Physiology 5th Ed.

SODIUM BALANCE

Of all functions of the kidney, reabsorption of sodium (Na+) is the most important. Consider that Na+ is the major cation of the ECF compartment, which consists of plasma and interstitial fluid. The amount of Na+ in ECF determines the ECF volume, which in turn determines plasma volume, blood volume, and blood pressure (see Chapter 4). The renal mechanisms involved in reabsorption of Na+ (i.e., returning Na+ to ECF after filtration), therefore, are critically important for the maintenance of normal ECF volume, normal blood volume, and normal blood pressure.

The kidneys are responsible for maintaining a normal body Na+ content. On a daily basis, the kidneys must ensure that Na+ excretion exactly equals Na+ intake, a matching process called Na+ balance. For example, to remain in Na+ balance, a person who ingests 150 mEq of Na+ daily must excrete exactly 150 mEq of Na+ daily.

If Na+ excretion is less than Na+ intake, then the person is in positive Na+ balance. In this case, extra Na+ is retained in the body, primarily in the ECF. When the Na+ content of ECF is increased, there is increased ECF volume or ECF volume expansion; blood volume and arterial pressure also increase, and there may be edema.

Conversely, if Na+ excretion is greater than Na+ intake, then a person is in negative Na+ balance. When excess Na+ is lost from the body, there is a decreased Na+ content of ECF, decreased ECF volume orECF volume contraction, and decreased blood volume and arterial pressure.

An important distinction should be made between Na+content of the body (which determines ECF volume) and Na+concentration. Na+ concentration is determined not only by the amount of Na+ present but also by the volume of water. For example, a person can have an increased Na+ content but a normal Na+ concentration (if water content is increased proportionately). Or, a person can have an increased Na+concentration with a normal Na+ content (if water content is decreased). In nearly all cases, changes in Na+concentration are caused by changes in body water content rather than Na+ content. The kidney has separate mechanisms for regulating Na and water reabsorption.

Overall Handling of Na+

Figure 6-19 shows the renal handling of Na+ in the nephron. Na+ is freely filtered across glomerular capillaries and subsequently reabsorbed throughout the nephron. The arrows show reabsorption in the various segments of the nephron, and the numbers give the approximate percentage of the filtered load reabsorbed in each segment. Excretion of Na+ is less than 1% of the filtered load, corresponding to net reabsorption of more than 99% of the filtered load.

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Figure 6–19 Na+ handling in the nephron. Arrows show locations of Na+ reabsorption; numbers are percentages of the filtered load reabsorbed or excreted.

By far, the bulk of the Na+ reabsorption occurs in the proximal convoluted tubule, where two thirds (or 67%) of the filtered load is reabsorbed. In the proximal tubule, water reabsorption is always linked to Na+ reabsorption and the mechanism is described as isosmotic.

The thick ascending limb of the loop of Henle reabsorbs 25% of the filtered load of Na+. In contrast to the proximal tubule, where water reabsorption is linked to Na+ reabsorption, the thick ascending limb is impermeable to water.

The terminal portions of the nephron (the distal tubule and the collecting ducts) reabsorb approximately 8% of the filtered load. The early distal convoluted tubule reabsorbs approximately 5% of the filtered load, and, like the thick ascending limb, it is impermeable to water. The late distal convoluted tubule and collecting ducts reabsorb the final 3% of the filtered load and are responsible for the fine-tuning of Na+ reabsorption, which ultimately ensures Na+ balance. Not surprisingly, then, the late distal convoluted tubule and collecting duct are the sites of action of the Na+-regulating hormone aldosterone.

As emphasized, for a person to remain in Na+ balance, the amount of Na+ excreted in the urine (e.g., mEq/day) must be exactly equal to daily Na+ intake. With an average Na+ intake of 150 mEq/day, to maintain Na+ balance, excretion should be 150 mEq/day, which is less than 1% of the filtered load. (If GFR is 180 L/day and plasma Na+ concentration is 140 mEq/L, then the filtered load of Na+ is 25,200 mEq/day. Excretion of 150 mEq/day, therefore, is 0.6% of the filtered load [150 mEq/day divided by 25,200 mEq/day], as shown in Fig. 6-19.)

In terms of maintaining overall Na+ balance, each nephron segment plays a different role. Therefore, the segments will be discussed individually with regard to the quantity of the filtered Na+ reabsorbed and the cellular transport mechanisms. For a summary of the functions of each nephron segment, see Table 6-7.

