability of the capillaries of the glomerulus, which is about 100-500 times as great as that of the usual capillary. Yet, despite the tremendous permeability of the glomerular membrane, it has an extremely high degree of selectivity. The selectivity of the glomerular membrane depends on: Size of the molecules: Neutral substance with effective molecular diameter of less than 4 nm are freely filtrated, and those with diameter more than 8 nm (80 A), filtration is zero. Between these two values, filtration is inversely proportional with diameter. The electrical charges of the molecules: This is because the inner side of the pores of the glomerular membrane is negatively charged repelling other negatively charged molecules that tend to pass through pores. For these two reasons, the glomerular membrane is almost completely impermeable to all plasma proteins but is highly permeable to all other dissolved substances in normal plasma. The composition of the glomerular filtrate is the same as plasma except that it has no significant amount of proteins. The filtration fraction (figure 14) is the fraction of the renal plasma flow that becomes glomerular filtrate. Since the normal plasma flow through both kidneys is 650 ml/min and the normal GFR is 125 ml/min, the average filtration fraction is about 1/5 or 19%. Renal clearance: is the volume of blood plasma from which a particular waste is completely removed in 1 minute. It represents the net effect of three processes: Glomerular filtration of the waste + Amount added by tubular secretion - Amount reclaimed by tubular reabsorption = Renal clearance In principle, we could determine renal clearance by sampling blood entering and leaving the kidney and comparing their waste concentrations. In practice, it is not practical to draw blood samples from the renal vessels, but clearance can be assessed indirectly by collecting samples of blood and urine, measuring the waste concentration in each, and measuring the rate of urine output. Suppose the following values were obtained for urea: U (urea concentration in urine) = 6.0 mg/mL, V (rate of urine output) = 2 mL/min, P (urea concentration in plasma) = 0.2 mg/mL. Renal clearance (C) is C = UV/P = (6.0 mg/mL) (2 mL/min)/ 0.2 mg/mL = 60 mL/min This means the equivalent of 60 mL of blood plasma is completely cleared of urea per minute. If this person has a normal GFR of 125 mL/min, then the kidneys have cleared urea from only 60/125 = 48% of the glomerular filtrate. This is a normal rate of urea clearance, however, and is sufficient to maintain safe levels of urea in the blood. Using clearance to estimate GFR (figure 15): GFR can be measured indirectly by calculating the clearance of a substance. The substance is called glomerular filtration marker. The substance used as glomerular filtration marker to measure the clearance should fulfill the following criteria: Freely filtered. Neither reabsorbed nor secreted by the tubules. Not metabolized or stored in the kidney. Not toxic and not affecting the GFR. Such of these substances are inulin, creatinine, and para-aminohippuric acid. For inulin, GFR is equal to the renal clearance (figure 15). Inulin is a low- molecular-weight polysaccharide that is small enough to pass freely through the glomerular filtration barrier. Inulin is neither reabsorbed nor secreted by the nephron and cannot be metabolized. Therefore, the rate of inulin filtration equals the rate of inulin excretion in urine so the volume of plasma cleared per minute equals GFR. Inulin usually is not used clinically because it must be intravenously infused. Suppose, for example, that a patient‟s plasma concentration of inulin is P = 0.5 mg/mL, the urine concentration is U =30 mg/mL, and urine output is V = 2 mL/min. This person has a inulin clearance = UV/P = (30 mg/mL)(2 mL/min)/ 0.5 mg/mL = 120 mL/min. Therefore, for inulin, its clearance is equal to GFR. In clinical practice, GFR is more often estimated from creatinine excretion. This has a small but acceptable error of measurement, and is an easier procedure than injecting inulin and drawing blood to measure its concentration. Using clearance to estimate renal plasma flow (RPF): Para-aminohippuric acid (PAH) clearance is used as a measure of renal plasma flow (figure 16). PAH, like inulin and creatinine in its criteria. However, it is different from inulin and creatinine in that it is cleared from the plasma by a single passage through the kidney and the remaining PAH in the plasma after the glomerular filtrate is formed, is secreted into the tubules by the proximal tubule, i.e. zero PAH in renal vein. Where a substance is completely cleared from the plasma by a single passage through the kidney and all the cleared material is excreted in the urine, the clearance is equal to the renal plasma flow. Therefore: Renal plasma blood flow = [PAH] in urine x urine flow ml/min/ [PAH] in plasma. Renal blood flow (RBF) = RPF/1-Hct (RPF abbreviations of Renal Plasma