Guyton and Hall Textbook of Medical Physiology, 14ed GIT (dragged) 3.pdf

CHAPTER 27 GLOMERULAR FILTRATION—THE FIRST STEP IN URINE FORMATION The first step in urine formation is filtration of large amounts of fluid through the glomerular capillaries into Bowman’s capsule—almost 180 L/day. Most of this filtrate is reabsorbed, leaving only about 1 liter of fluid to be exc...

CHAPTER 27 GLOMERULAR FILTRATION—THE FIRST STEP IN URINE FORMATION The first step in urine formation is filtration of large amounts of fluid through the glomerular capillaries into Bowman’s capsule—almost 180 L/day. Most of this filtrate is reabsorbed, leaving only about 1 liter of fluid to be excreted each day, although the renal fluid excretion rate is highly variable, depending on fluid intake. The high rate of glomerular filtration depends on a high rate of kidney blood flow, as well as the special properties of the glomerular capillary membranes. In this chapter, we discuss the physical forces that determine the glomerular filtration rate (GFR), as well as the physiological mechanisms that regulate GFR and renal blood flow. COMPOSITION OF THE GLOMERULAR FILTRATE Like most capillaries, the glomerular capillaries are relatively impermeable to proteins, so the filtered fluid (called the glomerular filtrate) is essentially protein-free and devoid of cellular elements, including red blood cells. The concentrations of other constituents of the glomerular filtrate, including most salts and organic molecules, are similar to the concentrations in the plasma. Exceptions to this generalization include a few low-molecular-weight substances such as calcium and fatty acids that are not freely filtered because they are partially bound to the plasma proteins. For example, almost half of the plasma calcium and most of the plasma fatty acids are bound to proteins, and these bound portions are not filtered through the glomerular capillaries.! GLOMERULAR FILTRATION RATE IS ABOUT 20% OF RENAL PLASMA FLOW Similar to other capillaries, the glomerular capillaries filter fluid at a rate that is determined by the following: (1) the balance of hydrostatic and colloid osmotic forces acting across the capillary membrane; and (2) the capillary filtration coefficient (Kf), the product of the permeability and filtering surface area of the capillaries. The glomerular capillaries have a much higher rate of filtration than most other capillaries because of a high glomerular hydrostatic pressure and a large Kf. In the average adult human, the GFR is about 125 ml/min, or 180 L/day. The fraction of the renal plasma flow that is filtered (the filtration fraction) averages about 0.2, which means that about 20% of the plasma flowing through the kidney is filtered through the glomerular capillaries (Figure 27-1). The filtration fraction is calculated as follows: Filtration fraction = GFR/Renal plasma flow ! GLOMERULAR CAPILLARY MEMBRANE The glomerular capillary membrane is similar to that of other capillaries, except that it has three (instead of the usual two) major layers: (1) the endothelium of the capillary; (2) a basement membrane; and (3) a layer of epithelial cells (podocytes) surrounding the outer surface of the capillary basement membrane (Figure 27-2). Together, these layers make up the filtration barrier, which, despite the three layers, filters several hundred times as much water and solutes as the usual capillary membrane. Even with this high rate of filtration, the glomerular capillary membrane normally filters only a small amount of plasma proteins. The high filtration rate across the glomerular capillary membrane is due partly to its special characteristics. The capillary endothelium is perforated by thousands of small holes called fenestrae, similar to the fenestrated capillaries found in the liver, although smaller than the fenestrae of the liver. Although the fenestrations are relatively large, endothelial cell proteins are richly endowed with fixed negative charges that hinder the passage of plasma proteins. Surrounding the endothelium is the basement membrane, which consists of a meshwork of collagen and proteoglycan fibrillae that have large spaces through which large amounts of water and small solutes can filter. The basement membrane greatly hinders filtration of plasma proteins, partly because of strong negative electrical charges associated with the proteoglycans. The final part of the glomerular membrane is a layer of epithelial cells (podocytes) that line the outer surface of the glomerulus. These podocytes are not continuous but have long footlike processes (pedicels) that encircle the outer surface of the capillaries (see Figure 27-2). The foot 331 UNIT V Glomerular Filtration, Renal Blood Flow, and Their Control UNIT V The Body Fluids and Kidneys RPF (625 ml/min) Afferent arteriole Table 27-1 Filterability of Substances by Glomerular Capillaries Based on Molecular Weight Efferent arteriole Glomerular capillaries Bowman's capsule GFR (125 ml/min) REAB (124 ml/min) Peritubular capillaries Renal vein Urinary excretion (1 ml/min) Figure 27-1. Average values for total renal plasma flow (RPF), glomerular filtration rate (GFR), tubular reabsorption (REAB), and urine flow rate. RPF is equal to renal blood flow × (1 − hematocrit). Note that the GFR averages about 20% of the RPF, whereas urine flow rate is less than 1% of the GFR. Therefore, more than 99% of the fluid filtered is normally reabsorbed. The filtration fraction is GFR/RPF. Proximal tubule Podocytes Capillary loops Bowman's space Afferent arteriole Bowman's capsule Efferent arteriole A Slit pores Epithelium Basement membrane Endothelium B Fenestrations Figure 27-2. A, Basic ultrastructure of the glomerular capillaries. B, Cross section of the glomerular capillary membrane and its major components: capillary endothelium, basement membrane, and epithelium (podocytes). 