Table 6–7 Summary of the Functions of the Major Nephron Segments

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ADH, Antidiuretic hormone; PTH, parathyroid hormone; ENaC, epithelial Na+ channel; AQP2, aquaporin 2.

Proximal Convoluted Tubule

The proximal convoluted tubule consists of an early proximal convoluted tubule and a late proximal convoluted tubule. The mechanisms for Na+ reabsorption in the early and late proximal tubules are different, as reflected in the anions and other solutes that accompany Na+. In the early proximal tubule, Na+ is reabsorbed primarily with HCO3 and organic solutes such as glucose and amino acids. In the late proximal tubule, Na+ is reabsorbed primarily with Cl, but without organic solutes.

Despite these differences, several statements can be made that describe the proximal tubule as a whole. (1) The entire proximal tubule reabsorbs 67% of the filtered Na+. (2) The entire proximal tubule also reabsorbs 67% of the filtered water. The tight coupling between Na+ and water reabsorption is called isosmotic reabsorption. (3) This bulk reabsorption of Na+ and water (the major constituents of ECF) is critically important for maintaining ECF volume. (4) The proximal tubule is the site of glomerulotubular balance, a mechanism for coupling reabsorption to the GFR.

The features of the early and late proximal tubule are described first, followed by a discussion of those general properties of the proximal tubule.

Early Proximal Convoluted Tubule

The first half of the proximal convoluted tubule is called the early proximal tubule. In this segment, the most essential solutes are reabsorbed along with Na+: glucose, amino acids, and HCO3. Because of the critical metabolic roles of glucose and amino acids and the critical buffering role of HCO3, the early proximal tubule can be thought of as performing the “highest priority” reabsorptive work.

The cellular mechanisms for reabsorption in the early proximal tubule are shown in Figure 6-20. The luminal membrane contains multiple secondary active transport mechanisms, which derive their energy from the transmembrane Na+ gradient. Recall from Chapter 1 that secondary active transport can be cotransport, where all solutes move in the same direction across the cell membrane, or countertransport or exchange, where solutes move in opposite directions across the cell membrane.

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Figure 6–20 Cellular mechanisms of Na+ reabsorption in the early proximal tubule. The transepithelial potential difference is the difference between the potential in the lumen and the potential in blood, −4 mV. ATP, Adenosine triphosphate.

The cotransport mechanisms in the luminal membrane of the early proximal tubule are Na+-glucose (SGLT), Na+-amino acid, Na+-phosphate, Na+-lactate, and Na+-citrate. In each case, Na+ moves into the cell and down its electrochemical gradient coupled to glucose, amino acid, phosphate, lactate, or citrate, which move into the cell against their electrochemical gradients. Na+ then is extruded from the cell into blood by the Na+-K+ ATPase; glucose and the other solutes are extruded by facilitated diffusion.

There is one countertransport or exchange mechanism in the luminal membrane of the early proximal tubule, Na+-H+ exchange. The details of this mechanism are discussed in relation to acid-base physiology in Chapter 7. Briefly, hydrogen (H+) is transported into the lumen in exchange for Na+. The H+ combines with filtered HCO3, converting it to carbon dioxide (CO2) and water, which then move from the lumen into the cell. Inside the cell, CO2and water are reconverted to H+ and HCO3. The H+ is transported again by the Na+-H+ exchanger, and HCO3 is reabsorbed into the blood by facilitated diffusion. The net result of the cycle is the reabsorption of filtered HCO3. Thus, in the early proximal tubule, HCO3, not Cl, is the anion that is reabsorbed with Na+.

There is a lumen-negative potential difference across the cells of the early proximal tubule, which is created by Na+-glucose and Na+-amino acid cotransport. These transporters bring net positive charge into the cell and leave negative charge in the lumen. The other transporters are electroneutral (e.g., Na+-H+ exchange) and, therefore, do not contribute to the transepithelial potential difference.

As a result of these secondary active transport processes, the following modifications are made to the glomerular filtrate by the time it reaches the midpoint of the proximal tubule: (1) 100% of the filtered glucose and amino acids have been reabsorbed; (2) 85% of the filtered HCO3 has been reabsorbed; (3) most of the filtered phosphate, lactate, and citrate have been reabsorbed; and (4) because Na+reabsorption is coupled to each of these transport processes, it, too, has been extensively reabsorbed.

