Glomerular Filtration, Renal Blood Flow, and Their Control PDF

CHAPTER 27 Glomerular Filtration, Renal Blood Flow, UNIT V and Their Control GLOMERULAR FILTRATION—TH...

CHAPTER 27 Glomerular Filtration, Renal Blood Flow, UNIT V and Their Control GLOMERULAR FILTRATION—THE FIRST GFR is about 125 ml/min, or 180 L/day. The fraction of STEP IN URINE FORMATION the renal plasma flow that is filtered (the filtration frac- The first step in urine formation is filtration of large tion) averages about 0.2, which means that about 20% of amounts of fluid through the glomerular capillaries into the plasma flowing through the kidney is filtered through Bowman’s capsule—almost 180 L/day. Most of this fil- the glomerular capillaries (Figure 27-­1). The filtration trate is reabsorbed, leaving only about 1 liter of fluid to be fraction is calculated as follows: excreted each day, although the renal fluid excretion rate Filtration fraction = GFR/Renal plasma flow is highly variable, depending on fluid intake. The high rate of glomerular filtration depends on a high rate of kidney GLOMERULAR CAPILLARY MEMBRANE blood flow, as well as the special properties of the glo- merular capillary membranes. In this chapter, we discuss The glomerular capillary membrane is similar to that of the physical forces that determine the glomerular filtra- other capillaries, except that it has three (instead of the tion rate (GFR), as well as the physiological mechanisms usual two) major layers: (1) the endothelium of the capil- that regulate GFR and renal blood flow. lary; (2) a basement membrane; and (3) a layer of epithe- lial cells (podocytes) surrounding the outer surface of the COMPOSITION OF THE GLOMERULAR capillary basement membrane (Figure 27-­2). Together, FILTRATE these layers make up the filtration barrier, which, despite Like most capillaries, the glomerular capillaries are rela- the three layers, filters several hundred times as much tively impermeable to proteins, so the filtered fluid (called water and solutes as the usual capillary membrane. Even the glomerular filtrate) is essentially protein-­ free and with this high rate of filtration, the glomerular capillary devoid of cellular elements, including red blood cells. The membrane normally filters only a small amount of plasma concentrations of other constituents of the glomerular fil- proteins. trate, including most salts and organic molecules, are sim- The high filtration rate across the glomerular capillary ilar to the concentrations in the plasma. Exceptions to this membrane is due partly to its special characteristics. The generalization include a few low-­molecular-­weight sub- capillary endothelium is perforated by thousands of small stances such as calcium and fatty acids that are not freely holes called fenestrae, similar to the fenestrated capillar- filtered because they are partially bound to the plasma ies found in the liver, although smaller than the fenes- proteins. For example, almost half of the plasma calcium trae of the liver. Although the fenestrations are relatively and most of the plasma fatty acids are bound to proteins, large, endothelial cell proteins are richly endowed with and these bound portions are not filtered through the glo- fixed negative charges that hinder the passage of plasma merular capillaries. proteins. Surrounding the endothelium is the basement mem- GLOMERULAR FILTRATION RATE IS ABOUT brane, which consists of a meshwork of collagen and pro- 20% OF RENAL PLASMA FLOW teoglycan fibrillae that have large spaces through which Similar to other capillaries, the glomerular capillaries fil- large amounts of water and small solutes can filter. The ter fluid at a rate that is determined by the following: (1) basement membrane greatly hinders filtration of plasma the balance of hydrostatic and colloid osmotic forces act- proteins, partly because of strong negative electrical ing across the capillary membrane; and (2) the capillary charges associated with the proteoglycans. filtration coefficient (Kf), the product of the permeability The final part of the glomerular membrane is a layer of and filtering surface area of the capillaries. The glomerular epithelial cells (podocytes) that line the outer surface of capillaries have a much higher rate of filtration than most the glomerulus. These podocytes are not continuous but other capillaries because of a high glomerular hydrostatic have long footlike processes (pedicels) that encircle the pressure and a large Kf. In the average adult human, the outer surface of the capillaries (see Figure 27-­2). The foot 331 https://ebook2book.ir/ UNIT V The Body Fluids and Kidneys RPF Afferent Efferent Table 27-­1 Filterability of Substances by Glomerular (625 ml/min) arteriole arteriole Capillaries Based on Molecular Weight Substance Molecular Weight Filterability Water 18 1.0 Glomerular Sodium 23 1.0 capillaries Glucose 180 1.0 Bowman's capsule Inulin 5500 1.0 Myoglobin 17,000 0.75 GFR Albumin 69,000 0.005 (125 ml/min) REAB processes are separated by gaps called slit pores through (124 ml/min) Peritubular which the glomerular filtrate moves. The epithelial cells, capillaries 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 Renal filtration of plasma proteins but permit rapid filtration of vein water and most solutes in the plasma. Urinary excretion (1 ml/min) Filterability of Solutes Inversely Related to Their Figure 27-­1. Average values for total renal plasma flow (RPF), glo- Size. The glomerular capillary membrane is thicker than merular filtration rate (GFR), tubular reabsorption (REAB), and urine most other capillaries, but it is also much more porous flow rate. RPF is equal to renal blood flow × (1 − hematocrit). Note and therefore filters fluid at a high rate. Despite the high 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 filtration rate, the glomerular filtration barrier is selective fluid filtered is normally reabsorbed. The filtration fraction is GFR/RPF. in determining which molecules will be filtered, based on their size and electrical charge. Table 27-­1 lists the effect of molecular size on filter- ability of different molecules. A filterability of 1.0 means that the substance is filtered as freely as water, whereas Proximal tubule a filterability of 0.75 means that the substance is filtered only 75% as rapidly as water. Note that electrolytes such Podocytes as sodium and small organic compounds such as glucose are freely filtered. As the molecular weight of the mol- Capillary loops ecule approaches that of albumin, the filterability rapidly decreases, approaching zero. Bowman's space Afferent arteriole Negatively Charged Large Molecules Are Filtered Bowman's capsule Efferent arteriole Less Easily Than Positively Charged Molecules of A Equal Molecular Size. The molecular diameter of the Slit pores 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 Epithelium