332 Substance Molecular Weight Filterability Water 18 1.0 Sodium 23 1.0 Glucose 180 1.0 Inulin 5500 1.0 Myoglobin 17,000 0.75 Albumin 69,000 0.005 processes are separated by gaps called slit pores through which the glomerular filtrate moves. The epithelial cells, which also have negative charges, provide additional restriction to filtration of plasma proteins. Thus, all layers of the glomerular capillary wall provide a barrier to the filtration of plasma proteins but permit rapid filtration of water and most solutes in the plasma. Filterability of Solutes Inversely Related to Their Size. The glomerular capillary membrane is thicker than most other capillaries, but it is also much more porous and therefore filters fluid at a high rate. Despite the high filtration rate, the glomerular filtration barrier is selective in determining which molecules will be filtered, based on their size and electrical charge. Table 27-1 lists the effect of molecular size on filterability of different molecules. A filterability of 1.0 means that the substance is filtered as freely as water, whereas a filterability of 0.75 means that the substance is filtered only 75% as rapidly as water. Note that electrolytes such as sodium and small organic compounds such as glucose are freely filtered. As the molecular weight of the molecule approaches that of albumin, the filterability rapidly decreases, approaching zero.! Negatively Charged Large Molecules Are Filtered Less Easily Than Positively Charged Molecules of Equal Molecular Size. The molecular diameter of the plasma protein albumin is only about 6 nanometers, whereas the pores of the glomerular membrane are thought to be about 8 nanometers (80 angstroms [Å]). Albumin is restricted from filtration, however, because of its negative charge and the electrostatic repulsion exerted by negative charges of the glomerular capillary wall proteoglycans. Figure 27-3 shows how electrical charge affects the filtration of different molecular weight dextrans by the glomerulus. Dextrans are polysaccharides that can be manufactured as neutral molecules or with negative or positive charges. Note that for any given molecular radius, positively charged molecules are filtered much more readily than negatively charged molecules. Neutral dextrans are also filtered more readily than negatively charged dextrans of equal molecular weight. The Chapter 27 Glomerular Filtration, Renal Blood Flow, and Their Control Afferent arteriole 0.8 Polycationic dextran 0.6 Glomerular Glomerular hydrostatic colloid osmotic pressure pressure (60 mm Hg) (32 mm Hg) Efferent arteriole Neutral dextran UNIT V Relative filterability 1.0 0.4 Polyanionic dextran 0.2 Bowman's capsule pressure (18 mm Hg) 0 18 22 26 30 34 38 42 Effective molecular radius (Å) Figure 27-3. Effect of molecular radius and electrical charge of dextran on its filterability by the glomerular capillaries. A value of 1.0 indicates that the substance is filtered as freely as water, whereas a value of 0 indicates that it is not filtered. Dextrans are polysaccharides that can be manufactured as neutral molecules or with negative or positive charges and with varying molecular weights. reason for these differences in filterability is that the negative charges of the basement membrane and podocytes provide an important means for restricting large negatively charged molecules, including the plasma proteins.! Minimal-Change Nephropathy and Increased Glomerular Permeability to Plasma Proteins. In minimal- change nephropathy, the glomeruli become more permeable to plasma proteins, even though they may look normal when viewed with a standard light microscope. However, when viewed at high magnification with an electron microscope, the glomeruli usually display flattened podocytes with foot processes that may be detached from the glomerular basement membrane (podocyte effacement). The causes of minimal change nephropathy are unclear but may be at least partly related to an immunological response and abnormal T-cell secretion of cytokines that injure the podocytes and increase their permeability to some of the lower molecular weight proteins, especially albumin. This increased permeability permits the proteins to be filtered by the glomerular capillaries and excreted in the urine, a condition known as proteinuria or albuminuria. Minimal change nephropathy is most common in young children but can also occur in adults, especially in those who have autoimmune disorders.! DETERMINANTS OF THE GLOMERULAR FILTRATION RATE The GFR is determined by the following: (1) the sum of the hydrostatic and colloid osmotic forces across the glomerular membrane, which gives the net filtration pressure; and (2) the glomerular Kf. Expressed mathematically, Net filtration = pressure (10 mm Hg) Glomerular hydrostatic – pressure (60 mm Hg) Bowman's capsule – pressure (18 mm Hg) Glomerular colloid osmotic pressure (32 mm Hg) Figure 27-4. Summary of forces causing filtration by the glomerular capillaries. The values shown are estimates for healthy humans. the GFR equals the product of Kf and the net filtration pressure: The net filtration pressure represents the sum of the hydrostatic and colloid osmotic forces that favor or oppose filtration across the glomerular capillaries (Figure 27-4). These forces include the following: (1) hydrostatic pressure inside the glomerular capillaries (glomerular hydrostatic pressure, PG), which promotes filtration; (2) the hydrostatic pressure in Bowman’s capsule (PB) outside the capillaries, which opposes filtration; (3) the colloid osmotic pressure of the glomerular capillary plasma proteins (πG), which opposes filtration; and (4) the colloid osmotic pressure of the proteins in Bowman’s capsule (πB), which promotes filtration. Under normal conditions, the concentration of protein in the glomerular filtrate is so low that the colloid osmotic pressure of the Bowman’s capsule fluid is considered to be zero. The GFR can therefore be expressed as follows: GFR = K f × ( PG PB – πG + πB ) Although the normal values for the determinants of GFR have not been measured directly in humans, they have been estimated in animals such as dogs and rats. Based on the results in experimental animals, the approximate normal forces favoring and opposing glomerular filtration in humans are believed to be as follows (see Figure 27-4): Forces Favoring Filtration (mm Hg) Glomerular hydrostatic pressure 60 Bowman’s capsule colloid osmotic pressure 0 Forces Opposing Filtration (mm Hg) Bowman’s capsule hydrostatic pressure 18 Glomerular capillary colloid osmotic pressure 32 Thus, the net filtration pressure = 60 − 18 − 32 = +10 mm Hg. 333 UNIT V The Body Fluids and Kidneys INCREASED GLOMERULAR CAPILLARY FILTRATION COEFFICIENT INCREASES GLOMERULAR FILTRATE RATE The Kf is a measure of the product of the hydraulic conductivity and surface area of the glomerular capillaries. The Kf cannot be measured directly, but can be is estimated experimentally by dividing the GFR by the net filtration pressure: K f = GFR/Net filtration pressure Because the total GFR for both kidneys is about 125 ml/min, and the net filtration pressure is 10 mm Hg, the normal Kf is calculated to be about 12.5 ml/min per mm Hg of filtration pressure. When Kf is expressed per 100 grams of kidney weight, it averages about 4.2 ml/min per mm Hg, a value about 400 times as high as the Kf of most other capillary systems of the body. The average Kf of many other tissues in the body is only about 0.01 ml/min per mm Hg/100 g. This high Kf for the glomerular capillaries contributes to their rapid rate of fluid filtration. Although increased Kf raises the GFR and decreased Kf reduces the GFR, changes in Kf probably do not provide a primary