Flow). Factors that affect GFR: GFR is determined by: The filtration pressure is the net pressure forcing fluid through glomerular membrane (the Starling forces) which is determined by: [A] Glomerular capillary hydrostatic pressure: This can be affected by several factors: Renal blood flow: Increase blood flow through the nephrons greatly increases the GFR for two reasons: (A) The increasing flow increases the glomerular pressure which enhances filtration. (B) The increased flow through the nephrons allows less time for plasma proteins to be more concentrated at the venous end of the glomerular capillaries bed. Therefore, oncotic pressure has far less inhibitory influence on glomerular filtration. Afferent arteriolar constriction: Leads to decrease the rate of blood flow into the glomeruli and also decrease the glomerular pressure and decrease the GFR, and vice versa. Efferent arteriolar constriction: A slight efferent arteriolar constriction increases the glomerular pressure causing slight increase in GFR. However, moderate and severe efferent arteriolar constriction causes a paradoxical decrease in the GFR despite the elevated glomerular pressure. This is due to the fact that plasma in this case will remain for long period of time in the glomerulus, and extra large portion of plasma will filter out. This will increase the plasma colloid osmotic pressure to excessive level causing a decrease in the GFR. [B] A change in Bowman‟s capsule hydrostatic pressure: Increasing the hydrostatic pressure in Bowman‟s capsule (as in urinary tract obstruction) reduces GFR and vice versa. [C] A change in glomerular capillary colloid osmotic pressure: A decrease in the glomerular capillary colloid osmotic pressure increases GFR and vice versa. [D] An increase in the Bowman‟s colloid osmotic pressure: This may occur in diseases that causes filtration of proteins across glomerular membrane and consequently increases GFR. The capillary filtration coefficient, which is the product of the permeability and filtering surface area of the capillaries. It can be affected by: [A] The changes in the permeability of the glomerular capillaries, which may be changed in disease state with consequent changes in the GFR. Normally, anionic glycoproteins line the filtration barrier and restrict the filtration of plasma proteins, which are also negatively charged. In glomerular disease, the anionic charges on the barrier may be removed, resulting in proteinuria. [B] The thickness and the surface area of the capillary bed across which filtration is taking place which can be changed with a consequent change in the GFR. An example of such change is contraction or relaxation of mesangial cells in response to various substances can induce a decrease or an increase in the effective filtration surface area and eventual changes in the GFR. In summary: GFR can be affected by : The filtration pressure, which is influenced by: A. Glomerular capillary hydrostatic pressure which is affected by: I. Renal blood flow. II. Afferent arteriolar constriction. III. Efferent arteriolar constriction. B. Bowman‟s capsule hydrostatic pressure. C. Glomerular capillary colloid osmotic pressure. D. Bowman‟s colloid osmotic pressure. : The capillary filtration coefficient (K f), which can be affected by: A. The permeability of the glomerular capillaries. B. The thickness and surface area of capillary bed. Therefore, the factors that determine the final urine volume are the following: Presence of excessive quantities of osmotic particles (osmotic diuresis): An important example on the osmotic diuresis is the diabetes mellitus in which the proximal tubules fail to reabsorb all the glucose, as normally occurs. Instead, the nonabsorbed glucose passes the entire distance through the tubules and carries with it a large portion of the tubular water. Osmotic diuresis also occurs when substances that are poorly or cannot be reabsorbed by the tubules are filtered in excessive quantities from the plasma into glomerular filtrate. Examples of such substances are sucrose, mannitol, and urea. Plasma colloid osmotic pressure: A sudden increase in plasma colloid osmotic pressure instantaneously decreases the rate of fluid volume excretion. The cause of this is due to (A) a decrease in GFR and (2) an increase tubular reabsorption.  