of its negative charge and the electrostatic repulsion exerted by negative charges of the glomerular capillary wall proteoglycans. Basement Figure 27-­3 shows how electrical charge affects the membrane filtration of different molecular weight dextrans by the glomerulus. Dextrans are polysaccharides that can be Endothelium manufactured as neutral molecules or with negative B Fenestrations or positive charges. Note that for any given molecular radius, positively charged molecules are filtered much Figure 27-­2. A, Basic ultrastructure of the glomerular capillaries. B, Cross section of the glomerular capillary membrane and its major more readily than negatively charged molecules. Neu- components: capillary endothelium, basement membrane, and epi- tral dextrans are also filtered more readily than nega- thelium (podocytes). tively charged dextrans of equal molecular weight. The 332 https://ebook2book.ir/  Chapter 27 Glomerular Filtration, Renal Blood Flow, and Their Control 1.0 Afferent Efferent arteriole Glomerular Glomerular arteriole 0.8 hydrostatic colloid osmotic Relative filterability Polycationic dextran pressure pressure (60 mm Hg) (32 mm Hg) 0.6 Neutral UNIT V dextran 0.4 Polyanionic dextran Bowman's 0.2 capsule pressure 0 (18 mm Hg) 18 22 26 30 34 38 42 Effective molecular radius (Å) Net filtration Glomerular Bowman's Glomerular pressure = hydrostatic – capsule – colloid osmotic Figure 27-­3. Effect of molecular radius and electrical charge of dex- (10 mm Hg) pressure pressure pressure tran on its filterability by the glomerular capillaries. A value of 1.0 (60 mm Hg) (18 mm Hg) (32 mm Hg) indicates that the substance is filtered as freely as water, whereas a value of 0 indicates that it is not filtered. Dextrans are polysaccharides Figure 27-­4. Summary of forces causing filtration by the glomerular that can be manufactured as neutral molecules or with negative or capillaries. The values shown are estimates for healthy humans. positive charges and with varying molecular weights. the GFR equals the product of Kf and the net filtration pressure: reason for these differences in filterability is that the GFR = Kf × Net filtration pressure negative charges of the basement membrane and podo- The net filtration pressure represents the sum of cytes provide an important means for restricting large the hydrostatic and colloid osmotic forces that favor or negatively charged molecules, including the plasma oppose filtration across the glomerular capillaries (Figure proteins. 27-­4). These forces include the following: (1) hydrostatic Minimal-­ Change Nephropathy and Increased Glo- pressure inside the glomerular capillaries (glomerular merular Permeability to Plasma Proteins. In minimal-­ hydrostatic pressure, PG), which promotes filtration; (2) change nephropathy, the glomeruli become more per- the hydrostatic pressure in Bowman’s capsule (PB) out- meable to plasma proteins, even though they may look side the capillaries, which opposes filtration; (3) the col- normal when viewed with a standard light microscope. loid osmotic pressure of the glomerular capillary plasma However, when viewed at high magnification with an proteins (πG), which opposes filtration; and (4) the col- electron microscope, the glomeruli usually display flat- loid osmotic pressure of the proteins in Bowman’s capsule tened podocytes with foot processes that may be de- (πB), which promotes filtration. Under normal conditions, tached from the glomerular basement membrane (po- the concentration of protein in the glomerular filtrate is docyte effacement). so low that the colloid osmotic pressure of the Bowman’s The causes of minimal change nephropathy are capsule fluid is considered to be zero. unclear but may be at least partly related to an immu- The GFR can therefore be expressed as follows: nological response and abnormal T-­ cell secretion of GFR = K f × ( PG PB – πG + πB ) cytokines that injure the podocytes and increase their permeability to some of the lower molecular weight Although the normal values for the determinants of proteins, especially albumin. This increased permeabil- GFR have not been measured directly in humans, they have ity permits the proteins to be filtered by the glomeru- been estimated in animals such as dogs and rats. Based on lar capillaries and excreted in the urine, a condition the results in experimental animals, the approximate nor- known as proteinuria or albuminuria. Minimal change mal forces favoring and opposing glomerular filtration in nephropathy is most common in young children but can humans are believed to be as follows (see Figure 27-­4): also occur in adults, especially in those who have auto- Forces Favoring Filtration (mm Hg) immune disorders. Glomerular hydrostatic pressure 60 Bowman’s capsule colloid osmotic pressure 0 DETERMINANTS OF THE GLOMERULAR Forces Opposing Filtration (mm Hg) FILTRATION RATE Bowman’s capsule hydrostatic pressure 18 The GFR is determined by the following: (1) the sum of Glomerular capillary colloid osmotic pressure 32 the hydrostatic and colloid osmotic forces across the glo- merular membrane, which gives the net filtration pres- sure; and (2) the glomerular Kf. Expressed mathematically, Thus, the net filtration pressure = 60 − 18 − 32 = +10 mm Hg. 333 https://ebook2book.ir/ UNIT V The Body Fluids and Kidneys Some of these values can change markedly under dif- 40 Filtration ferent physiological conditions, whereas others are altered 38 fraction Glomerular colloid osmotic pressure mainly in disease states, as discussed later. 36 Normal (mm Hg) INCREASED GLOMERULAR CAPILLARY 34 FILTRATION COEFFICIENT INCREASES 32 GLOMERULAR FILTRATE RATE 30 Filtration fraction The Kf is a measure of the product of the hydraulic con- 28 ductivity and surface area of the glomerular capillaries. The Kf cannot be measured directly, but can be is esti- Afferent Efferent mated experimentally by dividing the GFR by the net fil- end Distance along end glomerular capillary tration pressure: Figure 27-­5. Increase in colloid osmotic pressure in plasma flowing K f = GFR/Net filtration pressure through the glomerular capillary. Normally, about one-fifth of the fluid in the glomerular capillaries filters into Bowman’s capsule, there- Because the total GFR for both kidneys is about 125 by concentrating the plasma proteins that are not filtered. Increases ml/min, and the net filtration pressure is 10 mm Hg, the in the filtration fraction (glomerular filtration rate/renal plasma flow) normal Kf is calculated to be about 12.5 ml/min per mm increase the rate at which the plasma colloid osmotic pressure rises Hg of filtration pressure. When Kf is expressed per 100 along the glomerular capillary; decreases in the filtration fraction have the opposite effect. 