Guyton and Hall Textbook of Medical Physiology, 14ed Renal Tubular Reabsorption PDF

CHAPTER 28 As the glomerular filtrate enters the renal tubules, it flows sequentially through the successive parts of the tubule— the proximal tubule, loop of Henle, distal tubule, collecting tubule, and collecting duct—before it is excreted as urine. Along this course, some substances are selecti...

CHAPTER 28 As the glomerular filtrate enters the renal tubules, it flows sequentially through the successive parts of the tubule— the proximal tubule, loop of Henle, distal tubule, collecting tubule, and collecting duct—before it is excreted as urine. Along this course, some substances are selectively reabsorbed from the tubules back into the blood, whereas others are secreted from the blood into the tubular lumen. Eventually, the urine that is formed and all the substances in the urine represent the sum of three basic renal processes—glomerular filtration, tubular reabsorption, and tubular secretion: Urinary excretion = Glomerular filtration − Tubular reabsorption + Tubular secretion For many substances, tubular reabsorption plays a much more important role than secretion in determining the final urinary excretion rate. However, tubular secretion accounts for significant amounts of potassium ions, hydrogen ions, and a few other substances that appear in the urine. TUBULAR REABSORPTION IS QUANTITATIVELY LARGE AND HIGHLY SELECTIVE Table 28-1 shows the renal handling of several substances that are all freely filtered in the kidneys and reabsorbed at variable rates. The rate at which each of these substances is filtered is calculated as follows: This calculation assumes that the substance is freely filtered and not bound to plasma proteins. For example, if plasma glucose concentration is 1 g/L, the amount of glucose filtered each day is about 180 L/day × 1 g/L, or 180 g/day. Because virtually none of the filtered glucose is normally excreted, the rate of glucose reabsorption is also 180 g/day. From Table 28-1, two things are immediately apparent. First, the processes of glomerular filtration and tubular reabsorption are quantitatively large relative to urinary excretion for many substances. Thus, a small change in glomerular filtration or tubular reabsorption can potentially cause a relatively large change in urinary excretion. For example, a 10% decrease in tubular reabsorption, from 178.5 to 160.7 L/day, would increase urine volume from 1.5 to 19.3 L/day (almost a 13-fold increase) if the glomerular filtration rate (GFR) remained constant. In reality, changes in tubular reabsorption and glomerular filtration are closely coordinated so that large fluctuations in urinary excretion are avoided. Second, unlike glomerular filtration, which is relatively nonselective (essentially all solutes in the plasma are filtered except the plasma proteins or substances bound to them), tubular reabsorption is highly selective. Some substances, such as glucose and amino acids, are almost completely reabsorbed from the tubules, so the urinary excretion rate is essentially zero. Many ions in the plasma, such as sodium, chloride, and bicarbonate, are also highly reabsorbed, but their rates of reabsorption and urinary excretion are variable, depending on the needs of the body. Waste products, such as urea and creatinine, conversely, are poorly reabsorbed from the tubules and are excreted in relatively large amounts. Therefore, by controlling their reabsorption of different substances, the kidneys regulate excretion of solutes independently of one another, a capability that is essential for precise control of the body fluid composition. In this chapter, we discuss the mechanisms that allow the kidneys to selectively reabsorb or secrete different substances at variable rates.! TUBULAR REABSORPTION INCLUDES PASSIVE AND ACTIVE MECHANISMS For a substance to be reabsorbed, it must first be transported (1) across the tubular epithelial membranes into the renal interstitial fluid and then (2) through the peritubular capillary membrane back into the blood (Figure 28-1). Thus, reabsorption of water and solutes includes a series of transport steps. Reabsorption across the tubular epithelium into the interstitial fluid includes active or passive transport by the same basic mechanisms discussed 343 UNIT V Renal Tubular Reabsorption and Secretion UNIT V The Body Fluids and Kidneys Table 28-1 Filtration, Reabsorption, and Excretion Rates of Different Substances by the Kidneys Substance Amount Filtered Glucose (g/day) Amount Reabsorbed 180 Bicarbonate (mEq/day) 180 Amount Excreted % of Filtered Load Reabsorbed 0 100 4320 4318 2 >99.9 Sodium (mEq/day) 25,560 25,410 150 99.4 Chloride (mEq/day) 19,440 19,260 180 99.1 Potassium (mEq/day) 756 664 92 87.8 Urea (g/day) 46.8 23.4 23.4 50 Creatinine (g/day) 1.8 0 1.8 0 Peritubular capillary Tubular cells FILTRATION Lumen Paracellular path Bulk flow Active ATP Blood Passive (diffusion) Osmosis REABSORPTION Transcellular path Solutes H2O EXCRETION Figure 28-1 Reabsorption of filtered water and solutes from the tubular lumen across the tubular epithelial cells, through the renal interstitium, and back into the blood. Solutes are transported through the cells (transcellular path) by passive diffusion or active transport, or between the cells (paracellular path) by diffusion. Water is transported through the cells and between the tubular cells by osmosis. Transport of water and solutes from the interstitial fluid into the peritubular capillaries occurs by ultrafiltration (bulk flow). in Chapter 4 for transport across other cell membranes of the body. For example, water and solutes can be transported through the cell membranes (transcellular route) or through the spaces between the cell junctions (paracellular route). Then, after absorption across the tubular epithelial cells into the interstitial fluid, water and solutes are transported through the peritubular capillary walls into the blood by ultrafiltration (bulk flow) that is mediated by hydrostatic and colloid osmotic forces. The peritubular capillaries behave like the venous ends of most other capillaries because there is a net reabsorptive force that moves the fluid and solutes from the interstitium into the blood. ACTIVE TRANSPORT Active transport can move a solute against an electrochemical gradient; this requires energy derived from metabolism. Transport that is coupled directly to an energy source, such as the hydrolysis of adenosine 344 triphosphate (ATP), is termed primary active transport. An example of this mechanism is the sodiumpotassium adenosine triphosphatase (ATPase) pump (Na+-K+ ATPase pump) that functions throughout most parts of the renal tubule. Transport that is coupled indirectly to an energy source, such as that due to an ion gradient, is referred to as secondary active transport. Reabsorption of glucose by the renal tubule is an example of secondary active transport. Although solutes can be reabsorbed by active and/or passive mechanisms by the tubule, water is always reabsorbed passively across the tubular epithelial membrane by the process of osmosis. Solutes Can Be Transported Through Epithelial Cells or Between Cells. Renal tubular cells, like other epithe- lial cells, are held together by tight junctions. Lateral intercellular spaces lie behind the tight junctions and separate the epithelial cells of the tubule. Solutes can be reabsorbed or secreted across the cells through the transcellular