Sympathetic stimulation: Sympathetic stimulation (via Norepinephrine, a neurotransmitter released by the sympathetic nerves) preferentially causes located mainly on the afferent arterioles). It greatly decreases the glomerular pressure and simultaneously decreases GFR (figure 16A). At the same time, the blood flow into the peritubular capillaries is decreased and consequently, the capillary pressure is decreased, thus increasing tubular reabsorption (figure 16A). Also sympathetic stimulation stimulate juxtaglomerular complex (via β1 receptors) to release renin. Dehydration or strong emotional stimuli, such as fear and pain, activate sympathetic nerves and reduce GFR and RBF Arterial pressure: Under normal condition (when the renal autoregulatory mechanism is intact), a change in blood pressure causes a slight change diuresis and natriuresis. Unlike in renal diseases (when the renal autoregulatory mechanism is impaired), small increase in arterial pressure often causes marked increase in urinary excretion of Na and water. This results from two separate effects: (A) the increase in arterial pressure increases glomerular pressure, which in turn increases GFR, thus leading to increased urine output. (B) The increase in arterial pressure also increases the peritubular capillary pressure, thereby decreasing tubular reabsorption. Hormonal control: Such as: ADH: When excess antidiuretic hormone is secreted by the posterior pituitary gland, the effect is to increase the water permeability of the distal tubule, collecting tubule and collecting duct with a consequent decrease the urinary volume output acutely. However, when excess ADH is secreted for long periods of time, the acute effect of decreasing urinary output is not sustained. The reason is that other factors, such as the arterial pressure, colloid osmotic pressure, and concentrations of the osmolar substances in the glomerular filtrate all change in the direction that leads eventually to a urinary volume output equal to the daily need. Aldosterone: This is secreted by the zona glomerulosa cells of the adrenal cortex by its action on the principal cells of the cortical collecting tubule to increase Na reabsorption and to increase K secretion. Prostaglandins (figure 17) do not play a major role in regulating RBF in healthy, resting people. However, during pathophysiologic conditions such as hemorrhage, prostaglandins (PGI2, PGE1, and PGE2) are produced locally within the kidneys, and they increase RBF without changing the GFR. Prostaglandins increase RBF by dampening the vasoconstrictor effects of sympathetic nerves and angiotensin II. This effect is important because it prevents severe and potentially harmful vasoconstriction and renal ischemia. Prostaglandin synthesis is stimulated by dehydration and stress (e.g., surgery and anesthesia), angiotensin II, and sympathetic nerves. Nonsteroidal antiinflammatory drugs (NSAIDs), such as aspirin and ibuprofen, inhibit the synthesis of prostaglandins. Thus administration of these drugs during renal ischemia and hemorrhagic shock is contraindicated because, by blocking the production of prostaglandins, they decrease RBF and increase renal ischemia. Prostaglandins play an increasingly important role in maintaining RBF and GFR as people age. Accordingly, NSAIDs can significantly reduce RBF and GFR in the elderly. Angiotensin II: Angiotensin II: It increases Na and water reabsorption through following mechanisms: It stimulates aldosterone secretion, which in turn increases Na and water reabsorption. It constricts the efferent arterioles and consequently increases Na and water reabsorption through the following mechanisms: [A] When the angiotensin constricts the efferent arterioles, this reduces the peritubular capillary pressure causing an increase in the rate of reabsorption of water and electrolytes from the tubular system especially from the proximal tubule, because the balance forces at the capillary membrane is now in favor of absorption. [B] Because of the constriction of the efferent arterioles, the blood flow through glomeruli is decreased while the GFR is still near normal. This will lead that a very high proportion of plasma fluid to filter through the glomerular membrane into tubules. Therefore, the concentration of the plasma proteins in the blood leaving the glomeruli becomes very high and this concentrated plasma flows on into the peritubular capillaries. As the result, the colloid osmotic pressure in these capillaries is greatly increased, which is an additional factor that enhances reabsorption of water and salt. NOTES: The efferent arteriole is more sensitive to angiotensin II than the afferent arteriole. Thus with low concentrations of angiotensin II, constriction of the efferent arteriole predominates, GFR increases, and RBF decreases. However, with high concentrations of angiotensin II, constriction of both afferent and efferent arterioles occurs and both GFR and RBF fall There is evidence that angiotensin also has a direct effect on the distal tubules and on the proximal tubule in causing increased active reabsorption of Na and water by stimulating Na-K ATPase pump (at the basolateral membrane of the tubular cell) and Na-H exchange (at the luminal side of the tubular cell). Mesangial cells constrict in response to angiotensin II and reduce the capillary filtration coefficient resulting in an overall decrease in GFR. This reduction in GFR means less tubular fluid flow and more Na and water reabsorption. Nitric Oxide (figure 17): NO, an endothelium-derived relaxing factor is an important vasodilator under basal conditions, and it