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 to formation of stones that lodge in the urinary tract, often Kf of many other tissues in the body is only about 0.01 in the ureter, thereby obstructing outflow of the urinary ml/min per mm Hg/100 g. This high Kf for the glomer- tract and raising Bowman’s capsule pressure. This situa- ular capillaries contributes to their rapid rate of fluid tion reduces GFR and eventually can cause hydronephro- filtration. sis (distention and dilation of the renal pelvis and calyces) Although increased Kf raises the GFR and decreased and can damage or even destroy the kidney unless the Kf reduces the GFR, changes in Kf probably do not pro- obstruction is relieved. vide a primary mechanism for the normal daily regu- INCREASED GLOMERULAR CAPILLARY lation of GFR. Some diseases, however, lower Kf by COLLOID OSMOTIC PRESSURE DECREASES reducing the number of functional glomerular capillar- GLOMERULAR FILTRATION RATE ies (thereby reducing the surface area for filtration) or by increasing the thickness of the glomerular capillary As blood passes from the afferent arteriole through membrane and reducing its hydraulic conductivity. For the glomerular capillaries to the efferent arterioles, example, chronic uncontrolled hypertension may grad- the plasma protein concentration increases about 20% ually reduce Kf by increasing the thickness of the glo- ­(Figure 27-­5). The reason for this increase is that about merular capillary basement membrane and, eventually, one-fifth of the fluid in the capillaries filters into Bow- by damaging the capillaries so severely that there is loss man’s capsule, thereby concentrating the glomerular of capillary function. 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 INCREASED BOWMAN’S CAPSULE rises to about 36 mm Hg by the time the blood reaches HYDROSTATIC PRESSURE DECREASES the efferent end of the capillaries. Therefore, the aver- GLOMERULAR FILTRATION RATE age colloid osmotic pressure of the glomerular capillary Direct measurements of hydrostatic pressure in Bow- plasma proteins is midway between 28 and 36 mm Hg, man’s capsule and at different points in the proximal or about 32 mm Hg. tubule in experimental animals using micropipettes have Two factors that influence the glomerular capillary suggested that a reasonable estimate for Bowman’s cap- colloid osmotic pressure are the following: (1) the arte- sule pressure in humans is about 18 mm Hg under normal rial plasma colloid osmotic pressure; and (2) the fraction conditions. Increasing the hydrostatic pressure in Bow- of plasma filtered by the glomerular capillaries (filtration man’s capsule reduces GFR, whereas decreasing this pres- fraction). Increasing the arterial plasma colloid osmotic sure raises GFR. However, changes in Bowman’s capsule pressure raises the glomerular capillary colloid osmotic pressure normally do not serve as a primary means for pressure, which in turn tends to decrease the GFR. regulating GFR. Increasing the filtration fraction also concentrates the In certain pathological states associated with obstruc- plasma proteins and raises the glomerular colloid osmotic tion of the urinary tract, Bowman’s capsule pressure can pressure (see Figure 27-­5). Because the filtration fraction increase markedly, causing serious reduction of GFR. For is defined as the GFR divided by the renal plasma flow, the example, precipitation of calcium or of uric acid may lead filtration fraction can be increased by raising the GFR or 334 https://ebook2book.ir/  Chapter 27 Glomerular Filtration, Renal Blood Flow, and Their Control by reducing renal plasma flow. For example, a reduction RA in renal plasma flow with no initial change in GFR would tend to increase the filtration fraction, which would raise PG the glomerular capillary colloid osmotic pressure and Renal tend to reduce the GFR. For this reason, changes in renal blood blood flow can influence GFR independently of changes flow UNIT V GFR in glomerular hydrostatic pressure. With increasing renal blood flow, a lower fraction of the plasma is initially filtered out of the glomerular cap- illaries, causing a slower rise in the glomerular capillary colloid osmotic pressure and less inhibitory effect on RE the GFR. Consequently, even with a constant glomerular PG hydrostatic pressure, a greater rate of blood flow into the glomerulus tends to increase the GFR and a lower rate of Renal blood blood flow into the glomerulus tends to decrease the GFR. flow GFR INCREASED GLOMERULAR CAPILLARY HYDROSTATIC PRESSURE INCREASES GLOMERULAR FILTRATION RATE Figure 27-­6. Effect of increases in afferent arteriolar resistance (RA, top panel) or efferent arteriolar resistance (RE, bottom panel) on re- The glomerular capillary hydrostatic pressure has been nal blood flow, glomerular hydrostatic pressure (PG), and glomerular estimated to be about 60 mm Hg under normal condi- filtration rate (GFR). tions. Changes in glomerular hydrostatic pressure serve as the primary means for physiological regulation of GFR. 150 Glomerular 2000 Increases in glomerular hydrostatic pressure raise the filtration rate Glomerular filtration GFR, whereas decreases in glomerular hydrostatic pres- Renal blood flow rate (ml/min) sure reduce the GFR. 100 Normal 1400 (ml/min) Glomerular hydrostatic pressure is determined by three variables, each of which is under physiological con- 50 800 trol: (1) arterial pressure; (2) afferent arteriolar resistance; and (3) efferent arteriolar resistance. Renal blood flow Increased arterial pressure tends to raise glomerular 0 200 hydrostatic pressure and, therefore, to increase the GFR. 0 1 2 3 4 However, as discussed later, this effect is buffered by auto- Efferent arteriolar resistance (× normal) regulatory mechanisms that maintain a relatively constant glomerular pressure as arterial pressure fluctuates. Increased resistance of afferent arterioles reduces 250 2000 glomerular hydrostatic pressure and decreases the GFR Glomerular filtration 100 Renal blood flow (Figure 27-­6). Conversely, dilation of the afferent arte- rate (ml/min) 1400 rioles increases glomerular hydrostatic pressure and (ml/min) 150 Normal GFR. 100 Constriction of the efferent arterioles increases the Renal blood 800 Glomerular flow resistance to outflow from the glomerular capillaries. 