Late Proximal Convoluted Tubule

As noted, the tubular fluid that leaves the early proximal tubule differs significantly from the original glomerular filtrate. All of the filtered glucose and amino acids and most of the filtered HCO3 have been reabsorbed. Therefore, the fluid entering the late proximal tubule has no glucose or amino acids and little HCO3. Furthermore, this fluid has a high Clconcentration, although it may not be immediately evident why this is so. The Cl concentration is high because HCO3 has been preferentially reabsorbed in the early proximal tubule, leaving Cl behind in the tubular fluid. As water is reabsorbed isosmotically along with solute, the tubular fluid Cl concentration increases and becomes higher than the Cl concentration of the glomerular filtrate and of blood.

In contrast to the early proximal tubule, the late proximal tubule reabsorbs primarily NaCl (Fig. 6-21). The high tubular fluid Cl concentration is the driving force for this reabsorption, for which there are both cellular and paracellular (between cells) components.

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Figure 6–21 Cellular mechanisms of Na+ reabsorption in the late proximal tubule. The transepithelial potential difference is +4 mV. ATP, Adenosine triphosphate.

The cellular component of NaCl reabsorption is explained as follows: The luminal membrane of late proximal cells contains two exchange mechanisms, including the familiar Na+-H+ exchanger and a Cl-formate anion exchanger, which is driven by the high tubular fluid Cl concentration. The combined function of the two exchangers is to transport NaCl from the lumen into the cell. Na+ then is extruded into blood by the Na+-K+ ATPase, and Clmoves into blood by diffusion.

The paracellular component also depends on the high tubular fluid Cl concentration. The tight junctions between cells of the proximal tubule are, in fact, not tight: They are quite permeable to small solutes, such as NaCl, and to water. Thus, the Cl concentration gradient drives Cl diffusion between the cells, from lumen to blood. This Cl diffusion establishes a Cldiffusion potential, making the lumen positive with respect to blood. Na+ reabsorption follows, driven by the lumen-positive potential difference. Like the cellular route, the net result of the paracellular route is reabsorption of NaCl.

Isosmotic Reabsorption

Isosmotic reabsorption is a hallmark of proximal tubular function: Solute and water reabsorption are coupled and are proportional to each other. Thus, if 67% of the filtered solute is reabsorbed by the proximal tubule, then 67% of the filtered water also will be reabsorbed.

What solutes are included in the general term “solute”? The major cation is Na+, with its accompanying anions HCO3 (early proximal tubule) and Cl (late proximal tubule). Minor anions are phosphate, lactate, and citrate. Other solutes are glucose and amino acids. Quantitatively, however, most of the solute reabsorbed by the proximal tubule is NaCl and NaHCO3.

One of the consequences of isosmotic reabsorption has already been mentioned: The values for [TF/P]Na+ and [TF/P]osmolarity = 1.0 along the entire proximal tubule. This is remarkable because there is extensive reabsorption of both Na+ and solute (osmoles) along the proximal tubule. The reason that these ratios remain at a value of 1.0 is that water reabsorption is coupled directly to both Na+ reabsorption and total solute reabsorption.

Figure 6-22 is a schematic diagram of the mechanism of isosmotic reabsorption. A fundamental question to be asked is Does solute follow water reabsorption, or does water follow solute reabsorption? The answer is that solute reabsorption is the primary event, and water follows passively, as explained in Figure 6-22. The routes of solute and water reabsorption are shown by the dashed lines, and the circled numbers in the figure correlate with the following steps:

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Figure 6–22 Mechanism of isosmotic reabsorption in the proximal tubule. Dashed arrows show the pathways for reabsorption. See the text for an explanation of the circled numbers. πc, Peritubular capillary oncotic pressure.

1.          Na+ enters the cell across the luminal membrane by any one of the mechanisms described in the preceding sections. Because the luminal membrane is permeable to water, water follows the solute to maintain isosmolarity.

2.          Na+ is pumped out of the cell by the Na+-K+ ATPase, which is located in the peritubular or basolateral membranes. (“Basal” refers to the cell membranes facing the peritubular capillary [2a], and “lateral” refers to the cell membranes facing the lateral intercellular spaces between cells [2b].) As Na+ is pumped out of the cell, water again follows passively.