pathway or between the cells by moving across the tight junctions and intercellular spaces via the paracellular pathway. Sodium is a substance that moves through both routes, although most of the sodium is transported through the transcellular pathway. In some nephron segments, especially the proximal tubule, water is also reabsorbed across the paracellular pathway, and substances dissolved in the water, especially potassium, magnesium, and chloride ions, are carried with the reabsorbed fluid between the cells.! Primary Active Transport Through the Tubular Membrane Linked to Hydrolysis of Adenosine Triphosphatase. The special importance of primary active trans- port is that it can move solutes against an electrochemical gradient. The energy for this active transport comes from the hydrolysis of ATP by way of membrane-bound ATPase, which is also a component of the carrier mechanism that binds and moves solutes across the cell membranes. The primary active transporters in the kidneys that are known include Na+-K+ ATPase, hydrogen ATPase, hydrogen-potassium ATPase, and calcium ATPase. A good example of a primary active transport system is the reabsorption of sodium ions across the proximal tubular membrane, as shown in Figure 28-2. On the Chapter 28 Renal Tubular Reabsorption and Secretion Peritubular capillary Tubular epithelial cells Tubular lumen Na+ ATP K+ K+ (–70 mV) Basal channels Interstitial fluid Basement membrane Na+ (–3 mV) Tight junction Brush border (luminal membrane) Intercellular space Figure 28-2 Basic mechanism for active transport of sodium through the tubular epithelial cell. The sodium-potassium pump transports sodium from the interior of the cell across the basolateral membrane, creating a low intracellular sodium concentration and a negative intracellular electrical potential. The low intracellular sodium concentration and negative electrical potential cause sodium ions to diffuse from the tubular lumen into the cell through the brush border. basolateral sides of the tubular epithelial cell, the cell membrane has an extensive Na+-K+ ATPase system that hydrolyzes ATP and uses the released energy to transport sodium ions out of the cell into the interstitium. At the same time, potassium is transported from the interstitium to the inside of the cell. The operation of this ion pump maintains low intracellular sodium and high intracellular potassium concentrations and creates a net negative charge of about −70 millivolts within the cell. This active pumping of sodium out of the cell across the basolateral membrane of the cell favors passive diffusion of sodium across the luminal membrane of the cell, from the tubular lumen into the cell, for two reasons: (1) there is a concentration gradient favoring sodium diffusion into the cell because the intracellular sodium concentration is low (12 mEq/L) and tubular fluid sodium concentration is high (140 mEq/L); and (2) the negative, −70-millivolt, intracellular potential attracts the positive sodium ions from the tubular lumen into the cell. Active reabsorption of sodium by Na+-K+ ATPase occurs in most parts of the tubule. In certain parts of the nephron, there are also additional provisions for moving large amounts of sodium into the cell. In the proximal tubule, there is an extensive brush border on the luminal side of the membrane (the side that faces the tubular lumen) that multiplies the surface area by about 20-fold. There are also carrier proteins that bind sodium ions on the luminal surface of the membrane and release them inside the cell, providing facilitated diffusion of sodium through the membrane into the cell. These sodium carrier proteins are also important for secondary active transport of other substances, such as glucose and amino acids, as discussed later. Secondary Active Reabsorption Through the Tubular Membrane. In secondary active transport, two or more substances interact with a specific membrane protein (a carrier molecule) and are transported together across the membrane. As one of the substances (e.g., sodium) diffuses down its electrochemical gradient, the energy released is used to drive another substance (e.g., glucose) against its electrochemical gradient. Thus, secondary active transport does not require energy directly from ATP or from other high-energy phosphate sources. Rather, the direct source of the energy is that liberated by the simultaneous facilitated diffusion of another transported substance down its own electrochemical gradient. Figure 28-3 shows secondary active transport of glucose and amino acids in the proximal tubule. In both cases, specific carrier proteins in the brush border combine with a sodium ion and an amino acid or a glucose molecule at the same time. These transport mechanisms are so efficient that they remove virtually all the glucose and amino acids from the tubular lumen. After entry into the cell, glucose and amino acids exit across the basolateral membranes by diffusion, driven by the high glucose and amino acid concentrations in the cell facilitated by specific transport proteins. Sodium glucose co-transporters (SGLT2 and SGLT1) are located on the brush border of proximal tubular cells and carry glucose into the cell cytoplasm against a concentration gradient, as described previously. Approximately 90% of the filtered glucose is reabsorbed by SGLT2 in the early part of the proximal tubule (S1 segment), and the residual 10% is transported by SGLT1 in the latter segments of the proximal tubule. On the basolateral side of the membrane, glucose diffuses out of the cell into the interstitial spaces with the help of glucose transporters—GLUT2 in the S1 segment and GLUT1 in the latter part (S3 segment) of the proximal tubule. Although transport of glucose against a chemical gradient does not directly use ATP, the reabsorption of glucose depends on energy expended by the primary active Na+K+ ATPase pump in the basolateral membrane. Because of the activity of this pump, an electrochemical gradient for 345 UNIT V ATP Na+ Thus, the net reabsorption of sodium ions from the tubular lumen back into the blood involves at least three steps: 1. Sodium diffuses across the luminal membrane (also called the apical membrane) into the cell down an electrochemical gradient established by the Na+-K+ ATPase pump on the basolateral side of the membrane. 