50 filtration This mechanism raises glomerular hydrostatic pressure rate 0 200 and, as long as the increase in efferent resistance does not 0 1 2 3 4 reduce renal blood flow too much, GFR increases slightly Afferent arteriolar resistance (see Figure 27-­6). However, because efferent arteriolar (× normal) constriction also reduces renal blood flow, filtration frac- Figure 27-­7. Effect of change in afferent arteriolar resistance or tion and glomerular colloid osmotic pressure increase as efferent arteriolar resistance on glomerular filtration rate and renal efferent arteriolar resistance increases. Therefore, if con- blood flow. striction of efferent arterioles is severe (more than about a threefold increase in efferent arteriolar resistance), the Thus, efferent arteriolar constriction has a bipha- rise in colloid osmotic pressure exceeds the increase in sic effect on GFR (Figure 27-­7). At moderate levels of glomerular capillary hydrostatic pressure caused by effer- constriction, there is a slight increase in GFR but, with ent arteriolar constriction. When this situation occurs, severe constriction, there is a decrease in GFR. The pri- the net force for filtration actually decreases, causing a mary cause of the eventual decrease in GFR is as follows. reduction in GFR. As efferent constriction becomes severe, and as plasma 335 https://ebook2book.ir/ UNIT V The Body Fluids and Kidneys Table 27-­2 Factors That Can Decrease the Glomerular 3.0 Filtration Rate Physical Physiological or Pathophysiological 2.5 (ml/min/100 g kidney weight) Determinantsa Causes Oxygen consumption ↓Kf → ↓GFR Renal disease, diabetes mellitus, 2.0 hypertension, aging ↑PB → ↓GFR Urinary tract obstruction (e.g., kidney stones) 1.5 ↑πG → ↓GFR ↓ Renal blood flow, increased plasma proteins 1.0 ↓PG → ↓GFR ↓AP → ↓PG ↓ Arterial pressure (has only a small 0.5 effect because of autoregulation) Basal oxygen consumption ↓RE → ↓PG ↓ Angiotensin II (drugs that block angiotensin II formation) 0 0 5 10 15 20 ↑RA → ↓PG ↑ Sympathetic activity, vasoconstrictor hormones (e.g., norepinephrine, Sodium reabsorption endothelin) (mEq/min per 100 g kidney weight) aOpposite changes in the determinants usually increase the GFR. Figure 27-­8. Relationship between oxygen consumption and so- AP, Systemic arterial pressure; GFR, glomerular filtration rate; Kf, glo- dium reabsorption in dog kidneys. (From Kramer K, Deetjen P: [Rela- merular filtration coefficient; PB, Bowman’s capsule hydrostatic tion of renal oxygen consumption to blood supply and glomerular pressure; πG, glomerular capillary colloid osmotic pressure; PG, filtration during variations of blood pressure.] Pflugers Arch Physiol glomerular capillary hydrostatic pressure; RA, afferent arteriolar 271:782, 1960.) resistance; RE, efferent arteriolar resistance. protein concentration increases, there is a rapid nonlinear RENAL BLOOD FLOW AND OXYGEN increase in colloid osmotic pressure caused by the Don- CONSUMPTION nan effect; the higher the protein concentration, the more On a per gram-­weight basis, the kidneys normally con- rapidly the colloid osmotic pressure rises because of the sume oxygen at twice the rate of the brain but have almost interaction of ions bound to the plasma proteins, which seven times the blood flow of the brain. Thus, the oxygen also exert an osmotic effect, as discussed in Chapter 16. delivered to the kidneys far exceeds their metabolic needs, To summarize, constriction of afferent arterioles and the arterial-­venous extraction of oxygen is relatively reduces GFR. However, the effect of efferent arteriolar low compared with that of most other tissues. constriction depends on the severity of the constriction; A large fraction of the oxygen consumed by the kid- modest efferent constriction raises GFR, but severe effer- neys is related to the high rate of active sodium reabsorp- ent constriction (more than a threefold increase in resis- tion by the renal tubules. If renal blood flow and GFR tance) tends to reduce GFR. are reduced, and less sodium is filtered, less sodium is Table 27-­2 summarizes the factors that can decrease reabsorbed and less oxygen is consumed. Therefore, renal the GFR. oxygen consumption varies in proportion to renal tubular sodium reabsorption, which in turn is closely related to RENAL BLOOD FLOW GFR and the rate of sodium filtered (Figure 27-­8). If glo- merular filtration ceases completely, renal sodium reab- In a 70-­kg man, the combined blood flow through both sorption also ceases and oxygen consumption decreases kidneys is about 1100 ml/min, or about 22% of the car- to about one-­fourth normal. This residual oxygen con- diac output. Considering that the two kidneys constitute sumption reflects the basic metabolic needs of the renal only about 0.4% of the total body weight, one can readily cells. see that they receive extremely high blood flow compared with other organs. DETERMINANTS OF RENAL BLOOD FLOW As with other tissues, blood flow supplies the kidneys Renal blood flow (RBF) is determined by the pressure gra- with nutrients and removes waste products. However, dient across the renal vasculature (the difference between the high blood flow to the kidneys greatly exceeds this renal artery and renal vein hydrostatic pressures), divided need. The purpose of this additional flow is to supply by the total renal vascular resistance: enough plasma for the high rates of glomerular filtration ( Renal artery pressure − Renal vein pressure) that are necessary for precise regulation of body fluid vol- RBF = umes and solute concentrations. As might be expected, Total renal vascular resistance the mechanisms that regulate renal blood flow are closely Renal artery pressure is about equal to systemic arte- linked to control of GFR and excretory functions of the rial pressure, and renal vein pressure averages about 3 to kidneys. 4 mm Hg under most conditions. As in other vascular 336 https://ebook2book.ir/  Chapter 27 Glomerular Filtration, Renal Blood Flow, and Their Control Table 27-­3 Approximate Pressures and Vascular Table 27-­4 Hormones and Autacoids That Influence Resistances in Circulation of a Normal Kidney the Glomerular Filtration Rate (GFR) Pressure in Vessel Percentage Hormone or Autacoid Effect on GFR (mm Hg) of Total Re- Norepinephrine ↓ nal Vascular Vessel Beginning End Resistance Epinephrine ↓ UNIT V Renal artery 100 100 ≈0 Endothelin ↓ Interlobar, arcuate, ≈100 85 ≈16 Angiotensin II ↔ (prevents ↓) and interlobular Endothelial-­derived nitric oxide ↑ arteries Prostaglandins ↑ Afferent arteriole 85 60 ≈26 Glomerular capillaries 60 59 ≈1 Efferent arteriole 59 18 ≈43 the vasa recta play an important role in allowing the kid- Peritubular capillaries 18 8 ≈10 neys to form concentrated urine. Interlobar, 8 4 ≈4 interlobular, and PHYSIOLOGICAL CONTROL OF arcuate veins GLOMERULAR FILTRATION AND Renal vein 4 ≈4 ≈0 RENAL BLOOD FLOW The determinant of GFR that is most variable and sub- ject to physiological control is the glomerular hydrostatic beds, the total vascular resistance through the kidneys is pressure. This variable, in turn, is influenced by the sym- determined by the sum of the resistances in the individual pathetic nervous system, hormones, autacoids (vasoac- vasculature segments, including the arteries, arterioles, tive substances that are released in the kidneys and act capillaries, and veins (Table 27-­3). locally), and other feedback controls that are intrinsic to Most of the renal vascular resistance resides in three the kidneys. major segments—interlobular arteries, afferent arteri- oles, and efferent