counteracts the vasoconstriction produced by angiotensin II and catecholamines. When blood flow increases, a greater shear force acts on the endothelial cells in the arterioles and increases the production of NO. In addition, a number of vasoactive hormones, including acetylcholine, histamine, bradykinin, and ATP, cause the release of NO from endothelial cells. Increased production of NO causes dilation of the afferent and efferent arterioles in the kidneys. Whereas increased levels of NO decrease the total peripheral resistance, inhibition of NO production increases the total peripheral resistance. Atrial natriuretic peptide: It is released from specific cells of the cardiac atria upon distension as a result of plasma volume expansion. It inhibits the reabsorption of Na and water by the renal tubules especially in the collecting ducts with consequent increase in the urinary output. Parathyroid hormone: It increases the reabsorption of Ca and Mg ions from the ascending limb of loop of Henle and distal tubule. It inhibits the reabsorption of phosphate from the proximal tubule Autoregulation of GFR (and renal blood flow): It is the feedback intrinsic mechanisms by which the kidneys normally keep the renal blood flow (and consequently GFR) relatively constant, despite marked changes in arterial blood pressure within the range of 80-200 mm Hg. GFR (125 ml/min) and renal blood flow (1200 ml/min) normally they have to remain relatively constant for both kidneys even the blood pressure changes from 80-200 mm Hg (figure 18). This is because that even a 5% too great or too little rate of glomerular filtration can have considerable effects in causing either excess loss of solutes and water into the urine, or at the other extreme too little of necessary excretion of waste products. There are specialized negative feedback mechanisms which add together to provide the degree of GF and renal blood flow that is required. These negative feedback mechanisms are: [A] Tubuloglomerular feedback mechanism [B] Myogenic mechanism [A] Tubuloglomerular feedback mechanism: This occurs through JG complex (figure 19). The afferent arteriolar vasodilator and vasoconstrictor feedback tubular fluid. The ↓flow rate of tubular fluid leads to over-reabsorption of Na and Cl ions in the ascending limb of the loop of Henle and therefore decreases the ions concentration at the macula densa. This decrease in ion concentrations initiates a signal (not completely understood) from the macula densa to the juxtaglomerular cells to dilate the afferent arteriole which results to an increased blood flow into the glomerulus causing an increase in glomerular pressure and hence GFR back toward the required level. If GFR rises, however, it increases the flow of tubular fluid and the rate and more delivery of NaCl in the ascending limb of the loop of Henle and therefore increases the ions concentration at the macula densa. The macula densa apparently senses variations in flow or fluid composition and initiates a signal (not completely understood) from the macula densa to the juxtaglomerular cells to constrict the afferent arteriole which results to a decreased blood flow into the glomerulus causing a decrease in glomerular pressure and hence GFR back toward the required level.  The efferent arteriolar vasoconstrictor feedback mechanism (figure 19): Too few Na and Cl ions at the macula densa are believed to cause JG cells to release renin and this in turn causes the formation of angiotensin II which constricts mainly the efferent arterioles (much more than the afferent arterioles). Therefore, the constriction of the efferent arterioles causes the pressure in the glomerulus to rise leading to increase in GFR back to normal. Renin is an enzyme that release from renal juxtaglomerular cells and acts on a substrate angiotensinogen. The cascade reaction is as shown in figure 19. Renin release is increased if: Renal perfusion pressure is decreased, Renal blood flow is decreased, Stimulation of renal nerves (β1 receptors). [B] Myogenic mechanism: This mechanism of stabilizing the GFR is based on the tendency of smooth muscle to contract when stretched. When the arterial pressure rises, it stretches the wall of the arteriole, and this in turn causes a secondary contraction of the arteriole. This decreases the renal blood flow and GFR back toward normal, thus opposing the effect of the rising arterial pressure to increase the flow. Conversely, when the pressure falls too low, an opposite myogenic response allows the artery to dilate and therefore increases the flow and GFR. Glomerulotubular balance: It is the ability of the tubules to increase reabsorption rate in response to increased tubular load, which means that when the GFR increases, the rate of tubular reabsorption increases in exact proportion to the increase in filtration. Glomerulotubular balance is especially good in the proximal tubules and loop of Henle and less effective in the more distal segments