mechanism for the normal daily regulation of GFR. Some diseases, however, lower Kf by reducing the number of functional glomerular capillaries (thereby reducing the surface area for filtration) or by increasing the thickness of the glomerular capillary membrane and reducing its hydraulic conductivity. For example, chronic uncontrolled hypertension may gradually reduce Kf by increasing the thickness of the glomerular capillary basement membrane and, eventually, by damaging the capillaries so severely that there is loss of capillary function.! INCREASED BOWMAN’S CAPSULE HYDROSTATIC PRESSURE DECREASES GLOMERULAR FILTRATION RATE Direct measurements of hydrostatic pressure in Bowman’s capsule and at different points in the proximal tubule in experimental animals using micropipettes have suggested that a reasonable estimate for Bowman’s capsule pressure in humans is about 18 mm Hg under normal conditions. Increasing the hydrostatic pressure in Bowman’s capsule reduces GFR, whereas decreasing this pressure raises GFR. However, changes in Bowman’s capsule pressure normally do not serve as a primary means for regulating GFR. In certain pathological states associated with obstruction of the urinary tract, Bowman’s capsule pressure can increase markedly, causing serious reduction of GFR. For example, precipitation of calcium or of uric acid may lead 334 40 Glomerular colloid osmotic pressure (mm Hg) Some of these values can change markedly under different physiological conditions, whereas others are altered mainly in disease states, as discussed later. Filtration fraction 38 Normal 36 34 32 Filtration fraction 30 28 Afferent end Distance along glomerular capillary Efferent end Figure 27-5. Increase in colloid osmotic pressure in plasma flowing through the glomerular capillary. Normally, about one-fifth of the fluid in the glomerular capillaries filters into Bowman’s capsule, thereby concentrating the plasma proteins that are not filtered. Increases in the filtration fraction (glomerular filtration rate/renal plasma flow) increase the rate at which the plasma colloid osmotic pressure rises along the glomerular capillary; decreases in the filtration fraction have the opposite effect. to formation of stones that lodge in the urinary tract, often in the ureter, thereby obstructing outflow of the urinary tract and raising Bowman’s capsule pressure. This situation reduces GFR and eventually can cause hydronephrosis (distention and dilation of the renal pelvis and calyces) and can damage or even destroy the kidney unless the obstruction is relieved.! INCREASED GLOMERULAR CAPILLARY COLLOID OSMOTIC PRESSURE DECREASES GLOMERULAR FILTRATION RATE As blood passes from the afferent arteriole through the glomerular capillaries to the efferent arterioles, the plasma protein concentration increases about 20% (Figure 27-5). The reason for this increase is that about one-fifth of the fluid in the capillaries filters into Bowman’s capsule, thereby concentrating the glomerular plasma proteins that are not filtered. Assuming that the normal colloid osmotic pressure of plasma entering the glomerular capillaries is 28 mm Hg, this value usually rises to about 36 mm Hg by the time the blood reaches the efferent end of the capillaries. Therefore, the average colloid osmotic pressure of the glomerular capillary plasma proteins is midway between 28 and 36 mm Hg, or about 32 mm Hg. Two factors that influence the glomerular capillary colloid osmotic pressure are the following: (1) the arterial plasma colloid osmotic pressure; and (2) the fraction of plasma filtered by the glomerular capillaries (filtration fraction). Increasing the arterial plasma colloid osmotic pressure raises the glomerular capillary colloid osmotic pressure, which in turn tends to decrease the GFR. Increasing the filtration fraction also concentrates the plasma proteins and raises the glomerular colloid osmotic pressure (see Figure 27-5). Because the filtration fraction is defined as the GFR divided by the renal plasma flow, the filtration fraction can be increased by raising the GFR or Chapter 27 Glomerular Filtration, Renal Blood Flow, and Their Control by reducing renal plasma flow. For example, a reduction in renal plasma flow with no initial change in GFR would tend to increase the filtration fraction, which would raise the glomerular capillary colloid osmotic pressure and tend to reduce the GFR. For this reason, changes in renal blood flow can influence GFR independently of changes in glomerular hydrostatic pressure. With increasing renal blood flow, a lower fraction of the plasma is initially filtered out of the glomerular capillaries, causing a slower rise in the glomerular capillary colloid osmotic pressure and less inhibitory effect on the GFR. Consequently, even with a constant glomerular hydrostatic pressure, a greater rate of blood flow into the glomerulus tends to increase the GFR and a lower rate of blood flow into the glomerulus tends to decrease the GFR.! RA PG UNIT V Renal blood flow GFR RE PG Renal blood flow GFR 100 2000 1400 Normal 50 800 Renal blood flow 0 0 Renal blood flow (ml/min) Glomerular filtration rate 150 200 1 2 3 4 Efferent arteriolar resistance (× normal) 250 2000 100 1400 150 Normal 100 Glomerular filtration rate 50 0 0 Renal blood flow 800 Renal blood flow (ml/min) Glomerular filtration rate (ml/min) The glomerular capillary hydrostatic pressure has been estimated to be about 60 mm Hg under normal conditions. Changes in glomerular hydrostatic pressure serve as the primary means for physiological regulation of GFR. Increases in glomerular hydrostatic pressure raise the GFR, whereas decreases in glomerular hydrostatic pressure reduce the GFR. Glomerular hydrostatic pressure is determined by three variables, each of which is under physiological control: (1) arterial pressure; (2) afferent arteriolar resistance; and (3) efferent arteriolar resistance. Increased arterial pressure tends to raise glomerular hydrostatic pressure and, therefore, to increase the GFR. However, as discussed later, this effect is buffered by autoregulatory mechanisms that maintain a relatively constant glomerular pressure as arterial pressure fluctuates. Increased resistance of afferent arterioles reduces glomerular hydrostatic pressure and decreases the GFR (Figure 27-6). Conversely, dilation of the afferent arterioles increases glomerular hydrostatic pressure and GFR. Constriction of the efferent arterioles increases the resistance to outflow from the glomerular capillaries. This mechanism raises glomerular hydrostatic pressure and, as long as the increase in efferent resistance does not reduce renal blood flow too much, GFR increases slightly (see Figure 27-6). However, because efferent arteriolar constriction also reduces renal blood flow, filtration