arterioles. Resistance of these vessels STRONG SYMPATHETIC NERVOUS is controlled by the sympathetic nervous system, various SYSTEM ACTIVATION DECREASES hormones, and local internal renal control mechanisms, GLOMERULAR FILTRATION RATE as discussed later. An increase in the resistance of any of the vascular segments of the kidneys tends to reduce the Essentially all the blood vessels of the kidneys, including renal blood flow, whereas a decrease in vascular resis- the afferent and efferent arterioles, are richly innervated tance increases renal blood flow if renal artery and renal by sympathetic nerve fibers. Strong activation of the vein pressures remain constant. renal sympathetic nerves can constrict the renal arteri- Although changes in arterial pressure have some oles and decrease renal blood flow and GFR. Moderate influence on renal blood flow, the kidneys have effective or mild sympathetic stimulation has little influence on mechanisms for maintaining renal blood flow and GFR renal blood flow and GFR. For example, reflex activa- relatively constant over an arterial pressure range between tion of the sympathetic nervous system resulting from 80 and 170 mm Hg, a process called autoregulation. This moderate decreases in pressure at the carotid sinus capacity for autoregulation occurs through mechanisms baroreceptors or cardiopulmonary receptors has little that are intrinsic to the kidneys, as discussed later in this influence on renal blood flow or GFR. However, as dis- chapter. cussed in Chapter 28, even mild increases in renal sym- pathetic activity can stimulate renin release and increase renal tubular reabsorption, causing decreased sodium BLOOD FLOW IN VASA RECTA OF RENAL and water excretion. MEDULLA IS LOW COMPARED WITH The renal sympathetic nerves seem to be the most RENAL CORTEX FLOW important in reducing GFR during severe acute distur- The outer part of the kidney, the renal cortex, receives bances lasting for a few minutes to a few hours, such as most of the kidney’s blood flow. Blood flow in the renal those elicited by the defense reaction, brain ischemia, or medulla accounts for only 1% to 2% of the total renal blood severe hemorrhage. flow. Flow to the renal medulla is supplied by a specialized portion of the peritubular capillary system called the vasa HORMONAL AND AUTACOID CONTROL recta. These vessels descend into the medulla in parallel OF RENAL CIRCULATION with the loops of Henle and then loop back along with the loops of Henle and return to the cortex before empty- Several hormones and autacoids can influence GFR and ing into the venous system. As discussed in Chapter 29, renal blood flow, as summarized in Table 27-­4. 337 https://ebook2book.ir/ UNIT V The Body Fluids and Kidneys Norepinephrine, Epinephrine, and Endothelin Constrict reabsorption of sodium and water, as discussed in Chap- Renal Blood Vessels and Decrease Glomerular ter 28. ­Filtration Rate. Hormones that constrict afferent and Thus, increased angiotensin II levels that occur with a efferent arterioles, causing reductions in GFR and renal low-­sodium diet or volume depletion help maintain GFR blood flow, include norepinephrine and epinephrine re- and normal excretion of metabolic waste products, such leased from the adrenal medulla. In general, blood levels as urea and creatinine, which depend on glomerular fil- of these hormones parallel the activity of the sympathetic tration for their excretion. At the same time, the angioten- nervous system; thus, norepinephrine and epinephrine sin II–induced constriction of efferent arterioles increases have little influence on renal hemodynamics except under tubular reabsorption of sodium and water, which helps conditions associated with strong activation of the sym- restore blood volume and blood pressure. This effect of pathetic nervous system, such as severe hemorrhage. angiotensin II in helping autoregulate GFR is discussed in Another vasoconstrictor, endothelin, is a peptide that more detail later in this chapter. can be released by damaged vascular endothelial cells of the kidneys, as well as by other tissues. The physiologi- Endothelial-­ Derived Nitric Oxide Decreases ­ Renal cal role of this autacoid is not completely understood. Vascular Resistance and Increases Glomerular ­ However, endothelin may contribute to hemostasis ­Filtration Rate. An autacoid that decreases renal vascu- (minimizing blood loss) when a blood vessel is severed, lar resistance and is released by the vascular endothelium which damages the endothelium and releases this pow- throughout the body is endothelial-­derived nitric oxide. erful vasoconstrictor. Plasma endothelin levels are also A basal level of nitric oxide production appears to be im- increased in many disease states associated with vascular portant for maintaining vasodilation of the kidneys and injury, such as toxemia of pregnancy, acute renal failure, normal excretion of sodium and water. Therefore, admin- and chronic uremia, and may contribute to renal vaso- istration of drugs that inhibit formation of nitric oxide in- constriction and decreased GFR in some of these patho- creases renal vascular resistance and decreases GFR and physiological conditions. urinary sodium excretion, eventually causing high blood pressure. In some hypertensive patients or in patients Angiotensin II Preferentially Constricts Efferent with atherosclerosis, damage of the vascular endotheli- ­Arterioles in Most Physiological Conditions. A pow- um and impaired nitric oxide production may contribute erful renal vasoconstrictor, angiotensin II, can be consid- to increased renal vasoconstriction and elevated blood ered to be a circulating hormone and a locally produced pressure. autacoid or paracrine hormone because it is formed in the kidneys and in the systemic circulation. Receptors for Prostaglandins and Bradykinin Decrease Renal angiotensin II are present in virtually all blood vessels of ­Vascular Resistance and Tend to Increase G ­ lomerular the kidneys. However, the preglomerular blood vessels, Filtration Rate. Prostaglandins (PGE2 and PGI2) and especially the afferent arterioles, appear to be relatively bradykinin serve as hormones and autacoids that cause protected from angiotensin II–mediated constriction in vasodilation, increased renal blood flow, and increased most physiological conditions associated with activation GFR. These substances are discussed in Chapter 17. Al- of the renin-­angiotensin system, such as during a low-­ though these vasodilators do not appear to be of major sodium diet or reduced renal perfusion pressure due to importance in regulating renal blood flow or the GFR in renal artery stenosis. This protection is due to release of normal conditions, they may dampen the renal vasocon- vasodilators, especially nitric oxide and prostaglandins, strictor effects of the sympathetic nerves or angiotensin which