Renal Tubular Reabsorption and Secretion

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

$Urinary excretion = Glomerular filtration - Tubular reabsorption + Tubular secretion$

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:

Filtration=Glomerular filtration rate×Plasma concentration

$Filtration=Glomerular filtration rate×Plasma concentration$

Table 28-1

Filtration, Reabsorption, and Excretion Rates of Different Substances by the Kidneys

Substance	Amount Filtered	Amount Reabsorbed	Amount Excreted	% of Filtered Load Reabsorbed
Glucose (g/day)	180	180	0	100
Bicarbonate (mEq/day)	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

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 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.

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 ).

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 triphosphate (ATP), is termed primary active transport . An example of this mechanism is the sodium-potassium 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 epithelial 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 transport 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 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.

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.

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.

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.

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.

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.

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 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.

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 sodium-hydrogen 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, especially 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 reabsorbed 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 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.

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.

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:

Substance	Transport Maximum
Creatinine	16 mg/min
Para-aminohippuric acid	80 mg/min

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 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 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.

Figure 28-5, Mechanisms whereby water, chloride, and urea reabsorption are coupled with sodium reabsorption.

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.

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.

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