2. Sodium is transported across the basolateral membrane against an electrochemical gradient by the Na+-K+ ATPase pump. 3. Sodium, water, and other substances are reabsorbed from the interstitial fluid into the peritubular capillaries by ultrafiltration, a passive process driven by the hydrostatic and colloid osmotic pressure gradients.! UNIT V The Body Fluids and Kidneys Interstitial fluid Tubular lumen Tubular cells Co-transport Glucose GLUT Glucose Na+ ATP SGLT Na+ −70 mV Na+ K+ Amino acids Amino acids One example of counter-transport, shown in Figure 28-3, is the active secretion of hydrogen ions coupled to sodium reabsorption in the luminal membrane of the proximal tubule. In this case, sodium entry into the cell is coupled with hydrogen extrusion from the cell by sodiumhydrogen counter-transport. This transport is mediated by a specific protein (sodium-hydrogen exchanger) in the brush border of the luminal membrane. As sodium is carried to the interior of the cell, hydrogen ions are forced outward in the opposite direction into the tubular lumen. The basic principles of primary and secondary active transport are discussed in Chapter 4.! Pinocytosis Is an Active Transport Mechanism for Reabsorption of Proteins. Some parts of the tubule, espe- Na+ ATP K+ Na+ −70 mV NHE H+ Counter-transport Figure 28-3 Mechanisms of secondary active transport. The upper cell shows the co-transport of glucose and amino acids along with sodium ions through the apical side of the tubular epithelial cells, followed by facilitated diffusion through the basolateral membranes. The lower cell shows the counter-transport of hydrogen ions from the interior of the cell across the apical membrane and into the tubular lumen; movement of sodium ions into the cell, down an electrochemical gradient established by the sodium-potassium pump on the basolateral membrane, provides the energy for transport of the hydrogen ions from inside the cell into the tubular lumen. ATP, Adenosine triphosphate; GLUT, glucose transporter; NHE, sodium-hydrogen exchanger; SGLT, sodium-glucose co-transporter. facilitated diffusion of sodium across the luminal membrane is maintained, and it is this downhill diffusion of sodium to the interior of the cell that provides the energy for the simultaneous uphill transport of glucose across the luminal membrane. Thus, this reabsorption of glucose is referred to as secondary active transport because glucose itself is reabsorbed uphill against a chemical gradient, but it is secondary to primary active transport of sodium. Another important point is that a substance is said to undergo active transport when at least one of the steps in the reabsorption involves primary or secondary active transport, even though other steps in the reabsorption process may be passive. For glucose reabsorption, secondary active transport occurs at the luminal membrane, but passive facilitated diffusion occurs at the basolateral membrane, and passive uptake by bulk flow occurs at the peritubular capillaries.! Secondary Active Secretion Into the Tubules. Some substances are secreted into the tubules by secondary active transport, which often involves counter-transport of the substance with sodium ions. In counter-transport, the energy liberated from the downhill movement of one of the substances (e.g., sodium ions) enables the uphill movement of a second substance in the opposite direction. 346 cially the proximal tubule, reabsorb large molecules such as proteins via pinocytosis, a type of endocytosis. In this process, the protein attaches to the brush border of the luminal membrane, and this portion of the membrane then invaginates to the interior of the cell until it is completely pinched off and a vesicle is formed containing the protein. Once inside the cell, the protein is digested into its constituent amino acids, which are reabsorbed through the basolateral membrane into the interstitial fluid. Because pinocytosis requires energy, it is considered a form of active transport.! Transport Maximum for Substances That Are Actively Reabsorbed. For most substances that are actively reab- sorbed or secreted, there is a limit to the rate at which the solute can be transported, which is often referred to as the transport maximum. This limit is due to saturation of the specific transport systems involved when the amount of solute delivered to the tubule (referred to as the tubular load) exceeds the capacity of the carrier proteins and specific enzymes involved in the transport process. The glucose transport system in the proximal tubule is a good example. Normally, measurable glucose does not appear in the urine because essentially all the filtered glucose is reabsorbed in the proximal tubule. However, when the filtered load exceeds the capability of the tubules to reabsorb glucose, urinary excretion of glucose does occur. In the adult human, the transport maximum for glucose averages about 375 mg/min, whereas the filtered load of glucose is only about 125 mg/min (GFR × plasma glucose = 125 ml/min × 1 mg/ml). With large increases in GFR and/or plasma glucose concentration that increase the filtered load of glucose above 375 mg/min, the excess glucose filtered is not reabsorbed and passes into the urine. Figure 28-4 shows the relationship between plasma concentration of glucose, filtered load of glucose, tubular transport maximum for glucose, and rate of glucose loss in the urine. Note that when the plasma glucose concentration is 100 mg/100 ml and the filtered load is at its normal level (125 mg/min), there is no loss of glucose in the urine. However, when the plasma concentration of glucose rises above about 200 mg/100 ml, increasing the filtered load to about 250 mg/min, a small amount of glucose begins to appear in the urine. This point is termed the threshold for 900 Substance Transport Maximum 800 Creatinine 16 mg/min Para-aminohippuric acid 80 mg/min 700 ! Filtered load 600 Excretion 500 400 Transport maximum 300 Reabsorption 200 Normal 100 Threshold 0 0 100 200 300 400 500 600 700 800 Plasma glucose concentration (mg/100 ml) Figure 28-4 Relationships among the filtered load of glucose, rate of glucose reabsorption by the renal tubules, and rate of glucose excretion in the urine. The transport maximum is the maximum rate at which glucose can be reabsorbed from the tubules. The threshold for glucose refers to the filtered load of glucose at which glucose first begins to be excreted in the urine. glucose. Note that this appearance of glucose in the urine (at the threshold) occurs before the transport maximum is reached. One reason for the difference between the threshold and transport maximum is that not all nephrons have the same transport maximum for glucose, and some of the nephrons therefore begin to excrete glucose before others have reached their transport maximum. The overall transport maximum for the kidneys, which is normally about 375 mg/min, is reached when all nephrons have reached their maximal capacity to reabsorb glucose. The plasma glucose of a healthy person almost never becomes high enough to cause glucose excretion in the urine, even after eating a meal. However, in uncontrolled diabetes mellitus, plasma glucose concentration may rise to high levels, causing the filtered load of glucose to exceed the transport maximum and resulting in urinary glucose excretion. Some of the important transport maximums for substances actively reabsorbed by the tubules are as follows: ! Substance Transport Maximum Glucose 375 mg/min Phosphate 0.10 mmol/min Sulfate 0.06 mmol/min Amino acids 1.5 mmol/min Urate 15 mg/min Lactate 75 mg/min Plasma protein 30 mg/min Transport Maximums for Actively Secreted Substances. Substances that are actively secreted also exhibit transport maximums, as follows: Substances That Are Actively Transported but Do Not Exhibit a Transport Maximum. The reason that actively transported solutes often exhibit a transport maximum is that the transport carrier system becomes saturated as the tubular load increases. Some substances that are actively reabsorbed do not demonstrate a transport maximum because their rate of transport is determined by other factors, such as the following: (1) the electrochemical gradient for diffusion of the substance across the membrane; (2) the permeability of the membrane for the substance; and (3) the time that the fluid containing the substance remains within the tubule. Transport of this type is referred to as gradient-time transport because the rate of transport depends on the electrochemical gradient and the time that the