counteract the vasoconstrictor effects of angioten- II, especially their effects to constrict the afferent arteri- sin II in these blood vessels. oles. The efferent arterioles, however, are highly sensitive By opposing vasoconstriction of afferent arterioles, the to angiotensin II. Because angiotensin II preferentially prostaglandins help prevent excessive reductions in GFR constricts efferent arterioles in most physiological con- and renal blood flow. Under stressful conditions, such as ditions, increased angiotensin II levels raise glomerular volume depletion or after surgery, the administration of hydrostatic pressure while reducing renal blood flow. nonsteroidal antiinflammatory drugs (NSAIDs), such as It should be kept in mind that increased angiotensin II aspirin, that inhibit prostaglandin synthesis may cause formation usually occurs in circumstances associated significant reductions in GFR. with decreased arterial pressure or volume depletion, which tend to decrease GFR. In these circumstances, the AUTOREGULATION OF GLOMERULAR increased level of angiotensin II, by constricting efferent FILTRATION RATE AND RENAL BLOOD arterioles, helps prevent decreases in glomerular hydro- FLOW static pressure and GFR. At the same time, though, the reduction in renal blood flow caused by efferent arterio- Feedback mechanisms intrinsic to the kidneys normally lar constriction contributes to decreased flow through keep renal blood flow and GFR relatively constant, the peritubular capillaries, which in turn increases the despite marked changes in arterial blood pressure. 338 https://ebook2book.ir/  Chapter 27 Glomerular Filtration, Renal Blood Flow, and Their Control 1600 160 the changes in renal excretion that would occur without Glomerular filtration Renal blood flow autoregulatory mechanisms. Renal blood flow rate (ml/min) 1200 120 Normally, GFR is about 180 L/day, and tubular reab- (ml/min) Glomerular filtration 800 rate 80 sorption is 178.5 L/day, leaving 1.5 L/day of fluid to be excreted in the urine. In the absence of autoregulation, 400 40 a relatively small increase in blood pressure (from 100 to UNIT V 125 mm Hg) would cause a similar 25% increase in GFR 0 0 (from about 180 to 225 L/day). If tubular reabsorption 8 remained constant at 178.5 L/day, the urine flow would increase to 46.5 L/day (the difference between GFR and 6 Urine output tubular reabsorption)—a total increase in urine of more (ml/min) 4 than 30-­fold. Because the total plasma volume is only about 3 liters, such a change would quickly deplete the 2 blood volume. In reality, changes in arterial pressure usually exert 0 50 100 150 200 much less of an effect on urine volume for two reasons: Mean arterial pressure (1) renal autoregulation prevents large changes in GFR that (mm Hg) would otherwise occur; and (2) there are additional adap- Figure 27-­9. Autoregulation of renal blood flow and glomerular fil- tive mechanisms in the renal tubules that cause them to tration rate but lack of autoregulation of urine flow during changes increase their reabsorption rate when GFR rises, a phen­ in renal arterial pressure. omenon referred to as glomerulotubular balance (dis- cussed in Chapter 28). Even with these special control These mechanisms still function in blood-­perfused kid- mechanisms, changes in arterial pressure still have signifi- neys that have been removed from the body, indepen- cant effects on renal excretion of water and sodium; this dent of systemic influences. This relative constancy of effect is referred to as pressure diuresis or pressure natriu­ GFR and renal blood flow is referred to as autoregula- resis, and it is crucial in the regulation of body fluid volumes tion (Figure 27-­9). and arterial pressure, as discussed in Chapters 19 and 30. The primary function of blood flow autoregulation TUBULOGLOMERULAR FEEDBACK AND in most tissues, other than the kidneys, is to maintain AUTOREGULATION OF GLOMERULAR the delivery of oxygen and nutrients at a normal level FILTRATION RATE and remove the waste products of metabolism, despite changes in the arterial pressure. In the kidneys, the nor- The kidneys have a special feedback mechanism that mal blood flow is much higher than that required for links changes in the sodium chloride concentration at the these functions. The major function of autoregulation in macula densa with the control of renal arteriolar resis- the kidneys is to maintain a relatively constant the GFR tance and autoregulation of GFR. This feedback helps and allow precise control of renal excretion of water and ensure a relatively constant delivery of sodium chloride solutes. to the distal tubule and helps prevent spurious fluctua- The GFR normally remains relatively constant, tions in renal excretion that would otherwise occur. In despite considerable arterial pressure fluctuations that many circumstances, this feedback autoregulates renal occur during a person’s usual activities. For example, a blood flow and GFR in parallel. However, because this decrease in arterial pressure to as low as 70 to 75 mm mechanism is specifically directed toward stabilizing Hg or an increase to as high as 160 to 180 mm Hg usu- sodium chloride delivery to the distal tubule, instances ally changes the GFR less than 10%. In general, renal occur when GFR is autoregulated at the expense of blood flow is autoregulated in parallel with GFR, but changes in renal blood flow, as discussed later. In other GFR is more efficiently autoregulated under certain cases, this mechanism may actually cause changes in conditions. GFR in response to primary changes in renal tubular sodium chloride reabsorption. Importance of Glomerular Filtration Rate The tubuloglomerular feedback mechanism has two Autoregulation in Preventing Extreme components that act together to control GFR: (1) an affer- Changes in Renal Excretion ent arteriolar feedback mechanism; and (2) an efferent Although the renal autoregulatory mechanisms are not arteriolar feedback mechanism. These feedback mecha- perfect, they do prevent potentially large changes in GFR nisms depend on special anatomical arrangements of the and renal excretion of water and solutes that would oth- juxtaglomerular complex (Figure 27-­10). erwise occur with changes in blood pressure. One can The juxtaglomerular complex consists of macula understand the quantitative importance of autoregula- densa cells in the initial portion of the distal tubule and tion by considering the relative magnitudes of glomerular juxtaglomerular cells in the walls of the afferent and effer- filtration, tubular reabsorption, and renal excretion and ent arterioles. The macula densa is a specialized group 339 https://ebook2book.ir/ UNIT V The Body Fluids and Kidneys Arterial pressure − − Glomerular hydrostatic pressure Glomerular epithelium GFR Proximal NaCl Macula densa reabsorption NaCl Juxtaglomerular cells Afferent