3.          The lateral intercellular space is an important route for reabsorption of solute and water. Isosmotic fluid accumulates in these spaces between the proximal tubule cells, as described in step 2. (Electron micrographs show the spaces actually widening when there is increased proximal tubule reabsorption.) This isosmotic fluid in the spaces is then acted upon by Starling forces in the peritubular capillary.

  The major Starling force driving reabsorption is the high oncotic pressure (πc) of peritubular capillary blood. Recall that glomerular filtration elevates the protein concentration (and πc) of the glomerular capillary blood; this blood leaves glomerular capillaries to become the peritubular capillary blood. The high πc is then a pressure favoring reabsorption of isosmotic fluid.

TF/P Ratios Along the Proximal Tubule

Functions of the proximal tubule can be envisioned graphically by plotting the TF/P concentration ratios for various substances as a function of length along the proximal tubule (Fig. 6-23). At the beginning of the proximal tubule (i.e., Bowman’s space), the TF/P ratio for all freely filtered substances is 1.0; because no reabsorption or secretion has yet occurred, the solute concentrations in tubular fluid equal their concentrations in plasma. Moving along the proximal tubule, because both Na+ and total solute are reabsorbed in proportion to water (i.e., isosmotic reabsorption), the values for [TF/P]Na and [TF/P]osmolarityboth remain at 1.0. Because reabsorption of glucose, amino acids, and HCO3 is proportionately greater than water reabsorption in the early proximal tubule, [TF/P]glucose, [TF/P]amino acids, and [TF/P]HCO3 fall below 1.0. Cl reabsorption is less than water reabsorption in the early proximal tubule (i.e., HCO3 is preferred over Cl); thus, [TF/P]Cl rises above 1.0. Finally, [TF/P]inulin rises steadily along the proximal tubule because inulin, once filtered, is not reabsorbed; [TF/P]inulin rises because as water is reabsorbed and inulin is left behind in the lumen, the tubular fluid inulin concentration increases. (Two thirds of the filtered water is reabsorbed along the entire proximal tubule; thus, the [TF/P]inulin ratio is approximately 3.0 at the end of the proximal tubule.)

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Figure 6–23 Changes in TF/P concentration ratios for various solutes along the proximal convoluted tubule.

Glomerulotubular Balance

Glomerulotubular balance is the major regulatory mechanism of the proximal tubule. It describes the balance between filtration (the glomerulus) and reabsorption (the proximal tubule), which is illustrated in the following example: If GFR were to spontaneously increase by 1%, the filtered load of Na+ also would increase by 1% (filtered load = GFR × [P]x). Thus, if GFR is 180 L/day and [P]Na+ is 140 mEq/L, the filtered load of Na+ is 25,200 mEq/day. An increase of 1% in the filtered load of Na+ corresponds to an increase of 252 mEq/day. If there was no accompanying increase in reabsorption, then an extra 252 mEq/day of Na+ would be excreted in the urine. Because the total amount of Na+ in ECF is only 1960 mEq (14 L × 140 mEq/L), a loss of 252 mEq/day is significant.

This loss of Na+ does not occur, however, because of the protective mechanism of glomerulotubular balance. Glomerulotubular balance ensures that a constant fraction of the filtered load is reabsorbed by the proximal tubule, even if the filtered load increases or decreases. This constant fraction (or percentage) is normally maintained at 67% of the filtered load (by now, a familiar number).

How does the glomerulus “communicate” with the proximal tubule to maintain constant fractional reabsorption? The mechanism of glomerulotubular balance involves the filtration fraction and the Starling forces in peritubular capillary blood (see Fig. 6-22). In the previous example, GFR was said to increase spontaneously by 1%, with no change in RPF. As a result, the filtration fraction (GFR/RPF) increased, meaning that a greater than usual fraction of fluid was filtered out of glomerular capillary blood. Consequently, the protein concentration and oncotic pressure of the glomerular capillary blood increased more than usual. This blood becomes the peritubular capillary blood, but now with a higher πc than usual. Because πc is the most important driving force for reabsorption of isosmotic fluid in the proximal tubule, reabsorption is increased.