substance is in the tubule, which in turn depends on the tubular flow rate. An example of gradient- time transport is sodium reabsorption in the proximal tubule, where the maximum transport capacity of the basolateral Na+-K+ ATPase pump is usually far greater than the actual rate of net sodium reabsorption because a significant amount of sodium transported out of the cell leaks back into the tubular lumen through junctions of the epithelial cells. The rate at which this backleak occurs depends on (1) the permeability of the tight junctions; and (2) the interstitial physical forces, which determine the rate of bulk flow reabsorption from the interstitial fluid into the peritubular capillaries. Therefore, sodium transport in the proximal tubules obeys mainly gradient- time transport principles rather than tubular maximum transport characteristics. This observation means that the higher the concentration of sodium in the proximal tubules, the higher is its reabsorption rate. Also, the slower the flow rate of tubular fluid, the greater the percentage of sodium that can be reabsorbed from the proximal tubules. In the more distal parts of the nephron, the epithelial cells have much tighter junctions and transport much smaller amounts of sodium. In these segments, sodium reabsorption exhibits a transport maximum similar to that for other actively transported substances. Furthermore, this transport maximum can be increased by certain hormones, such as aldosterone.! PASSIVE WATER REABSORPTION BY OSMOSIS COUPLED MAINLY TO SODIUM REABSORPTION When solutes are transported out of the tubule by primary or secondary active transport, their concentrations tend to decrease inside the tubule while increasing in the renal interstitium. This phenomenon creates a concentration difference that causes osmosis of water in the 347 UNIT V Glucose filtered load, reabsorption or excretion (mg/min) Chapter 28 Renal Tubular Reabsorption and Secretion UNIT V The Body Fluids and Kidneys same direction that the solutes are transported, from the tubular lumen to the renal interstitium. Some parts of the renal tubule, especially the proximal tubule, are highly permeable to water, and water reabsorption occurs so rapidly that there is only a small concentration gradient for solutes across the tubular membrane. A large part of the osmotic flow of water in the proximal tubules occurs through water channels (aquaporins) in the cell membranes, as well as through the tight junctions between the epithelial cells. As noted previously, the junctions between the cells are not as tight as their name would imply and permit significant diffusion of water and small ions. This condition is especially true in the proximal tubules, which have a high permeability for water and a smaller but significant permeability to most ions, such as sodium, chloride, potassium, calcium, and magnesium. Water moving across the tight junctions by osmosis also carries with it some of the solutes, a process referred to as solvent drag. In addition, because the reabsorption of water, organic solutes, and ions is coupled to sodium reabsorption, changes in sodium reabsorption significantly influence the reabsorption of water and many other solutes. In the more distal parts of the nephron, beginning in the loop of Henle and extending through the collecting tubule, the tight junctions become far less permeable to water and solutes, and the epithelial cells also have a greatly decreased membrane surface area. Therefore, water cannot move easily across the tight junctions of the tubular membrane by osmosis. However, antidiuretic hormone (ADH) greatly increases the water permeability in the distal and collecting tubules. Thus, water movement across the tubular epithelium can occur only if the membrane is permeable to water, no matter how large the osmotic gradient. In the proximal tubule and descending loop of Henle, water permeability is always high, and water is rapidly reabsorbed to reach osmotic equilibrium with the surrounding interstitial fluid. This high permeability is due to abundant expression of the water channel aquaporin-1 (AQP-1) in the luminal and basolateral membranes. In the ascending loop of Henle, water permeability is always low, so almost no water is reabsorbed, despite a large osmotic gradient. Water permeability in the last parts of the tubules—the distal tubules, collecting tubules, and collecting ducts— occurs through aquaporins and can be high or low, depending on the presence or absence of ADH.! REABSORPTION OF CHLORIDE, UREA, AND OTHER SOLUTES BY PASSIVE DIFFUSION When sodium is reabsorbed through the tubular epithelial cell, negative ions such as chloride are transported along with sodium because of electrical potentials. That is, transport of positively charged sodium ions out of the lumen leaves the inside of the lumen negatively charged, compared with the interstitial fluid causing chloride ions 348 Na+ reabsorption H2O reabsorption Lumen negative potential Luminal Cl– concentration Passive Cl– reabsorption Luminal urea concentration Passive urea reabsorption Figure 28-5 Mechanisms whereby water, chloride, and urea reabsorption are coupled with sodium reabsorption. to diffuse passively through the paracellular pathway. Additional reabsorption of chloride ions occurs because of a chloride concentration gradient that develops when water is reabsorbed from the tubule by osmosis, thereby concentrating the chloride ions in the tubular lumen (Figure 28-5). Thus, active reabsorption of sodium is closely coupled to passive reabsorption of chloride by way of an electrical potential and a chloride concentration gradient. Chloride ions can also be reabsorbed by secondary active transport. The most important of the secondary active transport processes for chloride reabsorption involves the co-transport of chloride with sodium across the luminal membrane. Urea is also passively reabsorbed from the tubule, but to a much lesser extent than chloride ions. As water is reabsorbed from the tubules (by osmosis coupled to sodium reabsorption), urea concentration in the tubular lumen increases (see Figure 28-5). This increase creates a concentration gradient favoring reabsorption of urea. However, urea does not permeate the tubule as readily as water. In some parts of the nephron, especially the inner medullary collecting duct, passive urea reabsorption is facilitated by specific urea transporters. Yet, only about half of the urea that is filtered by the glomerular capillaries is reabsorbed from the tubules. The remaining urea passes into the urine, allowing the kidneys to excrete large amounts of this waste product of metabolism. In mammals, more than 90% of waste nitrogen, mainly generated in the liver as a product of protein metabolism, is normally excreted by the kidneys as urea. Another waste product of metabolism, creatinine, is an even larger molecule than urea and is essentially impermeant to the tubular membrane. Therefore, almost none of the creatinine that is filtered is reabsorbed, so virtually all the creatinine filtered by the glomerulus is excreted in the urine.! Chapter 28 Renal Tubular Reabsorption and Secretion 65% Proximal tubule Isosmotic H+, organic acids, bases Figure 28-6 Cellular ultrastructure and primary transport characteristics of the proximal tubule. The proximal tubules reabsorb about 65% of the filtered sodium, chloride, bicarbonate, and potassium and essentially all the filtered glucose