Efferent arteriole arteriole Renin Internal elastic Macula densa Angiotensin II lamina Smooth Basement muscle membrane Efferent Afferent Distal fiber arteriolar arteriolar tubule resistance resistance Figure 27-­10. Structure of the juxtaglomerular apparatus, demon- strating its possible feedback role in the control of nephron function. Figure 27-­11. Macula densa feedback mechanism for autoregula- tion of glomerular hydrostatic pressure and glomerular filtration rate (GFR) during decreased renal arterial pressure. of epithelial cells in the distal tubules that comes in close contact with the afferent and efferent arterioles. The mac- ula densa cells contain the Golgi apparatus, which con- These two components of the tubuloglomerular sists of intracellular secretory organelles directed toward feedback mechanism, operating together by way of the the arterioles, suggesting that these cells may be secreting special anatomical structure of the juxtaglomerular a substance toward the arterioles. apparatus, provide feedback signals to the afferent and efferent arterioles for efficient autoregulation of GFR Decreased Macula Densa Sodium Chloride Causes during changes in arterial pressure. When both of these Dilation of Afferent Arterioles and Increased Renin mechanisms are functioning together, GFR changes by Release. The macula densa cells sense changes in so- only a few percentage points, even with large fluctua- dium chloride delivery to the distal tubule by way of sig- tions in arterial pressure between the limits of 75 and nals that are not completely understood. Experimental 160 mm Hg. studies have suggested that a decreased GFR slows the Blockade of Angiotensin II Formation Further Reduces flow rate in the loop of Henle, causing increased reab- Glomerular Filtration Rate During Renal Hypoperfusion. sorption of the percentage of sodium and chloride ions As discussed earlier, a preferential constrictor action of delivered to the ascending loop of Henle and thereby angiotensin II on efferent arterioles helps prevent serious reducing the concentration of sodium chloride at the reductions in glomerular hydrostatic pressure and GFR macula densa cells. This decrease in sodium chloride when renal perfusion pressure falls below normal. The ad- concentration initiates a signal from the macula densa ministration of drugs that block the formation of angioten- that has two effects (Figure 27-­11): (1) it decreases re- sin II (angiotensin-­converting enzyme inhibitors) or that sistance to blood flow in the afferent arterioles, which block the action of angiotensin II (angiotensin II receptor raises glomerular hydrostatic pressure and helps return antagonists) may cause greater reductions in GFR than usual when the renal arterial pressure falls below normal. GFR toward normal; and (2) it increases renin release Therefore, an important complication of using these drugs from the juxtaglomerular cells of the afferent and effer- to treat patients who have hypertension because of renal ent arterioles, which are the major storage sites for re- artery stenosis (partial blockage of the renal artery) is a se- nin. Renin released from these cells then functions as vere decrease in GFR that can, in some cases, cause acute an enzyme to increase the formation of angiotensin I, renal failure. Nevertheless, angiotensin II–blocking drugs which is converted to angiotensin II. Finally, angiotensin are important therapeutic agents in many patients with hy- II constricts the efferent arterioles, thereby increasing pertension, congestive heart failure, and other conditions, glomerular hydrostatic pressure and helping return GFR as long as the patients are monitored to ensure that severe toward normal. decreases in GFR do not occur. 340 https://ebook2book.ir/  Chapter 27 Glomerular Filtration, Renal Blood Flow, and Their Control MYOGENIC AUTOREGULATION OF Protein ingestion RENAL BLOOD FLOW AND GLOMERULAR FILTRATION RATE Another mechanism that contributes to the maintenance Amino acids of a relatively constant renal blood flow and GFR is the UNIT V ability of individual blood vessels to resist stretching dur- ing increased arterial pressure, referred to as the myogenic Proximal tubular amino acid mechanism. Studies of individual blood vessels (especially reabsorption 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 Proximal tubular vascular wall allows increased movement of calcium ions NaCl reabsorption 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 Macula densa NaCl and, at the same time, by raising vascular resistance, helps prevent excessive increases in renal blood flow and the GFR when arterial pressure increases. Macula Afferent arteriolar densa Although the myogenic mechanism probably operates feedback resistance in most arterioles throughout the body, its importance in renal blood flow and GFR autoregulation has been questioned by some physiologists because this pressure-­ GFR sensitive mechanism has no means of directly detecting changes in renal blood flow or GFR per se. On the other Figure 27-­12. Possible role of macula densa feedback in mediating increased glomerular filtration rate (GFR) after a high-­protein meal. hand, this mechanism may be more important in pro- tecting the kidney from hypertension-­induced injury. In response to sudden increases in blood pressure, the myo- A similar mechanism may also explain the marked in- genic constrictor response in afferent arterioles occurs creases in renal blood flow and the GFR that occur with within seconds and therefore attenuates transmission of large increases in blood glucose levels in persons with uncon- trolled diabetes mellitus. Because glucose, like some of the increased arterial pressure to the glomerular capillaries. amino acids, is also reabsorbed along with sodium in the proximal tubule, increased glucose delivery to the tubules High Protein Intake and Hyperglycemia Increase Re- causes them to reabsorb excess sodium along with glucose. nal Blood Flow and Glomerular Filtration Rate. Although This increased reabsorption of sodium, in turn, decreases renal blood flow and GFR are relatively stable under most the sodium chloride concentration at the macula densa, conditions, there are circumstances in which these vari- activating a tubuloglomerular feedback–mediated dilation ables change significantly. For example, a high protein in- of the afferent arterioles and subsequent increases in renal take is known to increase renal blood flow and GFR. With blood flow and GFR. a long-­term, high-­protein diet, such as one that contains These examples demonstrate that renal blood flow and large amounts of meat, increases in GFR and renal blood GFR per se are not the primary variables controlled by the flow are due partly to growth of the kidneys. However, tubuloglomerular feedback mechanism. The main purpose the GFR and renal blood flow also