fraction and glomerular colloid osmotic pressure increase as efferent arteriolar resistance increases. Therefore, if constriction of efferent arterioles is severe (more than about a threefold increase in efferent arteriolar resistance), the rise in colloid osmotic pressure exceeds the increase in glomerular capillary hydrostatic pressure caused by efferent arteriolar constriction. When this situation occurs, the net force for filtration actually decreases, causing a reduction in GFR. Figure 27-6. Effect of increases in afferent arteriolar resistance (RA, top panel) or efferent arteriolar resistance (RE, bottom panel) on renal blood flow, glomerular hydrostatic pressure (PG), and glomerular filtration rate (GFR). Glomerular filtration rate (ml/min) INCREASED GLOMERULAR CAPILLARY HYDROSTATIC PRESSURE INCREASES GLOMERULAR FILTRATION RATE 200 1 2 3 4 Afferent arteriolar resistance (× normal) Figure 27-7. Effect of change in afferent arteriolar resistance or efferent arteriolar resistance on glomerular filtration rate and renal blood flow. Thus, efferent arteriolar constriction has a biphasic effect on GFR (Figure 27-7). At moderate levels of constriction, there is a slight increase in GFR but, with severe constriction, there is a decrease in GFR. The primary cause of the eventual decrease in GFR is as follows. As efferent constriction becomes severe, and as plasma 335 UNIT V The Body Fluids and Kidneys Table 27-2 Factors That Can Decrease the Glomerular Filtration Rate Physiological or Pathophysiological Causes ↓Kf → ↓GFR Renal disease, diabetes mellitus, hypertension, aging ↑PB → ↓GFR Urinary tract obstruction (e.g., kidney stones) ↑πG → ↓GFR ↓ Renal blood flow, increased plasma proteins ↓PG → ↓GFR ↓AP → ↓PG ↓ Arterial pressure (has only a small effect because of autoregulation) ↓RE → ↓PG ↓ Angiotensin II (drugs that block angiotensin II formation) ↑RA → ↓PG ↑ Sympathetic activity, vasoconstrictor hormones (e.g., norepinephrine, endothelin) aOpposite changes in the determinants usually increase the GFR. AP, Systemic arterial pressure; GFR, glomerular filtration rate; Kf, glomerular filtration coefficient; PB, Bowman’s capsule hydrostatic pressure; πG, glomerular capillary colloid osmotic pressure; PG, glomerular capillary hydrostatic pressure; RA, afferent arteriolar resistance; RE, efferent arteriolar resistance. protein concentration increases, there is a rapid nonlinear increase in colloid osmotic pressure caused by the Donnan effect; the higher the protein concentration, the more rapidly the colloid osmotic pressure rises because of the interaction of ions bound to the plasma proteins, which also exert an osmotic effect, as discussed in Chapter 16. To summarize, constriction of afferent arterioles reduces GFR. However, the effect of efferent arteriolar constriction depends on the severity of the constriction; modest efferent constriction raises GFR, but severe efferent constriction (more than a threefold increase in resistance) tends to reduce GFR. Table 27-2 summarizes the factors that can decrease the GFR.! RENAL BLOOD FLOW In a 70-kg man, the combined blood flow through both kidneys is about 1100 ml/min, or about 22% of the cardiac output. Considering that the two kidneys constitute only about 0.4% of the total body weight, one can readily see that they receive extremely high blood flow compared with other organs. As with other tissues, blood flow supplies the kidneys with nutrients and removes waste products. However, the high blood flow to the kidneys greatly exceeds this need. The purpose of this additional flow is to supply enough plasma for the high rates of glomerular filtration that are necessary for precise regulation of body fluid volumes and solute concentrations. As might be expected, the mechanisms that regulate renal blood flow are closely linked to control of GFR and excretory functions of the kidneys. 336 Oxygen consumption (ml/min/100 g kidney weight) Physical Determinantsa 3.0 2.5 2.0 1.5 1.0 0.5 Basal oxygen consumption 0 0 5 10 15 20 Sodium reabsorption (mEq/min per 100 g kidney weight) Figure 27-8. Relationship between oxygen consumption and sodium reabsorption in dog kidneys. (From Kramer K, Deetjen P: [Relation of renal oxygen consumption to blood supply and glomerular filtration during variations of blood pressure.] Pflugers Arch Physiol 271:782, 1960.) 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 (Figure 27-8). If glomerular filtration ceases completely, 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.! DETERMINANTS OF RENAL BLOOD FLOW Renal blood flow (RBF) is determined by the pressure gradient across the renal vasculature (the difference between renal artery and renal vein hydrostatic pressures), divided by the total renal vascular resistance: RBF = ( Renal artery pressure − Renal vein pressure) Total renal vascular resistance Renal artery pressure is about equal to systemic arterial pressure, and renal vein pressure averages about 3 to 4 mm Hg under most conditions. As in other vascular Chapter 27 Glomerular Filtration, Renal Blood Flow, and Their Control Table 27-3 Approximate Pressures and Vascular Resistances in Circulation of a Normal Kidney Pressure in Vessel (mm Hg) Beginning End Percentage of Total Renal Vascular Resistance Hormone or Autacoid Effect on GFR Norepinephrine ↓ Epinephrine ↓ ↓ Renal artery 100 100 ≈0 Endothelin Interlobar, arcuate, and interlobular arteries ≈100 85 ≈16 Angiotensin II ↔ (prevents ↓) Endothelial-derived nitric oxide ↑ Afferent arteriole 85 60 ≈26 Prostaglandins ↑ Glomerular capillaries 60 59 ≈1 Efferent arteriole 59 18 ≈43 Peritubular capillaries 18 8 ≈10 Interlobar, interlobular, and arcuate veins 8 4 ≈4 Renal vein 4 ≈4 ≈0 beds, the total vascular resistance through the kidneys is determined by the sum of the resistances in the individual vasculature segments, including the arteries, arterioles, capillaries, and veins (Table 27-3). Most of the renal vascular resistance resides in three major segments—interlobular arteries, afferent arterioles, and efferent arterioles. Resistance of these vessels is controlled by the sympathetic nervous system, various hormones, and local internal renal control mechanisms, as discussed later. An increase in the resistance of any of the vascular segments of the kidneys tends to reduce the renal blood flow, whereas a decrease in vascular resistance increases renal blood flow if renal artery and renal vein pressures remain constant. Although changes in arterial pressure have some influence on renal blood flow, the kidneys have effective mechanisms for maintaining renal blood flow and GFR relatively constant over an arterial pressure range between 80 and 170 mm Hg, a process called autoregulation. This capacity for autoregulation occurs through mechanisms that are intrinsic to the kidneys, as