In summary, increases in GFR produce increases in the filtration fraction, which leads to increased πc and increased reabsorption in the proximal tubule; decreases in GFR produce decreases in the filtration fraction, which leads to decreased πc and decreased reabsorption. The proportionality of filtration and proximal tubule reabsorption is thereby maintained (i.e., there is glomerulotubular balance).

Changes in Extracellular Fluid Volume

Glomerulotubular balance ensures that normally 67% of the filtered Na+ and water is reabsorbed in the proximal tubule. This balance is maintained because the glomerulus communicates with the proximal tubule via changes in the πc of peritubular capillary blood. However, glomerulotubular balance can be altered by changes in ECF volume. The mechanisms underlying these changes can be explained by the Starling forces in the peritubular capillaries (Fig. 6-24).

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Figure 6–24 Effects of ECF volume expansion (A) and ECF volume contraction (B) on isosmotic fluid reabsorption in the proximal tubule. Changes in Starling forces in the peritubular capillary blood are responsible for the effects. πc, Peritubular capillary oncotic pressure; Pc, peritubular capillary hydrostatic pressure.

image ECF volume expansion produces a decrease in fractional reabsorption in the proximal tubule (see Fig. 6-24A). When ECF volume is increased (e.g., by infusion of isotonic NaCl), the plasma protein concentration is decreased by dilution and the capillary hydrostatic pressure (Pc) is increased. For the peritubular capillaries, these changes result in a decrease in πc and an increase in Pc. Both of these changes in Starling forces in the peritubular capillary produce a decrease in fractional reabsorption of isosmotic fluid in the proximal tubule. A portion of the fluid that would have been reabsorbed instead leaks back into the lumen of the tubule (across the tight junction) and is excreted. This alteration of glomerulotubular balance is one of several mechanisms that aids in the excretion of excess NaCl and water when there is ECF volume expansion.

image ECF volume contraction produces an increase in fractional reabsorption in the proximal tubule (see Fig. 6-24B). When ECF volume is decreased (e.g., diarrhea or vomiting), the plasma protein concentration increases (is concentrated) and the capillary hydrostatic pressure decreases. As a result, there is an increase in πc and a decrease in Pc of peritubular capillary blood. These changes in Starling forces in the peritubular capillaries produce an increase in fractional reabsorption of isosmotic fluid. This alteration of glomerulotubular balance is a logical protective mechanism, as the kidneys are trying to restore ECF volume by reabsorbing more solute and water than usual.

In addition to the Starling forces, a second mechanism contributes to the increased proximal tubule reabsorption that occurs in ECF volume contraction. A decrease in ECF volume causes a decrease in blood volume and arterial pressure that activates the renin-angiotensin-aldosterone system. Angiotensin II stimulates Na+-H+ exchange in the proximal tubule, and thereby stimulates reabsorption of Na+, HCO3, and water. Because the angiotensin II mechanism specifically stimulates HCO3 reabsorption (along with Na+ and water), ECF volume contraction causes contraction alkalosis (metabolic alkalosis secondary to volume contraction), which is discussed in Chapter 7.

Loop of Henle

The loop of Henle comprises three segments: the thin descending limb, the thin ascending limb, and the thick ascending limb. Together, the three segments are responsible for countercurrent multiplication, which is essential for the concentration and dilution of urine. Countercurrent multiplication is discussed later in the chapter.

Thin Descending Limb and Thin Ascending Limb

The thin descending limb and the thin ascending limb of the loop of Henle are characterized primarily by their high permeability to small solutes and water. The thin descending limb is permeable to water and small solutes such as NaCl and urea. In countercurrent multiplication, water moves out of the thin descending limb, solutes move into the thin descending limb, and the tubular fluid becomes progressively hyperosmotic as it flows down the descending limb. The thin ascending limb also is permeable to NaCl, but it is impermeable to water. During countercurrent multiplication, solute moves out of the thin ascending limb without water and the tubular fluid becomes progressively hyposmotic as it flows up the ascending limb.

Thick Ascending Limb

Unlike the thin limbs, which have only passive permeability properties, the thick ascending limb reabsorbs a significant amount of Na+ by an active mechanism. Normally, the thick ascending limb reabsorbs about 25% of the filtered Na+.