of the tubular system. This slight lack of glomerulotubular balance in the distal tubular segments can lead to a tremendous increase in urine output when the GFR is increased. Also, very slight changes in rate of reabsorption of tubular fluid can cause equally as great alteration in urine output. Glomerulotubular balance is a critical mechanism which protects distal segments of the nephron from being overloaded in contexts of short-term increases in GFR. Distal segments of the nephron have a very limited capacity to increase tubular resorption of water and solutes; consequently, a large increase in distal flow rates would result in catastrophic loss of fluid in the urine. Glomerulotubular balance thus guarantees that the majority of additional tubular flow, due to increases in GFR, is resorbed by proximal segments of the nephron which are significantly more capable of resorbing large fluid volumes. The mechanistic basis of glomerulotubular balance is poorly understood but appears to act completely independently of neuroendocrine regulatory mechanisms and is likely an intrinsic property of the nephron itself. It should be pointed out that glomerulotubular balance can be thought of as a second line of protection which follows mechanisms of Tubuloglomerular Feedback that attempt to maintain nearly constant rates of GFR. In response to a primary change in GFR, the percentage of the filtered sodium reabsorbed proximally remains approximately constant (about 65%). The fraction not reabsorbed also remains approximately constant (about 35%). The net result of fixed fractional reabsorption is to reduce the magnitude of difference in sodium leaving the proximal tubule The mechanisms responsible for matching changes in tubular reabsorption to changes in GFR are completely intra-renal, i.e. glomerulotubular balance requires no external neural or hormonal input. Glomerulotubular balance is actually a second line of defense preventing changes in renal hemodynamics per se from causing large changes in sodium excretion. The first line of defense is autoregulation of GFR as described previously. GFR autoregulation prevents GFR from changing too much in direct response to changes in blood pressure, and glomerulotubular balance blunts the sodium-excretion response to whatever GFR change does occur. Thus, tubule- glomerular feedback and glomerulotubular balance are processes that allow a large fraction of the responsibility for homeostatic control of sodium excretion to reside in those primary inputs that act to influence tubular reabsorption of sodium independently of GFR changes. Tubular load of a substance: Is the total amount of the substance that filters through the glomerular membrane into tubules per minute. Tubular load = conc. of the substance in the filtrate x GFR. It is expressed in gm/min. For example, if the plasma concentration of glucose is 100 mg/100 ml plasma, so the tubular load of glucose is equal to: Tubular transport maximum (Tm): It is the maximum rate (in mg/min) for actively reabsorbing or secreting substance by the tubule. The kidneys work efficiently to return valuable substances to the blood after glomerular filtration. However, the carriers that are needed for active transport of these substances can become overloaded. Thus, there is a limit to the amount of each substance that can be reabsorbed in a given time period. The limit of this reabsorption rate is called the transport maximum (Tm), or tubular maximum, and it is measured in milligrams (mg) per minute. For example, the Tm for glucose average 320 mg/min for adult human being, and if the tubular load becomes greater than 320 mg/min, the excess above this amount is not reabsorbed but instead passes on into the urine. The serum level of the substance below which none of it appears in the urine and above which progressively larger quantities appear is called the threshold concentration of that substance. The renal threshold for glucose occurs at a plasma glucose concentration somewhat below the value at which the renal Tm for glucose is reached. In fact, glucose begins to spill into the urine when its tubular load exceeds 220 mg/min which correspond to a concentration of glucose in plasma of 180 mg/100 ml when kidneys are operating at their normal glomerular filtration rate of 125 ml/min. This phenomenon, termed splay, occurs because not all of the two million nephrons have the same Tm for glucose, and those with lower Tm for glucose begin losing glucose to the urine before those with higher Tm for glucose. Renal handling of urea: At the proximal tubule: about 40% of the filtered urea is reabsorbed; however, because 60-80% of the filtered water is reabsorbed, the fluid leaving the proximal tubule has a urea concentration 2-3x that of plasma. At the thin loop of Henle: Somewhat permeable to urea. The high interstitial concentration of urea causes some of the interstitial urea to enter the lumen of the loop. At the thick ascending, distal