discussed later in this chapter.! BLOOD FLOW IN VASA RECTA OF RENAL MEDULLA IS LOW COMPARED WITH RENAL CORTEX FLOW The outer part of the kidney, the renal cortex, receives most of the kidney’s blood flow. Blood flow in the renal medulla accounts for only 1% to 2% of the total renal blood flow. Flow to the renal medulla is supplied by a specialized portion of the peritubular capillary system called the vasa recta. These vessels descend into the medulla in parallel with the loops of Henle and then loop back along with the loops of Henle and return to the cortex before emptying into the venous system. As discussed in Chapter 29, UNIT V Vessel Table 27-4 Hormones and Autacoids That Influence the Glomerular Filtration Rate (GFR) the vasa recta play an important role in allowing the kidneys to form concentrated urine.! PHYSIOLOGICAL CONTROL OF GLOMERULAR FILTRATION AND RENAL BLOOD FLOW The determinant of GFR that is most variable and subject to physiological control is the glomerular hydrostatic pressure. This variable, in turn, is influenced by the sympathetic nervous system, hormones, autacoids (vasoactive substances that are released in the kidneys and act locally), and other feedback controls that are intrinsic to the kidneys. STRONG SYMPATHETIC NERVOUS SYSTEM ACTIVATION DECREASES GLOMERULAR FILTRATION RATE Essentially all the blood vessels of the kidneys, including the afferent and efferent arterioles, are richly innervated by sympathetic nerve fibers. Strong activation of the renal sympathetic nerves can constrict the renal arterioles and decrease renal blood flow and GFR. Moderate or mild sympathetic stimulation has little influence on renal blood flow and GFR. For example, reflex activation of the sympathetic nervous system resulting from moderate decreases in pressure at the carotid sinus baroreceptors or cardiopulmonary receptors has little influence on renal blood flow or GFR. However, as discussed in Chapter 28, even mild increases in renal sympathetic activity can stimulate renin release and increase renal tubular reabsorption, causing decreased sodium and water excretion. The renal sympathetic nerves seem to be the most important in reducing GFR during severe acute disturbances lasting for a few minutes to a few hours, such as those elicited by the defense reaction, brain ischemia, or severe hemorrhage.! HORMONAL AND AUTACOID CONTROL OF RENAL CIRCULATION Several hormones and autacoids can influence GFR and renal blood flow, as summarized in Table 27-4. 337 UNIT V The Body Fluids and Kidneys Norepinephrine, Epinephrine, and Endothelin Constrict Renal Blood Vessels and Decrease Glomerular Filtration Rate. Hormones that constrict afferent and efferent arterioles, causing reductions in GFR and renal blood flow, include norepinephrine and epinephrine released from the adrenal medulla. In general, blood levels of these hormones parallel the activity of the sympathetic nervous system; thus, norepinephrine and epinephrine have little influence on renal hemodynamics except under conditions associated with strong activation of the sympathetic nervous system, such as severe hemorrhage. Another vasoconstrictor, endothelin, is a peptide that can be released by damaged vascular endothelial cells of the kidneys, as well as by other tissues. The physiological role of this autacoid is not completely understood. However, endothelin may contribute to hemostasis (minimizing blood loss) when a blood vessel is severed, which damages the endothelium and releases this powerful vasoconstrictor. Plasma endothelin levels are also increased in many disease states associated with vascular injury, such as toxemia of pregnancy, acute renal failure, and chronic uremia, and may contribute to renal vasoconstriction and decreased GFR in some of these pathophysiological conditions.! Angiotensin II Preferentially Constricts Efferent Arterioles in Most Physiological Conditions. A pow- erful renal vasoconstrictor, angiotensin II, can be considered to be a circulating hormone and a locally produced autacoid or paracrine hormone because it is formed in the kidneys and in the systemic circulation. Receptors for angiotensin II are present in virtually all blood vessels of the kidneys. However, the preglomerular blood vessels, especially the afferent arterioles, appear to be relatively protected from angiotensin II–mediated constriction in most physiological conditions associated with activation of the renin-angiotensin system, such as during a lowsodium diet or reduced renal perfusion pressure due to renal artery stenosis. This protection is due to release of vasodilators, especially nitric oxide and prostaglandins, which counteract the vasoconstrictor effects of angiotensin II in these blood vessels. The efferent arterioles, however, are highly sensitive to angiotensin II. Because angiotensin II preferentially constricts efferent arterioles in most physiological conditions, increased angiotensin II levels raise glomerular hydrostatic pressure while reducing renal blood flow. It should be kept in mind that increased angiotensin II formation usually occurs in circumstances associated with decreased arterial pressure or volume depletion, which tend to decrease GFR. In these circumstances, the increased level of angiotensin II, by constricting efferent arterioles, helps prevent decreases in glomerular hydrostatic pressure and GFR. At the same time, though, the reduction in renal blood flow caused by efferent arteriolar constriction contributes to decreased flow through the peritubular capillaries, which in turn increases the 338 reabsorption of sodium and water, as discussed in Chapter 28. Thus, increased angiotensin II levels that occur with a low-sodium diet or volume depletion help maintain GFR and normal excretion of metabolic waste products, such as urea and creatinine, which depend on glomerular filtration for their excretion. At the same time, the angiotensin II–induced constriction of efferent arterioles increases tubular reabsorption of sodium and water, which helps restore blood volume and blood pressure. This effect of angiotensin II in helping autoregulate GFR is discussed in more detail later in this chapter.! Endothelial-Derived Nitric Oxide Decreases Renal Vascular Resistance and Increases Glomerular Filtration Rate. An autacoid that decreases renal vascu- lar resistance and is released by the vascular endothelium throughout the body is endothelial-derived nitric oxide. A basal level of nitric oxide production appears to be important for maintaining vasodilation of the kidneys and normal excretion of sodium and water. Therefore, administration of drugs that inhibit formation of nitric oxide increases renal vascular resistance and decreases GFR and urinary sodium excretion, eventually causing high blood pressure. In