The reabsorption mechanism is load-dependent (a property shared by the distal tubule). Load-dependent means that the more Na+ delivered to the thick ascending limb, the more it reabsorbs. This property of load-dependency explains the observation that inhibition of Na+ reabsorption in the proximal tubule produces smaller than expected increases in Na+ excretion. For example, a diuretic that acts in the proximal tubule typically produces only mild diuresis. Although the diuretic does indeed inhibit proximal Na+ reabsorption, some of the “extra” Na+ then delivered to the loop of Henle is reabsorbed by the load-dependent mechanism. Thus, the loop of Henle (and the distal tubule) partially offsets the proximal diuretic effect.

The cellular mechanism in the thick ascending limb is shown in Figure 6-25. As the figure shows, the luminal membrane contains a Na+-K+-2Cl- cotransporter (a three-ion cotransporter). The energy for the cotransporter is derived from the familiar Na+ gradient, which is maintained by the Na+-K+ ATPase in the basolateral membranes. There is net reabsorption of Na+, K+, and Cl in the thick ascending limb, as follows: All three ions are transported into the cell on the cotransporter; Na+ is extruded from the cell by the Na+-K+ ATPase, and Cl and K+ diffuse through channels in the basolateral membrane, down their respective electrochemical gradients. As shown in the figure, most, but not all, of the K+ that enters the cell on the three-ion cotransporter leaves the cell across the basolateral membrane. A portion of the K+, however, diffuses back into the lumen. One consequence of this recycling of K+ across the luminal membrane is that the cotransporter is electrogenic: It brings slightly more negative than positive charge into the cell. The electrogenic property of the Na+-K+-2Cl cotransporter results in a lumen-positive potential difference across the cells of the thick ascending limb. (The role of the lumen-positive potential in driving the reabsorption of divalent cations such as Ca2+ and Mg2+ is discussed later in the chapter.)

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Figure 6–25 Cellular mechanism of Na+ reabsorption in the thick ascending limb of the loop of Henle. The transepithelial potential difference is +7 mV. ATP, Adenosine triphosphate.

The thick ascending limb is the site of action of the most potent diuretics, the loop diuretics (e.g., furosemide, bumetanide, ethacrynic acid). The loop diuretics are organic acids that are related to PAH. At physiologic pH, the loop diuretics are anions that attach to the Cl-binding site of the Na+-K+-2Cl cotransporter. When diuretic is bound to the Cl-binding site, the three-ion cotransporter is unable to cycle and transport stops. At maximal dosages, loop diuretics completely inhibit NaCl reabsorption in the thick ascending limb and, theoretically, can cause excretion of as much as 25% of the filtered Na+.

The cells of the thick ascending limb are impermeable to water, clearly an unusual characteristic because virtually all other cell membranes are highly permeable to water. As a consequence of the water impermeability, NaCl is reabsorbed by the thick ascending limb, but water is not reabsorbed along with it. For this reason, the thick ascending limb also is called the diluting segment: Solute is reabsorbed, but water remains behind, diluting the tubular fluid. Proof of this diluting function is seen in the values for tubular fluid Na+ concentration and tubular fluid osmolarity. The tubular fluid that leaves the thick ascending limb has a lower Na+ concentration and a lower osmolarity than blood and, accordingly, [TF/P]Na+ and [TF/P]osmolarity< 1.0.

Distal Tubule and Collecting Duct

The distal tubule and collecting duct constitute the terminal nephron, and together they reabsorb about 8% of the filtered Na+. Like the thick ascending limb, reabsorption in the terminal nephron is load-dependent, with considerable capacity to reabsorb extra Na+ that may be delivered from the proximal tubule. The mechanism of Na+ transport in the early distal tubule differs from that of the late distal tubule and collecting duct, and each segment is discussed separately.

Early Distal Tubule

The early distal tubule reabsorbs 5% of the filtered Na+. At the cellular level, the mechanism is an Na+-Clcotransporter in the luminal membrane, the energy for which derives from the Na+ gradient (Fig. 6-26). There is net reabsorption of Na+ and Cl in the early distal tubule, which is explained as follows: Both ions enter the cell on the Na+-Cl cotransporter; Na+ then is extruded from the cell into the blood by the Na+-K+ ATPase, and Cl diffuses out of the cell through Cl channels in the basolateral membrane.

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Figure 6–26 Cellular mechanism of Na+ reabsorption in the early distal tubule. The transepithelial potential difference is −10 mV. ATP, Adenosine triphosphate.