tubule and cortical segment of the collecting duct: All are imperable to urea; as water is reabsorbed, urea becomes concentrated in the lumen. At the medullary collecting duct: Slightly permeable to urea, and this permeability is increased under the effect of ADH. As water is reabsorbed, the urea remaining within the duct becomes progressively more concentrated, which therefore diffuses out of the lumen into the interstitium in accordance with its concentration gradient Renal Mechanisms for excreting diluted or concentrated urine: The kidneys can excrete urine with an osmolarity as low as 50 mOsmol/l, a concentration that is only about sixth the osmolarity of normal extracellular fluid. Conversely, when there is a deficit of water and extracellular fluid osmolarity is high, the kidney can excrete urine with a concentration of about 1200 to 1400 mOsmol/l. Equally important, the kidney can excrete a large volume of dilute urine or a small volume of concentrated urine without major changes in rates of excretion of solutes such as Na and K. This ability to regulate water excretion independently of solute excretion is necessary for survival, especially when fluid intake is limited. When the osmolality of the body fluids fall too low, i.e. when the fluids become too dilute, the kidney automatically excrete a great excess of water in urine causing the urine to be diluted and therefore increasing the body fluid osmolality back toward normal. Conversely, when the osmolality of body fluids is too great, the kidney automatically excrete an excess of solutes in urine causing the urine to be concentrated thereby reducing the body fluid osmolality again back toward normal. The Renal mechanism for excreting dilute urine (figure 20-A): As fluid flows through the proximal tubule, solutes and water are reabsorbed in equal proportions, so that little change in osmolarity occurs, that is the proximal tubule fluid remains isotonic to the plasma, with an osmolarity of about 300 mOsmol/l. As fluid passes down the descending loop of Henle, water is reabsorbed by osmosis and the tubular fluid reaches equilibrium with the surrounding interstitial fluid of the renal medulla, which is very hypertonic, of about 1200 mOsmol/l, i.e. four times the osmolarity of the original glomerular filtrate. Therefore, the tubular fluid becomes more concentrated as it flows into the inner medulla. In the ascending limb of the loop of Henle, especially the thick segment, Na, K, and Cl are avidly reabsorbed. However, this portion of the tubular segment is impermeable to water. Therefore, the tubular fluid becomes more dilute as it flows up the ascending loop of Henle into the early distal tubule, with the osmolarity decreasing progressively to about 100 mOsmol/l by the time the fluid enters the early distal tubular segment. Thus, the fluid leaving the early distal tubular segment is hypotonic with an osmolarity of only about one third the osmolarity of plasma. As the dilute fluid in the early distal tubule passes into the late distal tubule, cortical collecting tubule, and collecting duct, there is additional reabsorption of NaCl. This portion of the tubule is also impermeable to water (in the absence of ADH), and additional reabsorption of solutes causes the tubular fluid to become even more diluted with an osmolarity of about 50 mOsmol/l. Renal mechanism for excreting concentrated urine (figure 20-B): The basic requirements for forming concentrated urine is a high level of ADH: This increases the permeability of the distal tubules and collecting ducts to water, thereby allowing these tubular segments to avidly reabsorb water. The signal that tells the kidney whether to excrete diluted or concentrated urine is the hormone called antidiuretic hormone (ADH) or vasopressin that is secreted from the posterior pituitary gland. When the body fluids are too concentrated, the posterior pituitary gland secretes large amount of ADH, which causes the kidney to excrete excessive amounts of solutes but to conserve water in the body. Conversely, in the absence of ADH the kidney excretes dilute urine, thus removing excessive amount of water from the body fluids and causing them to become concentrated once again. The high osmotic gradient along the renal medullary interstitial fluid: Which means 300 mOsmol/l at the cortex, about 800 mOsmol/l at the outer medulla, and as high as 1200-1400 mOsmol/l at the inner medulla. This gradient is due to: By the operation of the loops of Henle as countercurrent multipliers and By medullary interstitial urea concentration (Countercurrent concentration of urea, urea cycle ) And is maintained By the operation of the vasa recta as countercurrent exchangers in addition to By the Slight medullar blood flow Countercurrent multiplier (figure 21): In general, a "countercurrent system" is a system in which the inflow runs parallel to, counter to (opposite to), and in close proximity to the outflow for some distance. This occurs for both the loop of Henle and the vasa recta of the renal medulla.  