and amino acids. The proximal tubules also secrete organic acids, bases, and hydrogen ions into the tubular lumen. REABSORPTION AND SECRETION ALONG DIFFERENT PARTS OF THE NEPHRON In the previous sections, we discussed the basic principles whereby water and solutes are transported across the tubular membrane. With these generalizations in mind, we can now discuss the different characteristics of the individual tubular segments that enable them to perform their specific functions. Only the tubular transport functions that are quantitatively most important will be discussed, especially as they relate to the reabsorption of sodium, chloride, and water. In subsequent chapters, we discuss the reabsorption and secretion of other substances in different parts of the tubular system. PROXIMAL TUBULAR REABSORPTION Normally, about 65% of the filtered load of sodium and water and a slightly lower percentage of filtered chloride are reabsorbed by the proximal tubule before the filtrate reaches the loops of Henle. These percentages can be increased or decreased in different physiological conditions, as discussed later. Proximal Tubules Have High Capacity for Active and Passive Reabsorption. The high capacity of the proxi- mal tubule for reabsorption results from its special cellular characteristics, as shown in Figure 28-6. The proximal tubule epithelial cells are highly metabolic and have large numbers of mitochondria to support powerful active transport processes. In addition, the proximal tubular cells have an extensive brush border on the luminal (apical) side of the membrane, as well as an extensive labyrinth of intercellular and basal channels, all of which together provide an extensive membrane surface area on the luminal and basolateral sides of the epithelium for rapid transport of sodium ions and other substances. Concentrations of Solutes Along Proximal Tubules. Figure 28-7 summarizes the changes in concentration of various solutes along the proximal tubule. Although the amount of sodium in the tubular fluid decreases markedly along the proximal tubule, sodium concentration (and total osmolarity) remains relatively constant because water permeability of the proximal tubules is so great that water reabsorption keeps pace with sodium reabsorption. Certain organic solutes, such as glucose, amino acids, and bicarbonate, are much more avidly reabsorbed than water, and their concentrations decrease markedly along the length of the proximal tubule. Other organic solutes that are less permeant and not actively reabsorbed, such as creatinine, increase their concentration along the proximal tubule. The total solute concentration, as reflected by osmolarity, remains essentially the same all along the proximal tubule because of the extremely high permeability of this part of the nephron to water.! 349 UNIT V Na+, Cl–, HCO3–, K+, H2O, glucose, amino acids The extensive membrane surface of the epithelial brush border is also loaded with protein carrier molecules that transport a large fraction of the sodium ions across the luminal membrane linked via the co-transport mechanism with multiple organic nutrients such as amino acids and glucose. Additional sodium is transported from the tubular lumen into the cell by counter-transport mechanisms that reabsorb sodium while secreting other substances into the tubular lumen, especially hydrogen ions. As discussed in Chapter 31, secretion of hydrogen ions into the tubular lumen is an important step in the removal of bicarbonate ions from the tubule (by combining H+ with the HCO3− to form H2CO3, which then dissociates into H2O and CO2). Although the Na+-K+ ATPase pump provides the major force for the reabsorption of sodium, chloride, and water throughout proximal tubule, there are some differences in the mechanisms whereby sodium and chloride are transported through the luminal side of the early and late portions of the proximal tubular membrane. In the first half of the proximal tubule, sodium is reabsorbed by co-transport along with glucose, amino acids, and other solutes. However, in the second half of the proximal tubule, little glucose and few amino acids remain to be reabsorbed. Instead, sodium is now reabsorbed, mainly with chloride ions. The second half of the proximal tubule has a relatively high concentration of chloride (≈140 mEq/L) compared with the early proximal tubule (≈105 mEq/L) because when sodium is reabsorbed, it preferentially carries with it glucose, bicarbonate, and organic ions in the early proximal tubule, leaving behind a solution that has a higher concentration of chloride. In the second half of the proximal tubule, the higher chloride concentration favors diffusion of this ion from the tubule lumen through the intercellular junctions into the renal interstitial fluid. Smaller amounts of chloride may also be reabsorbed through specific chloride channels in the proximal tubular cell membrane.! UNIT V The Body Fluids and Kidneys Thin descending loop of Henle 5.0 Tubular fluid/plasma concentration Creatinine 2.0 Cl− Urea 1.0 Na+ H2O Osmolarity 0.5 HCO3− 0.2 0.1 Thick ascending loop of Henle Glucose 0.05 Amino acids 25% Na+, Cl–, K+, Ca2+, HCO3–, Mg2+ 0.01 0 20 40 60 80 % Total proximal tubule length 100 Figure 28-7 Changes in concentrations of different substances in tubular fluid along the proximal convoluted tubule relative to the concentrations of these substances in the plasma and glomerular filtrate. A value of 1.0 indicates that the concentration of the substance in the tubular fluid is the same as the concentration in the plasma. Values below 1.0 indicate that the substance is reabsorbed more avidly than water, whereas values above 1.0 indicate that the substance is reabsorbed to a lesser extent than water or is secreted into the tubules. Secretion of Organic Acids and Bases by Proximal Tubules. The proximal tubule is also an important site for secretion of organic acids and bases such as bile salts, oxalate, urate, and catecholamines. Many of these substances are the end products of metabolism and must be rapidly removed from the body. The secretion of these substances into the proximal tubule plus filtration into the proximal tubule by the glomerular capillaries and almost total lack of reabsorption by the tubules, all combined, contribute to rapid excretion in the urine. In addition to the waste products of metabolism, the kidneys secrete many potentially harmful drugs or toxins into the tubules and rapidly clear these substances from the blood. In the case of certain drugs, such as penicillin and salicylates, the rapid clearance by the kidneys creates a challenge in maintaining a therapeutically effective drug concentration. Another compound that is rapidly secreted by the proximal tubule is para-aminohippuric acid (PAH). PAH is secreted so rapidly that the average person can clear about 90% of the PAH from the plasma flowing through the kidneys and excrete it in the urine. For this reason, the rate of PAH clearance can be used to estimate the renal plasma flow (RPF), as discussed later.! SOLUTE AND WATER TRANSPORT IN LOOPS OF HENLE The loop of Henle consists of three functionally distinct segments—the thin descending segment, thin ascending segment, and thick ascending segment. The thin 350 Hypoosmotic H+ Figure 28-8 Cellular ultrastructure and transport characteristics of the thin descending loop of Henle (top) and thick ascending segment of the loop of Henle (bottom). The descending part