The Na+-Cl cotransporter of the early distal tubule differs from the Na+-K+-2Cl cotransporter of the thick ascending limb in the following respects: It transports two ions (not three), it is electroneutral (not electrogenic), and it is inhibited by a different class of diuretics, the thiazide diuretics (e.g., chlorothiazide, hydrochlorothiazide, metolazone). Like the loop diuretics, the thiazides are organic acids, which are anions at physiologic pH. Thiazide diuretics bind to the Cl site of the Na+-Cl cotransporter and prevent it from cycling, thus inhibiting NaCl reabsorption in the early distal tubule.

Like the thick ascending limb, the early distal tubule is impermeable to water. Thus, it reabsorbs solute but leaves water behind, which then dilutes the tubular fluid. For this reason, the early distal tubule is called the corticaldiluting segment (“cortical” because distal tubules are in the kidney cortex). Recall that the tubular fluid entering the early distal tubule is already dilute (compared with blood) because of the function of the thick ascending limb; the early distal tubule further dilutes it.

Late Distal Tubule and Collecting Duct

Anatomically and functionally, the late distal tubule and collecting duct are similar and can be discussed together. There are two major cell types interspersed along these segments: the principal cells and theα-intercalated cells.The principal cells are involved in Na+ reabsorption, K+ secretion, and water reabsorption; the α-intercalated cells are involved in K+ reabsorption and H+ secretion. Discussion in this section focuses on Na+ reabsorption by the principal cells. (Water reabsorption, K+ reabsorption, and K+ secretion are discussed later in this chapter, and H+ secretion is discussed in Chapter 7.)

The late distal tubule and collecting duct reabsorb only 3% of the filtered Na+. Quantitatively, this amount is small when compared with the amounts reabsorbed in the proximal tubule, the thick ascending limb, and even the early distal tubule. The late distal tubule and collecting duct, however, are the last segments of the nephron to influence the amount of Na+ that is to be excreted (i.e., they make the fine adjustments of Na+ reabsorption).

The mechanism for Na+ reabsorption in the principal cells of the late distal tubule and collecting duct is shown in Figure 6-27. Rather than the coupled transport mechanisms seen in other nephron segments, the luminal membrane of the principal cells contains Na+ channels (epithelial Na+ channels, or ENaC). Na+ diffuses through these channels down its electrochemical gradient, from the lumen into the cell. Na+ then is extruded from the cell via the Na+-K+ATPase in the basolateral membrane. The anion that accompanies Na+ is mainly Cl, although the transport mechanism for Cl has not been elucidated.

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Figure 6–27 Cellular mechanism of Na+ reabsorption in the principal cells of the late distal tubule and collecting duct. The transepithelial potential difference is −50 mV. ATP, Adenosine triphosphate.

Given the critical role of the late distal tubule and collecting duct in the fine adjustments to Na+ excretion, it should not be surprising that Na+ reabsorption in these segments is hormonally regulated.Aldosterone is a steroid hormone that acts directly on the principal cells to increase Na+ reabsorption. Aldosterone is secreted by the zona glomerulosa of the adrenal cortex, is delivered to the principal cells via the circulation, and diffuses into the cells across the basolateral cell membrane. In the cell, the hormone is transferred to the nucleus, where it directs the synthesis of specific messenger RNAs (mRNAs). These mRNAs then direct the synthesis of new proteins that are involved in Na+ reabsorption by the principal cells. The aldosterone-induced proteins include the luminal membrane Na+ channel itself, the Na+-K+ ATPase, and enzymes of the citric acid cycle (e.g., citrate synthase).

Na+ reabsorption by the principal cells is inhibited by the K+-sparing diuretics (e.g., amiloride, triamterene, spironolactone). Spironolactone, a steroid and aldosterone-antagonist, prevents aldosterone from entering the nucleus of the principal cells and therefore blocks the synthesis of mRNAs and new proteins. Amiloride and triamterene bind to the luminal membrane Na+ channels and inhibit the aldosterone-induced increase in Na+ reabsorption. The K+-sparing diuretics produce only mild diuresis because they inhibit such a small percentage of the total Na+ reabsorption. However, as the name suggests, their main use is in combination with other diuretics to inhibit K+ secretion by the principal cells, as discussed in the section on K+ handling.