The operation of each loop of Henle as a countercurrent multiplier depends on the following: Active transport of Na, K, Cl, and other ions out of thick ascending limb from the tubular lumen to the interstium. This pump able to create about 200 Mosmol concentration gradient between the interstial fluid and the tubular lumen. Diffusion of water by osmosis from the thin descending loop of Henle to the interstitial fluid. Facilitated diffusion of large amounts of urea from the inner medullary collecting ducts into the medullary interstitium. All of the above processes are essential to produce the increasing osmotic gradient along the medullar interstitial fluid. With these characteristics of the loop of Henle in mind, let us now discuss how the renal medulla becomes hyperosmotic (figure 22): 1. First assume that the loop of Henle is filled with a concentration of 300 mOsmol/L, the same as that leaving the proximal tubule (figure A) 2. The active pump of the thick ascending limb on the loop of Henle is turned on, reducing the concentration inside the tubule and raising the interstitial concentration; this pump establishes a 200 mOsmol/L concentration gradient between the tubular fluid and interstitial fluid (step 1). 3. The tubular fluid in the descending limb loop of Henle and the interstitial fluid quickly reach osmotic equilibrium because of osmosis of water out of the descending limb. The interstitial fluid is maintained at 400 mOsmol/L. This is because of continued transport of ions out of the thick ascending loop of Henle (step 2). 4. Additional flow of fluid into the loop of Henle from proximal tubule causes the hyperosmotic fluid previously formed in the descending limb to flow into the ascending limb (step 3). 5. These steps are repeated over and over (steps 4, 5, 6, and 7, 8, 9) with the net effect of adding more and more solute to the medulla in excess of water. With sufficient time, this process gradually traps solutes in the medulla and multiplies the concentration gradient established by the active pumping of ions out of the thick ascending loop of Henle, eventually raising the interstitial fluid osmolarity to 1200-1400 mOsmol/L. The Countercurrent concentration of urea (figure 23): Urea contributes about 40-50% of the osmolarity of the renal medullary interstitium when kidney is forming maximally concentrated urine. Since the thick ascending limb of the loop of Henle, the distal convoluted tubule, and the cortical sections of the collecting duct are impermeable to urea, its concentration increases downstream in these parts of the nephron. ADH can make the inner medullary collecting duct more permeable to urea. Urea now diffuses back into the interstitium (where urea is responsible for about 40% of the high osmolality there) then transported back into the ascending limb of the loop of Henle, comprising the recirculation of urea. High urea concentration draws water out of the descending limb of the loop of Henle by osmosis. This concentrates NaCl in the descending limb, creating a diffusion gradient for NaCl to move passively out of the thin ascending limb into the interstitium. The importance of urea is illustrated in patients with a low protein intake who have a reduced capacity to concentrate their urine because of lower urea levels. Children younger than 1 year have a reduced urine-concentrating ability because of lower urea levels; young children utilize proteins for rapid body growth and as a result do not produce much urea. The net effect of the steps noted above is to recirculate or trap urea in the renal medulla, raising the osmotic activity of interstitial fluid (contributes about half of the osmolality; NaCl contributes most of the rest) Note 1: Not all urea is reabsorbed or trapped; in fact, because much of the nephron is only slightly permeable to urea, urea is concentrated in the tubular fluid as water is reabsorbed, so urea normally becomes concentrated in the urine. Note 2: During a water diuresis when a large amount of dilute urine is excreted, urea does not become concentrated as the fluid in the collecting duct passes through the renal medulla, so not much urea diffuses into the interstitium. This results in an interstitial osmolality about half maximum (600 mOsm/kg) Note 3: Patients on protein restricted diets have impaired ability to form concentrated urine. The fundamental role of urea in contributing to urine concentrating ability is evidenced by the fact that people, who fed a high protein diet, yielding large amounts of urea as a nitrogenous waste product, can concentrate their urine much better than people whose protein intake and urea production are low. To deliver nutrients to the cells of the medulla without carrying away extensive amounts of solute, which would weaken the osmotic gradient i.e. to maintain this high interstitial fluid osmotic gradient, the solutes are prevented from