of the thin segment of the loop of Henle is highly permeable to water and moderately permeable to most solutes but has few mitochondria and little or no active reabsorption. The thick ascending limb of the loop of Henle reabsorbs about 25% of the filtered loads of sodium, chloride, and potassium, as well as large amounts of calcium, bicarbonate, and magnesium. This segment also secretes hydrogen ions into the tubular lumen. descending and thin ascending segments, as their names imply, have thin epithelial membranes with no brush borders, few mitochondria, and minimal levels of metabolic activity (Figure 28-8). The descending part of the thin segment is highly permeable to water and moderately permeable to most solutes, including urea and sodium. The function of this nephron segment is mainly to allow simple diffusion of substances through its walls. About 20% of the filtered water is reabsorbed in the loop of Henle, and almost all of this occurs in the thin descending limb. The ascending limb, including both the thin and thick portions, is virtually impermeable to water, a characteristic that is important for concentrating the urine. The thick segment of the loop of Henle, which begins about halfway up the ascending limb, has thick epithelial cells that have high metabolic activity and are capable of active reabsorption of sodium, chloride, and potassium (see Figure 28-8). About 25% of the filtered loads of sodium, chloride, and potassium are reabsorbed in the loop of Henle, mostly in the thick ascending limb. Considerable amounts of other ions, such as calcium, bicarbonate, and magnesium, are also reabsorbed in the thick Chapter 28 Renal Tubular Reabsorption and Secretion Renal interstitial fluid Tubular lumen (+8 mV) Na+, K+ Mg2+, Ca2+ Tubular cells Paracellular diffusion ATP H+ Cl− K+ + 2Cl– − K+ Loop diuretics osemide Figure 28-9 Mechanisms of sodium, chloride, and potassium transport in the thick ascending loop of Henle. The Na+-K+ ATPase pump in the basolateral cell membrane maintains a low intracellular sodium concentration and a negative electrical potential in the cell. The 1-sodium, 2-chloride, 1-potassium co-transporter in the luminal membrane transports these three ions from the tubular lumen into the cells, using the potential energy released by the diffusion of sodium down an electrochemical gradient into the cells. Sodium is also transported into the tubular cell by sodium-hydrogen countertransport. The positive charge (+8 mV) of the tubular lumen relative to the interstitial fluid forces cations such as Mg2+ and Ca2+ to diffuse from the lumen to the interstitial fluid via the paracellular pathway. ascending loop of Henle. The thin segment of the ascending limb has a much lower reabsorptive capacity than the thick segment, and the thin descending limb does not reabsorb significant amounts of any of these solutes. An important component of solute reabsorption in the thick ascending limb is the Na+-K+ ATPase pump in the epithelial cell basolateral membranes. As in the proximal tubule, the reabsorption of other solutes in the thick segment of the ascending loop of Henle is closely linked to the reabsorptive capability of the Na+-K+ ATPase pump, which maintains a low intracellular sodium concentration. The low intracellular sodium concentration in turn provides a favorable gradient for movement of sodium from the tubular fluid into the cell. In the thick ascending loop, movement of sodium across the luminal membrane is mediated primarily by a 1-sodium, 2-chloride, 1-potassium cotransporter (NKCC2) (Figure 28-9). This co-transport protein in the luminal membrane uses the potential energy released by downhill diffusion of sodium into the cell to drive the reabsorption of potassium into the cell against a concentration gradient. The thick ascending limb of the loop of Henle is the site of action of the powerful loop diuretics furosemide, ethacrynic acid, and bumetanide, all of which inhibit the action of the NKCC2 co-transporter. These diuretics are DISTAL TUBULES The thick segment of the ascending limb of the loop of Henle empties into the distal tubule. The first portion of the distal tubule forms the macula densa, a group of closely packed epithelial cells that is part of the juxtaglomerular complex and provides feedback control of the GFR and blood flow in this same nephron. The next part of the distal tubule is highly convoluted and has many of the same reabsorptive characteristics of the thick segment of the ascending limb of the loop of Henle. That is, it avidly reabsorbs most of the ions, including sodium, potassium, and chloride, but is virtually impermeable to water and urea. For this reason, it is referred to as the diluting segment because it also dilutes the tubular fluid. Approximately 5% of the filtered load of sodium chloride is reabsorbed in the early distal tubule. The sodiumchloride co-transporter moves sodium chloride from the tubular lumen into the cell, and the Na+-K+ ATPase pump transports sodium out of the cell across the basolateral membrane (Figure 28-10). Chloride diffuses out of cell into the renal interstitial fluid through chloride channels in the basolateral membrane. The thiazide diuretics, which are widely used to treat disorders such as hypertension and heart failure, inhibit the sodium-chloride co-transporter.! LATE DISTAL TUBULES AND CORTICAL COLLECTING TUBULES The second half of the distal tubule and subsequent cortical collecting tubule have similar functional characteristics. Anatomically, they are composed of two distinct cell types, the principal cells and intercalated cells 351 UNIT V K+ Na+ Na+ discussed in Chapter 32. The thick ascending limb also has a sodium-hydrogen counter-transport mechanism in its luminal cell membrane that mediates sodium reabsorption and hydrogen secretion (see Figure 28-9). There is also significant paracellular reabsorption of cations, such as Mg2+, Ca2+, Na+, and K+, in the thick ascending limb as a result of the slight positive charge of the tubular lumen relative to the interstitial fluid. Although the NKCC2 co-transporter moves equal amounts of cations and anions into the cell, there is a slight backleak of potassium ions into the lumen, creating a positive charge of about +8 millivolts in the tubular lumen. This positive charge forces cations such as Mg2+ and Ca2+ to diffuse from the tubular lumen through the paracellular space and into the interstitial fluid. The thick segment of the ascending loop of Henle is virtually impermeable to water. Therefore, most of the water delivered to this segment remains in the tubule, despite reabsorption of large amounts of solute. The tubular fluid in the ascending limb becomes very dilute as it flows toward the distal tubule, a feature that is important in allowing the kidneys to dilute or concentrate the urine under different conditions, as discussed in more detail in Chapter 29.! UNIT V The Body Fluids and Kidneys Renal interstitial fluid Tubular cells Tubular lumen (−10 mV) Early distal tubule Na+, Cl–, Ca2+, Mg2+ K+ ATP Na+ Na+ − Cl– Cl– Late distal tubule and cortical collecting tubule Thiazide diuretics Principal cells Figure 28-10 Mechanism of sodium chloride transport in the early distal tubule. Sodium and chloride are transported from the tubular lumen into the cell by a co-transporter that is inhibited by thiazide diuretics. Sodium is pumped out of the cell by Na+-K+ ATPase adenosine triphosphatase, and chloride diffuses