some hypertensive patients or in patients with atherosclerosis, damage of the vascular endothelium and impaired nitric oxide production may contribute to increased renal vasoconstriction and elevated blood pressure.! Prostaglandins and Bradykinin Decrease Renal Vascular Resistance and Tend to Increase Glomerular Filtration Rate. Prostaglandins (PGE2 and PGI2) and bradykinin serve as hormones and autacoids that cause vasodilation, increased renal blood flow, and increased GFR. These substances are discussed in Chapter 17. Although these vasodilators do not appear to be of major importance in regulating renal blood flow or the GFR in normal conditions, they may dampen the renal vasoconstrictor effects of the sympathetic nerves or angiotensin II, especially their effects to constrict the afferent arterioles. By opposing vasoconstriction of afferent arterioles, the prostaglandins help prevent excessive reductions in GFR and renal blood flow. Under stressful conditions, such as volume depletion or after surgery, the administration of nonsteroidal antiinflammatory drugs (NSAIDs), such as aspirin, that inhibit prostaglandin synthesis may cause significant reductions in GFR.! AUTOREGULATION OF GLOMERULAR FILTRATION RATE AND RENAL BLOOD FLOW Feedback mechanisms intrinsic to the kidneys normally keep renal blood flow and GFR relatively constant, despite marked changes in arterial blood pressure. 1200 800 160 Renal blood flow 120 Glomerular filtration rate 80 400 40 0 0 Urine output (ml/min) 8 6 4 2 0 50 100 150 Mean arterial pressure (mm Hg) 200 Figure 27-9. Autoregulation of renal blood flow and glomerular filtration rate but lack of autoregulation of urine flow during changes in renal arterial pressure. These mechanisms still function in blood- perfused kidneys that have been removed from the body, independent of systemic influences. This relative constancy of GFR and renal blood flow is referred to as autoregulation (Figure 27-9). The primary function of blood flow autoregulation in most tissues, other than the kidneys, is to maintain the delivery of oxygen and nutrients at a normal level and remove the waste products of metabolism, despite changes in the arterial pressure. In the kidneys, the normal blood flow is much higher than that required for these functions. The major function of autoregulation in the kidneys is to maintain a relatively constant the GFR and allow precise control of renal excretion of water and solutes. The GFR normally remains relatively constant, despite considerable arterial pressure fluctuations that occur during a person’s usual activities. For example, a decrease in arterial pressure to as low as 70 to 75 mm Hg or an increase to as high as 160 to 180 mm Hg usually changes the GFR less than 10%. In general, renal blood flow is autoregulated in parallel with GFR, but GFR is more efficiently autoregulated under certain conditions. Importance of Glomerular Filtration Rate Autoregulation in Preventing Extreme Changes in Renal Excretion Although the renal autoregulatory mechanisms are not perfect, they do prevent potentially large changes in GFR and renal excretion of water and solutes that would otherwise occur with changes in blood pressure. One can understand the quantitative importance of autoregulation by considering the relative magnitudes of glomerular filtration, tubular reabsorption, and renal excretion and the changes in renal excretion that would occur without autoregulatory mechanisms. Normally, GFR is about 180 L/day, and tubular reabsorption is 178.5 L/day, leaving 1.5 L/day of fluid to be excreted in the urine. In the absence of autoregulation, a relatively small increase in blood pressure (from 100 to 125 mm Hg) would cause a similar 25% increase in GFR (from about 180 to 225 L/day). If tubular reabsorption remained constant at 178.5 L/day, the urine flow would increase to 46.5 L/day (the difference between GFR and tubular reabsorption)—a total increase in urine of more than 30-fold. Because the total plasma volume is only about 3 liters, such a change would quickly deplete the blood volume. In reality, changes in arterial pressure usually exert much less of an effect on urine volume for two reasons: (1) renal autoregulation prevents large changes in GFR that would otherwise occur; and (2) there are additional adaptive mechanisms in the renal tubules that cause them to increase their reabsorption rate when GFR rises, a phenomenon referred to as glomerulotubular balance (discussed in Chapter 28). Even with these special control mechanisms, changes in arterial pressure still have significant effects on renal excretion of water and sodium; this effect is referred to as pressure diuresis or pressure natriuresis, and it is crucial in the regulation of body fluid volumes and arterial pressure, as discussed in Chapters 19 and 30.! TUBULOGLOMERULAR FEEDBACK AND AUTOREGULATION OF GLOMERULAR FILTRATION RATE The kidneys have a special feedback mechanism that links changes in the sodium chloride concentration at the macula densa with the control of renal arteriolar resistance and autoregulation of GFR. This feedback helps ensure a relatively constant delivery of sodium chloride to the distal tubule and helps prevent spurious fluctuations in renal excretion that would otherwise occur. In many circumstances, this feedback autoregulates renal blood flow and GFR in parallel. However, because this mechanism is specifically directed toward stabilizing sodium chloride delivery to the distal tubule, instances occur when GFR is autoregulated at the expense of changes in renal blood flow, as discussed later. In other cases, this mechanism may actually cause changes in GFR in response to primary changes in renal tubular sodium chloride reabsorption. The tubuloglomerular feedback mechanism has two components that act together to control GFR: (1) an afferent arteriolar feedback mechanism; and (2) an efferent arteriolar feedback mechanism. These feedback mechanisms depend on special anatomical arrangements of the juxtaglomerular complex (Figure 27-10). The juxtaglomerular complex consists of macula densa cells in the initial portion of the distal tubule and juxtaglomerular cells in the walls of the afferent and efferent arterioles. The macula densa is a specialized group 339 UNIT V Renal blood flow (ml/min) 1600 Glomerular filtration rate (ml/min) Chapter 27 Glomerular Filtration, Renal Blood Flow, and Their Control UNIT V The Body Fluids and Kidneys Arterial pressure − Glomerular hydrostatic pressure − Glomerular epithelium GFR Juxtaglomerular cells Afferent arteriole Efferent arteriole Internal elastic lamina Macula densa Smooth muscle fiber Distal tubule Basement membrane Figure 27-10. Structure of the juxtaglomerular apparatus, demonstrating its possible feedback role in the control