being washed out to the circulation by: One characteristic of the medullary blood flow is that it is very slow representing less than 2% of the total renal blood flow. A second characteristic is the shape of the loop of the vasa recta capillaries in which the blood runs parallel to and opposite to the flow in the loop of Henle (figure 12A). Much fluid and solute exchange occurs between the medullary interstitial fluid and the vasa recta in both directions. Because of the parallel loop arrangement of the vasa recta and the loop of Henle, there is little net change in the concentration of the medullary interstitial fluid. Therefore, the action of vasa recta is a countercurrent exchanger (figure 24). The exchange mechanism works as follows:  The countercurrent exchange mechanism operates as follows (Figure 24): Blood enters and leaves the medulla by way of the vasa recta at the boundary of the cortex and renal medulla. The vasa recta, like other capillaries, are highly permeable to solutes in the blood, except for the plasma proteins. As blood descends into the medulla toward the papillae, it becomes progressively more concentrated, partly by solute entry from the interstitium and partly by loss of water into the interstitium. By the time the blood reaches the tips of the vasa recta, it has a concentration of about 1200 mOsm/L, the same as that of the medullary interstitium. As blood ascends back toward the cortex, it becomes progressively less concentrated as solutes diffuse back out into the medullary interstitium and as water moves into the vasa recta. Thus, although there is a large amount of fluid and solute exchange across the vasa recta, there is little net dilution of the concentration of the interstitial fluid at each level of the renal medulla because of the U shape. In countercurrent exchange in the vasa recta, plasma flowing down the descending limb of the vasa recta becomes more hyperos-motic because of diffusion of water out of the blood and diffusion of solutes from the renal interstitial fluid into the blood. In the ascending limb of the vasa recta, solutes diffuse back into the interstitial fluid and water diffuses back into the vasa recta. Large amounts of solutes would be lost from the renal medulla without the U shape of the vasa recta capillaries. (Numerical values are in milliosmoles per liter.) The net result is that the blood has brought nutrients to the cells of the medulla without carrying away extensive amounts of solute, which would weaken the osmotic gradient. These sluggish medullary blood flow and The countercurrent exchange mechanism cause the osmolal concentration in the capillary blood to raise progressively higher to a maximum concentration of 1200 mOsmol/l at the tip of vasa recta. Then, as the blood flows back up through the ascending limbs of vasa recta, all the extra NaCl and urea start to diffuse back out of the blood into the interstitial fluid while water diffuse back into the blood. Therefore, by the time the blood leaves the medulla, its osmolality is only slightly greater than that of the blood that had initially entered the vasa recta. As a result, the blood flowing through the vasa recta carries only a minute amount of the medullary interstitial solutes away from the medulla. Urea excretion: The rate of urea excretion determined by: Concentration of urea in the plasma. GFR. In general, the quantity of urea that passes on through the tubules into the urine average between 40-60% of the urea filtered. In many renal diseases the GFR of the two kidneys falls below normal and therefore excretion of urea is decreased. However, the body continues to form large quantities of urea which means that urea will progressively collect in the body fluids until the plasma concentration rises very high. Then the quantity of urea filtered in the glomerular filtrate (conc. of urea in the plasma x GFR) eventually will become great enough to allow excretion of the urea as rapidly as it formed. Many other waste products that must be excreted by the kidneys obey the same principles for excretion as urea such as creatinine, uric acid. The kidneys can excrete urea with minimum quantities of water and this can be achieved by two mechanisms: Formation of concentrated urine in the presence of ADH. Recirculation of urea from the collecting duct into the thin limb of the loop of Henle so that it passes upward through distal tubule, collecting tubule and then collecting duct again. In this way, urea can recirculate through these terminal portions of the tubular system several times before it is excreted and each time around these circuits contributes to the high concentration of urea so that very little water is excreted along with urea. Thus, this urea recirculation mechanism (which is also called urea cycle) through the loop of Henle, the distal tubule, and the collecting tubule and duct in a way to concentrate urea in the medullary interstitium and in the urine at the same time.