into the interstitial fluid via chloride channels. (Figure 28-11). The principal cells reabsorb sodium and water from the lumen and secrete potassium ions into the lumen. The type A intercalated cells reabsorb potassium ions and secrete hydrogen ions into the tubular lumen. Principal Cells Reabsorb Sodium and Secrete Potassium. Sodium reabsorption and potassium secretion by the principal cells depend on the activity of a Na+-K+ ATPase pump in each cell’s basolateral membrane (Figure 28-12). This pump maintains a low sodium concentration inside the cell and, therefore, favors sodium diffusion into the cell through special channels. Secretion of potassium by these cells from the blood into the tubular lumen involves two steps: (1) potassium enters the cell because of the Na+-K+ ATPase pump, which maintains a high intracellular potassium concentration; and (2) once in the cell, potassium diffuses down its concentration gradient across the luminal membrane into the tubular fluid. The principal cells are the primary sites of action of the potassium-sparing diuretics, including spironolactone, eplerenone, amiloride, and triamterene. Spironolactone and eplerenone are mineralocorticoid receptor antagonists that compete with aldosterone for receptor sites in the principal cells and therefore inhibit the stimulatory effects of aldosterone on sodium reabsorption and potassium secretion. Amiloride and triamterene are sodium channel blockers that directly inhibit the entry of sodium into the sodium channels of the luminal membranes and therefore reduce the amount of sodium that can be transported across the basolateral membranes by the Na+-K+ ATPase pump. This, in turn, decreases transport of potassium into the cells and ultimately reduces potassium secretion into the tubular fluid. For this reason, sodium channel blockers, as well as aldosterone antagonists, decrease urinary excretion of potassium and act as potassium-sparing diuretics.! 352 Na+, Cl– K+ (+ADH) H2O H+ Type A intercalated cells HCO3– K+ Figure 28-11 Cellular ultrastructure and transport characteristics of the early distal tubule and late distal tubule and collecting tubule. The early distal tubule has many of the same characteristics as the thick ascending loop of Henle and reabsorbs sodium, chloride, calcium, and magnesium but is virtually impermeable to water and urea. The late distal tubules and cortical collecting tubules are composed of two distinct cell types, the principal cells and intercalated cells. The principal cells reabsorb sodium from the lumen and secrete potassium ions into the lumen. Type A intercalated cells reabsorb potassium and bicarbonate ions from the lumen and secrete hydrogen ions into the lumen. The reabsorption of water from this tubular segment is controlled by the concentration of antidiuretic hormone. Intercalated Cells Can Secrete or Reabsorb Hydrogen, Bicarbonate, and Potassium Ions. Intercalated cells play a major role in acid–base regulation and constitute 30% to 40% of the cells in the collecting tubules and collecting ducts. There are two types of intercalated cells, type A and type B (Figure 28-13). Type A intercalated cells secrete hydrogen ions by a hydrogen-ATPase transporter and by a hydrogen-potassium-ATPase transporter. Hydrogen is generated in this cell by the action of carbonic anhydrase on water and carbon dioxide to form carbonic acid, which then dissociates into hydrogen ions and bicarbonate ions. The hydrogen ions are then secreted into the tubular lumen and, for each hydrogen ion secreted, a bicarbonate ion becomes available for reabsorption across the basolateral membrane. Type A intercalated cells are especially important in eliminating hydrogen ions while reabsorbing bicarbonate in acidosis. Type B intercalated cells have functions opposite to those of type A cells and secrete bicarbonate into the tubular lumen while reabsorbing hydrogen ions in alkalosis. Type B intercalated cells have hydrogen and bicarbonate Chapter 28 Renal Tubular Reabsorption and Secretion Renal interstitial fluid Tubular lumen (−50 mV) Tubular cells Renal interstitial fluid CO2 + H2O ATP H+ H2CO3 Na+ Na+ Cl– HCO3– + H+ − − ATP UNIT V CO2 K+ K+ Tubular lumen Type A intercalated cell HCO3– Cl− Cl– K+ Na+ channel blockers K+ ATP H+ Tr Figure 28-12 Mechanism of sodium-chloride reabsorption and potassium secretion in the principal cells of the late distal tubules and cortical collecting tubules. Sodium enters the cell through special channels and is transported out of the cell by the Na+-K+ ATPase pump. Aldosterone antagonists compete with aldosterone for binding sites in the cell and therefore inhibit the effects of aldosterone to stimulate sodium reabsorption and potassium secretion. Sodium channel blockers directly inhibit the entry of sodium into the sodium channels. transporters on opposite sides of the cell membrane compared with type A cells. The chloride-bicarbonate counter-transporter on the apical membrane of type B cells is called pendrin and is different than the chloridebicarbonate transporter of type A cells. Hydrogen ions are actively transported out of the type B intercalated cell on the basolateral side of the cell membrane by hydrogenATPase, and bicarbonate is secreted into the lumen, thus eliminating excess plasma bicarbonate in alkalosis. Induction of chronic metabolic alkalosis increases the number of type B intercalated cells, which contribute to increased excretion of bicarbonate, whereas acidosis increases the number of type A cells. A more detailed discussion of this mechanism is presented in Chapter 31. The intercalated cells can also reabsorb or secrete potassium ions, as shown in Figure 28-13. The functional characteristics of the late distal tubule and cortical collecting tubule can be summarized as follows: 1. The tubular membranes of both segments are almost completely impermeable to urea, similar to the diluting segment of the early distal tubule. Thus, almost all the urea that enters these segments passes on through and into the collecting duct to be excreted in the urine, although some reabsorption of urea occurs in the medullary collecting ducts. 2. Both the late distal tubule and cortical collecting tubule segments reabsorb sodium ions, and the rate of reabsorption is controlled by hormones, especially aldosterone. At the same time, these segments secrete potassium ions from the peritubular capillary blood Renal interstitial fluid CO2 CO2 + H2O H+ H2CO3 H+ ATP ATP Tubular lumen Type B intercalated cell H+ + HCO3– Cl– HCO3– Pendrin K+ Cl– K+ Figure 28-13 Type A and type B intercalated cells of the collecting tubule. Type A cells contain hydrogen-ATPase and hydrogenpotassium-ATPase in the luminal membrane and secrete hydrogen ions while reabsorbing bicarbonate and potassium ions in acidosis. In type B cells, the hydrogen-ATPase and hydrogen-potassium-ATPase transporters are located in the basolateral membrane and reabsorb hydrogen ions while secreting bicarbonate and potassium ions in alkalosis. The chloride-bicarbonate counter-transporter on the apical membrane of type B cells is called pendrin and is different than the chloride-bicarbonate transporter of type A intercalated cells. into the tubular lumen, a process that is also controlled by aldosterone and other factors, such as the concentration of potassium ions in the body fluids. 