of nephron function. of epithelial cells in the distal tubules that comes in close contact with the afferent and efferent arterioles. The macula densa cells contain the Golgi apparatus, which consists of intracellular secretory organelles directed toward the arterioles, suggesting that these cells may be secreting a substance toward the arterioles. Decreased Macula Densa Sodium Chloride Causes Dilation of Afferent Arterioles and Increased Renin Release. The macula densa cells sense changes in so- dium chloride delivery to the distal tubule by way of signals that are not completely understood. Experimental studies have suggested that a decreased GFR slows the flow rate in the loop of Henle, causing increased reabsorption of the percentage of sodium and chloride ions delivered to the ascending loop of Henle and thereby reducing the concentration of sodium chloride at the macula densa cells. This decrease in sodium chloride concentration initiates a signal from the macula densa that has two effects (Figure 27-11): (1) it decreases resistance to blood flow in the afferent arterioles, which raises glomerular hydrostatic pressure and helps return GFR toward normal; and (2) it increases renin release from the juxtaglomerular cells of the afferent and efferent arterioles, which are the major storage sites for renin. Renin released from these cells then functions as an enzyme to increase the formation of angiotensin I, which is converted to angiotensin II. Finally, angiotensin II constricts the efferent arterioles, thereby increasing glomerular hydrostatic pressure and helping return GFR toward normal. 340 Proximal NaCl reabsorption Macula densa NaCl Renin Angiotensin II Efferent arteriolar resistance Afferent arteriolar resistance Figure 27-11. Macula densa feedback mechanism for autoregulation of glomerular hydrostatic pressure and glomerular filtration rate (GFR) during decreased renal arterial pressure. These two components of the tubuloglomerular feedback mechanism, operating together by way of the special anatomical structure of the juxtaglomerular apparatus, provide feedback signals to the afferent and efferent arterioles for efficient autoregulation of GFR during changes in arterial pressure. When both of these mechanisms are functioning together, GFR changes by only a few percentage points, even with large fluctuations in arterial pressure between the limits of 75 and 160 mm Hg.! Blockade of Angiotensin II Formation Further Reduces Glomerular Filtration Rate During Renal Hypoperfusion. As discussed earlier, a preferential constrictor action of angiotensin II on efferent arterioles helps prevent serious reductions in glomerular hydrostatic pressure and GFR when renal perfusion pressure falls below normal. The administration of drugs that block the formation of angiotensin II (angiotensin-converting enzyme inhibitors) or that block the action of angiotensin II (angiotensin II receptor antagonists) may cause greater reductions in GFR than usual when the renal arterial pressure falls below normal. Therefore, an important complication of using these drugs to treat patients who have hypertension because of renal artery stenosis (partial blockage of the renal artery) is a severe decrease in GFR that can, in some cases, cause acute renal failure. Nevertheless, angiotensin II–blocking drugs are important therapeutic agents in many patients with hypertension, congestive heart failure, and other conditions, as long as the patients are monitored to ensure that severe decreases in GFR do not occur.! Chapter 27 Glomerular Filtration, Renal Blood Flow, and Their Control MYOGENIC AUTOREGULATION OF RENAL BLOOD FLOW AND GLOMERULAR FILTRATION RATE High Protein Intake and Hyperglycemia Increase Renal Blood Flow and Glomerular Filtration Rate. Although renal blood flow and GFR are relatively stable under most conditions, there are circumstances in which these variables change significantly. For example, a high protein intake is known to increase renal blood flow and GFR. With a long- term, high- protein diet, such as one that contains large amounts of meat, increases in GFR and renal blood flow are due partly to growth of the kidneys. However, the GFR and renal blood flow also increase 20% to 30% within 1 or 2 hours after a person eats a high- protein meal. One likely explanation for the increased GFR is the following. A high-protein meal releases into the blood amino acids, which are reabsorbed in the proximal tubules. Because amino acids and sodium are reabsorbed together by cotransport in the proximal tubules, increased amino acid reabsorption also stimulates sodium reabsorption. This increased reabsorption of sodium decreases sodium delivery to the macula densa (see Figure 27-12), which elicits a tubuloglomerular feedback–mediated decrease in resistance of the afferent arterioles, as discussed earlier. The decreased afferent arteriolar resistance then raises renal blood flow and GFR, allowing sodium excretion to be maintained at a nearly normal level while increasing excretion of the waste products of protein metabolism, such as urea. Amino acids UNIT V Another mechanism that contributes to the maintenance of a relatively constant renal blood flow and GFR is the ability of individual blood vessels to resist stretching during increased arterial pressure, referred to as the myogenic mechanism. Studies of individual blood vessels (especially small arterioles) throughout the body have shown that they respond to increased wall tension or wall stretch by contraction of the vascular smooth muscle. Stretch of the vascular wall allows increased movement of calcium ions from the extracellular fluid into the cells, causing them to contract through the mechanisms discussed in Chapter 8. This contraction prevents excessive stretch of the vessel and, at the same time, by raising vascular resistance, helps prevent excessive increases in renal blood flow and the GFR when arterial pressure increases. Although the myogenic mechanism probably operates in most arterioles throughout the body, its importance in renal blood flow and GFR autoregulation has been questioned by some physiologists because this pressuresensitive mechanism has no means of directly detecting changes in renal blood flow or GFR per se. On the other hand, this mechanism may be more important in protecting the kidney from hypertension-induced injury. In response to sudden increases in blood pressure, the myogenic constrictor response in afferent arterioles occurs within seconds and therefore attenuates transmission of increased arterial pressure to the glomerular capillaries. Protein ingestion Proximal tubular amino acid reabsorption Proximal tubular NaCl reabsorption Macula densa NaCl Macula densa feedback Afferent arteriolar resistance GFR Figure 27-12. Possible