Water reabsorption by the late distal tubule and collecting duct is variable, as described later in this chapter. Water permeability of the principal cells is controlled by ADH, which is secreted by the posterior lobe of the pituitary gland according to the body’s need for water. When ADH levels are low or absent, the water permeability of the principal cells is low, and little, if any, water is reabsorbed along with NaCl. When ADH levels are high, aquaporin 2 (AQP2) channels are inserted in the luminal membranes of the principal cells, turning on their water permeability; thus, in the presence of ADH water is reabsorbed along with NaCl.

Regulation of Na+ Balance

Na+ and its associated anions Cl and HCO3 are the major solutes of ECF. In turn, the amount of Na+ in the ECF determines the ECF volume. Consequently, an increase in the amount of Na+ in the body leads to an increase in ECF volume, blood volume, and blood pressure; a decrease in the amount of Na+ leads to a decrease in ECF volume, blood volume, and blood pressure.

A useful concept for understanding the regulation of Na+ balance is that of effective arterial blood volume (EABV). EABV is that portion of the ECF volume contained in the arteries and is the volume “effectively” perfusing the tissues. In general, changes in ECF volume lead to changes in EABV in the same direction. For example, increases in ECF volume are associated with increases in EABV and decreases in ECF volume are associated with decreases in EABV. There are exceptions, however, such as edema, in which an increase in ECF volume is associated with a decrease in EABV (due to excessive filtration of fluid out of the capillaries into the interstitial fluid). The kidneys detect changes in EABV and, through a variety of mechanisms, direct changes in Na+ excretion that attempt to restore EABV toward normal.

The renal mechanisms that regulate Na+ excretion include sympathetic nerve activity, atriopeptin (atrial natriuretic peptide [ANP]), Starling forces in peritubular capillaries, and the renin-angiotensin-aldosterone system, as follows:

1.          Sympathetic nerve activity. Sympathetic activity is activated by the baroreceptor mechanism in response to a decrease in arterial pressure and causes vasoconstriction of afferent arterioles and increased proximal tubule Na+reabsorption.

2.          Atriopeptin (ANP). ANP is secreted by the atria in response to an increase in ECF volume and causes vasodilation of afferent arterioles, vasoconstriction of efferent arterioles, increased GFR, and decreased Na+ reabsorption in the late distal tubule and collecting ducts. Other peptides in the ANP family have similar effects to increase GFR and decrease renal Na+ reabsorption. These include urodilatin,which is secreted by the kidney, and brain natriuretic peptide (BNP), which is secreted by cardiac atrial cells and the brain.

3.          Starling forces in peritubular capillaries. The role of Starling forces has been discussed previously in the context of glomerulotubular balance. Briefly, increases in ECF volume dilute πc and inhibit proximal tubule Na+reabsorption; decreases in ECF volume concentrate πc and stimulate proximal tubule Na+ reabsorption.

4.          Renin-angiotensin-aldosterone system. The renin-angiotensin-aldosterone system is activated in response to decreased arterial pressure (i.e., decreased renal perfusion pressure). As previously described, angiotensin II stimulates Na+ reabsorption in the proximal tubule (Na+-H+ exchange), and aldosterone stimulates Na+ reabsorption in the late distal tubule and the collecting duct.

Two examples will be considered in which these mechanisms are employed to restore Na+ balance: the response of the kidneys to increased Na+ intake and the response of the kidneys to decreased Na+ intake.

Response to Increased Na+ Intake

When a person eats a high Na+ diet, because Na+ is primarily distributed in the ECF, there is an increase in ECF volume and EABV. The increase in EABV is detected, and the kidneys orchestrate an increase in Na+ excretion that attempts to return ECF volume and EABV to normal (Fig. 6-28).

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Figure 6–28 Responses to increased Na+ intake. ANP, Atriopeptin; EABV, effective arterial blood volume; ECF, extracellular fluid; GFR, glomerular filtration rate; πc, peritubular capillary oncotic pressure.

Response to Decreased Na+ Intake

When a person eats a low Na+ diet, there is a decrease in ECF volume and EABV. The decrease in EABV is detected, and the kidneys orchestrate a decrease in Na+ excretion that attempts to return ECF volume and EABV to normal (Fig. 6-29).

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Figure 6–29 Responses to decreased Na+ intake. ANP, Atriopeptin; EABV, effective arterial blood volume; ECF, extracellular fluid; GFR, glomerular filtration rate; πc, peritubular capillary oncotic pressure.