3. The type A intercalated cells of these nephron segments can avidly secrete hydrogen ions by an active hydrogen-ATPase mechanism in acidosis. This process is different from the secondary active secretion of hydrogen ions by the proximal tubule because it is capable of secreting hydrogen ions against a large concentration gradient, as much as 1000 to 1. This is in contrast to the relatively small gradient (4- to 10-fold) for hydrogen ions that can be achieved by secondary active secretion in the proximal tubule. 353 2O Urea H+ HCO 3 – 2.0 1.0 40 12 K and Na 0.50 0.20 0.10 0.05 0.02 Cl Na HCO3 ein Prot cids Although the medullary collecting ducts usually reabsorb less than 5% of the filtered water and sodium, they are the final site for processing the urine and, therefore, play a critical role in determining the final urine output of water and solutes. The epithelial cells of the collecting ducts are nearly cuboidal in shape, with smooth surfaces and relatively few mitochondria (Figure 28-14). Special characteristics of this tubular segment are as follows: 1. The permeability of the medullary collecting duct to water is controlled by the level of ADH. With high levels of ADH, water is avidly reabsorbed into the medullary interstitium, thereby reducing the urine volume and concentrating most of the solutes in the urine. 2. Unlike the cortical collecting tubule, the medullary collecting duct is permeable to urea, and there are special urea transporters that facilitate urea diffusion across the luminal and basolateral membranes. Therefore, some of the tubular urea is reabsorbed into the medullary interstitium, helping raise the osmolality in this region of the kidneys and contributing to the kidneys’ overall ability to form concentrated urine. This topic is discussed in Chapter 29. 3. The medullary collecting duct is capable of secreting hydrogen ions against a large concentration ine tin a e Cr lin Cl Inu a Ure K 5.0 no a MEDULLARY COLLECTING DUCTS 10.0 Ami In alkalosis, the type B intercalated cells secrete bicarbonate and actively reabsorb hydrogen ions. Thus, the intercalated cells play a key role in acid– base regulation of the body fluids. 4. The permeability of the late distal tubule and cortical collecting duct to water is controlled by the concentration of ADH, which is also called vasopressin. With high levels of ADH, these tubular segments are permeable to water but, in the absence of ADH, they are virtually impermeable to water. This special characteristic provides an important mechanism for controlling the degree of dilution or concentration of the urine.! PAH 20.0 ose Gluc Figure 28-14 Cellular ultrastructure and transport characteristics of the medullary collecting duct. The medullary collecting ducts actively reabsorb sodium and secrete hydrogen ions and are permeable to urea, which is reabsorbed in these tubular segments. The reabsorption of water in medullary collecting ducts is controlled by the concentration of antidiuretic hormone. 5 50.0 to H) H D (+ A 354 58 100.0 to 1 – Cl to +, Na Tubular fluid/glomerular filtrate concentration Medullary collecting duct 5 UNIT V The Body Fluids and Kidneys Proximal tubule Loop of Henle Distal tubule Collecting tubule Figure 28-15 Changes in average concentrations of different substances at different points in the tubular system relative to the concentration of that substance in the plasma and glomerular filtrate. A value of 1.0 indicates that the concentration of the substance in the tubular fluid is the same as the concentration of that substance in the plasma. Values below 1.0 indicate that the substance is reabsorbed more avidly than water, whereas values above 1.0 indicate that the substance is reabsorbed to a lesser extent than water or is secreted into the tubules. PAH, Para-aminohippuric acid. gradient, as also occurs in the cortical collecting tubule. Thus, the medullary collecting duct also plays a key role in regulating acid-base balance.! SUMMARY OF CONCENTRATIONS OF DIFFERENT SOLUTES IN DIFFERENT TUBULAR SEGMENTS Whether a solute will become concentrated in the tubular fluid is determined by the relative degree of reabsorption of that solute versus the reabsorption of water. If a greater percentage of water is reabsorbed, the substance becomes more concentrated. If a greater percentage of the solute is reabsorbed, the substance becomes more diluted. Figure 28-15 shows the degree of concentration of several substances in different tubular segments. All the values in this figure represent the tubular fluid concentration divided by the plasma concentration of a substance. If plasma concentration of the substance is assumed to be constant, any change in the tubular fluid/plasma concentration ratio reflects changes in tubular fluid concentration. As the filtrate moves along the tubular system, the concentration rises progressively to higher than 1.0 if more water is reabsorbed than solute, or if there has been a net secretion of the solute into the tubular fluid. If the concentration ratio becomes progressively less than 1.0, this Chapter 28 Renal Tubular Reabsorption and Secretion Tubular Fluid/Plasma Inulin Concentration Ratio Can Be Used to Assess Water Reabsorption by Renal Tubules. Inulin, a polysaccharide used to measure the GFR, is not reabsorbed or secreted by the renal tubules. Changes in inulin concentration at different points along the renal tubule, therefore, reflect changes in the amount of water present in the tubular fluid. For example, the tubular fluid/plasma concentration ratio for inulin rises to about 3.0 at the end of the proximal tubules, indicating that inulin concentration in the tubular fluid is three times greater than in the plasma and glomerular filtrate. Because inulin is not secreted or reabsorbed from the tubules, a tubular fluid/plasma concentration ratio of 3.0 means that only one-third of the water that was filtered remains in the renal tubule and that two-thirds of the filtered water has been reabsorbed as the fluid passes through the proximal tubule. At the end of the collecting ducts, the tubular fluid/plasma inulin concentration ratio rises to about 125 (see Figure 28-15), indicating that only 1/125 of the filtered water remains in the tubule and that more than 99% has been reabsorbed.! REGULATION OF TUBULAR REABSORPTION Because it is essential to maintain a precise balance between tubular reabsorption and glomerular filtration, there are multiple nervous, hormonal, and local control mechanisms that regulate tubular reabsorption, just as there are for control of glomerular filtration. An important feature of tubular reabsorption is that reabsorption of some solutes can be regulated independently of others, especially through hormonal control mechanisms. GLOMERULOTUBULAR BALANCE— REABSORPTION RATE INCREASES IN RESPONSE TO INCREASED TUBULAR LOAD One of the most basic mechanisms for controlling tubular reabsorption is the intrinsic ability of the tubules to increase their reabsorption rate in response to increased tubular load (increased tubular inflow). This phenomenon is referred to as glomerulotubular balance. For example, if the GFR increases from 125 to 150 ml/min, the absolute rate of proximal tubular reabsorption also increases from about 81 ml/min (65% of GFR) to about 97.5 ml/min (65% of GFR). Thus, glomerulotubular balance refers to the fact that the total rate of reabsorption increases as the filtered load increases, even though the percentage of GFR reabsorbed in the proximal tubule remains relatively constant, at about 65%. Some degree of glo