increase 20% to 30% of this feedback is to ensure a constant delivery of sodium within 1 or 2 hours after a person eats a high-­protein chloride to the distal tubule, where final processing of the meal. urine takes place. Thus, disturbances that tend to increase One likely explanation for the increased GFR is the fol- the reabsorption of sodium chloride at tubular sites before lowing. A high-­protein meal releases into the blood amino the macula densa tend to elicit increased renal blood flow acids, which are reabsorbed in the proximal tubules. Be- and GFR, which helps return distal sodium chloride deliv- cause amino acids and sodium are reabsorbed together ery toward normal so that normal rates of sodium and wa- by cotransport in the proximal tubules, increased amino ter excretion can be maintained (see Figure 27-­12). acid reabsorption also stimulates sodium reabsorption. An opposite sequence of events occurs when proxi- This increased reabsorption of sodium decreases sodium mal tubular reabsorption is reduced. For example, when delivery to the macula densa (see Figure 27-­12), which the proximal tubules are damaged (which can occur as a elicits a tubuloglomerular feedback–mediated decrease result of poisoning by heavy metals, such as mercury, or in resistance of the afferent arterioles, as discussed earlier. large doses of drugs, such as tetracyclines), their ability The decreased afferent arteriolar resistance then raises re- to reabsorb sodium chloride is decreased. As a conse- nal blood flow and GFR, allowing sodium excretion to be quence, large amounts of sodium chloride are delivered to maintained at a nearly normal level while increasing excre- the distal tubule and, without appropriate compensation, tion of the waste products of protein metabolism, such as would quickly cause excessive volume depletion. One of urea. the important compensatory responses appears to be a 341 https://ebook2book.ir/ UNIT V The Body Fluids and Kidneys Table 27-­5 Some Conditions That Influence Renal Bibliography Blood Flow (RBF) and the Glomerular Filtration Anders HJ, Huber TB, Isermann B, Schiffer M: CKD in diabetes: dia- Rate (GFR) betic kidney disease versus nondiabetic kidney disease. Nat Rev Condition RBF GFR Nephrol 14:361, 2018. Baylis C: Sexual dimorphism: the aging kidney, involvement of nitric Aging ↓ ↓ oxide deficiency, and angiotensin II overactivity. J Gerontol A Biol High dietary protein ↑ ↑ Sci Med Sci 67:1365, 2012. Beierwaltes WH, Harrison-­Bernard LM, Sullivan JC, Mattson DL: As- Hyperglycemiaa ↑ ↑ sessment of renal function; clearance, the renal microcirculation, Obesitya ↑ ↑ renal blood flow, and metabolic balance. Compr Physiol 3:165, High NaCl intakea ↑ ↑ 2013. Bidani AK, Polichnowski AJ, Loutzenhiser R, Griffin KA: Renal mi- Glucocorticoids ↑ ↑ crovascular dysfunction, hypertension and CKD progression. Curr Fever, pyrogens ↑ ↑ Opin Nephrol Hypertens 22:1, 2013. aRefers to early effects, prior to development of glomerular injury Carlström M, Wilcox CS, Arendshorst WJ: Renal autoregulation in that may occur with chronic hyperglycemia, obesity, and high health and disease. Physiol Rev 95:405, 2015. salt intake. Cowley AW Jr, Abe M, Mori T, O’Connor PM, et. al: Reactive oxy- gen species as important determinants of medullary flow, sodium excretion, and hypertension. Am J Physiol Renal Physiol 308:F179, tubuloglomerular feedback–mediated renal vasoconstric- 2013. de Groat WC, Griffiths D, Yoshimura N: Neural control of the lower tion that occurs in response to the increased sodium chlo- urinary tract. Compr Physiol 5:327, 2015. ride delivery to the macula densa in these circumstances. DiBona GF: Physiology in perspective: the wisdom of the body. Neu- These examples again demonstrate the importance of this ral control of the kidney. Am J Physiol Regul Integr Comp Physiol feedback mechanism for ensuring that the distal tubules 289:R633, 2005. receive the proper rate of delivery of sodium chloride, Gomez RA, Sequeira-­Lopez MLS: Renin cells in homeostasis, regener- other tubular fluid solutes, and tubular fluid volume so ation and immune defence mechanisms. Nat Rev Nephrol 14:231, that appropriate amounts of these substances are excreted 2018. in the urine. Griffin KA: Hypertensive kidney injury and the progression of chronic Other Factors That Influence Renal Blood Flow and kidney disease. Hypertension 70:687, 2017. Guan Z, VanBeusecum JP, Inscho EW: Endothelin and the renal mi- Glomerular Filtration Rate. The GFR and renal blood flow crocirculation. Semin Nephrol 35:145, 2015. are low at birth, approach normal adult levels after about 2 Hall JE, Brands MW: The renin-­angiotensin-­aldosterone system: renal years of life, and in the absence of kidney disease, are main- mechanisms and circulatory homeostasis. In: Seldin DW, Giebisch tained relatively constant until the fourth decade. Thereaf- G (eds): The Kidney—Physiology and Pathophysiology, 3rd ed. New ter, GFR declines by about 5% to 10% per decade, although York: Raven Press, 2000, pp 1009-­1046. there is considerable variability among individuals. This Hall JE, do Carmo JM, da Silva AA, Wang Z, Hall ME: Obesity, kidney decline in GFR coincides with nitric oxide deficiency, in- dysfunction and hypertension: mechanistic links. Nature Reviews creased oxidative stress, and loss of functional nephrons, Nephrology 15: 367, 2019. which may be related partly to increasing blood pressure, Hall JE, do Carmo JM, da Silva AA, Wang Z, Hall ME: Obesity-­induced metabolic disorders, and other insults that cause cumula- hypertension: interaction of neurohumoral and renal mechanisms. Circ Res 116:991, 2015. tive glomerular injury with aging. Navar LG, Kobori H, Prieto MC, Gonzalez-­Villalobos RA: Intratubular Men have higher renal blood flow and GFR than renin-­angiotensin system in hypertension. Hypertension 57:355, women, even when corrected for body mass. However, 2011. men also have a more rapid decline in GFR with aging Schell C, Huber TB: The evolving complexity of the podocyte cytoskel- than premenopausal women. Although the mechanisms eton. J Am Soc Nephrol 28:3166-­, 2017. responsible for these sex differences are not fully under- Schnermann J, Briggs JP: Tubular control of renin synthesis and secre- stood, beneficial effects of estrogens and damaging effects tion. Pflugers Arch 465:39, 2013. of androgens on the kidneys have been suggested as a par- Speed JS, Pollock DM: Endothelin, kidney disease, and hypertension. tial explanation. Table 27-­5 summarizes some additional Hypertension 61:1142, 2013. factors that influence renal blood flow and GFR regula- Thomson SC, Blantz RC: Biophysics of glomerular filtration. Compr Physiol 2:1671. tion, and should be considered when assessing kidney Vivarelli M, Massella L, Ruggiero B, Emma F: Minimal change disease. function. Clin J Am Soc Nephrol 12:332, 2017. 342 https://ebook2book.ir/