role of macula densa feedback in mediating increased glomerular filtration rate (GFR) after a high-protein meal. A similar mechanism may also explain the marked increases in renal blood flow and the GFR that occur with large increases in blood glucose levels in persons with uncontrolled diabetes mellitus. Because glucose, like some of the amino acids, is also reabsorbed along with sodium in the proximal tubule, increased glucose delivery to the tubules causes them to reabsorb excess sodium along with glucose. This increased reabsorption of sodium, in turn, decreases the sodium chloride concentration at the macula densa, activating a tubuloglomerular feedback–mediated dilation of the afferent arterioles and subsequent increases in renal blood flow and GFR. These examples demonstrate that renal blood flow and GFR per se are not the primary variables controlled by the tubuloglomerular feedback mechanism. The main purpose of this feedback is to ensure a constant delivery of sodium chloride to the distal tubule, where final processing of the urine takes place. Thus, disturbances that tend to increase the reabsorption of sodium chloride at tubular sites before the macula densa tend to elicit increased renal blood flow and GFR, which helps return distal sodium chloride delivery toward normal so that normal rates of sodium and water excretion can be maintained (see Figure 27-12). An opposite sequence of events occurs when proximal tubular reabsorption is reduced. For example, when the proximal tubules are damaged (which can occur as a result of poisoning by heavy metals, such as mercury, or large doses of drugs, such as tetracyclines), their ability to reabsorb sodium chloride is decreased. As a consequence, large amounts of sodium chloride are delivered to the distal tubule and, without appropriate compensation, would quickly cause excessive volume depletion. One of the important compensatory responses appears to be a 341 UNIT V The Body Fluids and Kidneys Table 27-5 Some Conditions That Influence Renal Blood Flow (RBF) and the Glomerular Filtration Rate (GFR) Condition RBF GFR Aging ↓ ↓ High dietary protein ↑ ↑ Hyperglycemiaa ↑ ↑ Obesitya ↑ ↑ High NaCl intakea ↑ ↑ Glucocorticoids ↑ ↑ Fever, pyrogens ↑ ↑ aRefers to early effects, prior to development of glomerular injury that may occur with chronic hyperglycemia, obesity, and high salt intake. tubuloglomerular feedback–mediated renal vasoconstriction that occurs in response to the increased sodium chloride delivery to the macula densa in these circumstances. These examples again demonstrate the importance of this feedback mechanism for ensuring that the distal tubules receive the proper rate of delivery of sodium chloride, other tubular fluid solutes, and tubular fluid volume so that appropriate amounts of these substances are excreted in the urine.! Other Factors That Influence Renal Blood Flow and Glomerular Filtration Rate. The GFR and renal blood flow are low at birth, approach normal adult levels after about 2 years of life, and in the absence of kidney disease, are maintained relatively constant until the fourth decade. Thereafter, GFR declines by about 5% to 10% per decade, although there is considerable variability among individuals. This decline in GFR coincides with nitric oxide deficiency, increased oxidative stress, and loss of functional nephrons, which may be related partly to increasing blood pressure, metabolic disorders, and other insults that cause cumulative glomerular injury with aging. Men have higher renal blood flow and GFR than women, even when corrected for body mass. However, men also have a more rapid decline in GFR with aging than premenopausal women. Although the mechanisms responsible for these sex differences are not fully understood, beneficial effects of estrogens and damaging effects of androgens on the kidneys have been suggested as a partial explanation. Table 27-5 summarizes some additional factors that influence renal blood flow and GFR regulation, and should be considered when assessing kidney function. 342 Bibliography Anders HJ, Huber TB, Isermann B, Schiffer M: CKD in diabetes: diabetic kidney disease versus nondiabetic kidney disease. Nat Rev Nephrol 14:361, 2018. Baylis C: Sexual dimorphism: the aging kidney, involvement of nitric oxide deficiency, and angiotensin II overactivity. J Gerontol A Biol Sci Med Sci 67:1365, 2012. Beierwaltes WH, Harrison-Bernard LM, Sullivan JC, Mattson DL: Assessment of renal function; clearance, the renal microcirculation, renal blood flow, and metabolic balance. Compr Physiol 3:165, 2013. Bidani AK, Polichnowski AJ, Loutzenhiser R, Griffin KA: Renal microvascular dysfunction, hypertension and CKD progression. Curr Opin Nephrol Hypertens 22:1, 2013. Carlström M, Wilcox CS, Arendshorst WJ: Renal autoregulation in health and disease. Physiol Rev 95:405, 2015. Cowley AW Jr, Abe M, Mori T, O’Connor PM, et. al: Reactive oxygen species as important determinants of medullary flow, sodium excretion, and hypertension. Am J Physiol Renal Physiol 308:F179, 2013. de Groat WC, Griffiths D, Yoshimura N: Neural control of the lower urinary tract. Compr Physiol 5:327, 2015. DiBona GF: Physiology in perspective: the wisdom of the body. Neural control of the kidney. Am J Physiol Regul Integr Comp Physiol 289:R633, 2005. Gomez RA, Sequeira-Lopez MLS: Renin cells in homeostasis, regeneration and immune defence mechanisms. Nat Rev Nephrol 14:231, 2018. Griffin KA: Hypertensive kidney injury and the progression of chronic kidney disease. Hypertension 70:687, 2017. Guan Z, VanBeusecum JP, Inscho EW: Endothelin and the renal microcirculation. Semin Nephrol 35:145, 2015. Hall JE, Brands MW: The renin-angiotensin-aldosterone system: renal mechanisms and circulatory homeostasis. In: Seldin DW, Giebisch G (eds): The Kidney—Physiology and Pathophysiology, 3rd ed. New York: Raven Press, 2000, pp 1009-1046. Hall JE, do Carmo JM, da Silva AA, Wang Z, Hall ME: Obesity, kidney dysfunction and hypertension: mechanistic links. Nature Reviews Nephrology 15: 367, 2019. Hall JE, do Carmo JM, da Silva AA, Wang Z, Hall ME: Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ Res 116:991, 2015. Navar LG, Kobori H, Prieto MC, Gonzalez-Villalobos RA: Intratubular renin-angiotensin system in hypertension. Hypertension 57:355, 2011. Schell C, Huber TB: The evolving complexity of the podocyte cytoskeleton. J Am Soc Nephrol 28:3166-, 2017. Schnermann J, Briggs JP: Tubular control of renin synthesis and secretion. Pflugers Arch 465:39, 2013. Speed JS, Pollock DM: Endothelin, kidney disease, and hypertension. Hypertension 61:1142, 2013. Thomson SC, Blantz RC: Biophysics of glomerular filtration. Compr Physiol 2:1671. Vivarelli M, Massella L, Ruggiero B, Emma F: Minimal change disease. Clin J Am Soc Nephrol 12:332, 2017.