7: Regulation of Sodium and Water Excretion

• ▸ Describe how the excretion of salt and water serves the needs of the cardiovascular system.

• ▸ Name the major regulators of sodium excretion.

• ▸ Describe the systemic renin-angiotensin-aldosterone system and where its components are formed.

• ▸ State the major actions of angiotensin II.

• ▸ State the major actions of aldosterone.

• ▸ Describe the 3 major regulators of renin secretion.

• ▸ Describe the functions of the macula densa.

• ▸ Define tubuloglomerular feedback and describe the mechanism for tubuloglomerular feedback and autoregulation of glomerular filtration rate.

• ▸ State the origin of atrial natriuretic peptides, the stimulus for their secretion, and their effect on sodium reabsorption and glomerular filtration rate.

• ▸ State the 2 urinary factors that determine water excretion.

• ▸ Describe the origin of antidiuretic hormone and the major controls of its secretion.

Sodium and water excretion are regulated by an array of control systems. Seemingly every hormone, cytokine, sympathetic transmitter, and paracrine agent exerts an influence somewhere in the kidney. Given this complexity it might seem impossible to present a meaningful description of how sodium and water excretion are regulated. Certainly we cannot begin with each of the known regulated processes and predict their behavior in every situation. However, if we look at the goals of regulation—what regulation accomplishes—we can fit the various regulated processes into a framework of cooperative actions that serve the needs of the body.¹

The overriding goals of regulating sodium and water excretion are to support the requirements of the cardiovascular (CV) system. This is manifested in 2 ways: (1) the kidneys maintain a sufficient ECF volume to fill the vascular space and (2) keep the osmolality of the ECF at a level consistent with cellular health. As explained in more detail in the next section, the kidneys and the CV system work cooperatively to ensure that peripheral tissue is sufficiently perfused. An adequate circulating volume is one of the essential requirements for tissue perfusion and it is the kidneys that control this volume. Osmolality is the ratio of solute content to water content. Sodium and chloride together account for 80% of the normal extracellular solute; thus the excretion of sodium and water by the kidneys regulates osmolality in the tight range that is needed for the health of tissue cells. These goals are another way of looking at the concept of balance that we described earlier. When the kidneys alter excretion of sodium and water to preserve proper amounts in the body, they are maintaining balance.

There is a separate goal of regulation that differs from those stated above. Variations in renal blood flow (RBF) and glomerular filtration rate (GFR) are major means of regulating sodium excretion. However, the kidneys cannot change blood flow and filtration to such extreme values that they compromise the metabolic health of the kidneys or interfere with the excretion of substances other than sodium, particularly organic waste. Thus, another goal is to limit the sodium-related changes in RBF and GFR that might otherwise reach deleterious levels.

The kidneys work in partnership with the CV system. The CV system generates the pressure necessary for glomerular filtration and drives the high flow needed to maintain a stable cortical interstitial solute composition. In turn, the kidneys maintain blood volume, regulate plasma osmolality, and secrete mediators that affect both cardiac performance and vascular tone (Figure 7–1).

Blood is composed primarily of red blood cells (approximately 45%) and blood plasma (approximately 55%). The kidneys are crucial for both parts—they secrete the hormone erythropoietin, which stimulates production of red blood cells, and they regulate the extracellular fluid (ECF) volume, of which blood plasma is a significant part (see Figure 6–1). Although not exact, there is an approximate proportionality between blood volume and total ECF volume. Blood volume tends to increase and decrease as ECF volume increases and decreases due to shifts of fluid between the plasma and tissue interstitial space. Thus, maintenance of blood volume is largely a matter of maintaining ECF volume.

It is obvious why water is crucial for ECF volume, but why is sodium so important? The answer stems from 2 facts. First, ECF osmolality is tightly regulated, and second, the osmotic content of the ECF depends critically on its sodium content. We can approximate ECF osmolality as follows:

By rearrangement this expression becomes:

Furthermore, since almost all of the ECF solute is accounted for by sodium and an equivalent number of anions (mostly chloride and bicarbonate), the amount of ECF solute is approximately twice the sodium content. We can write the previous expression as:

Therefore, in the face of tightly controlled ECF osmolality (see later discussion), ECF volume varies directly with sodium content.

This raises a question—how do the kidneys know how much sodium there is in the ECF; in other words, how do they know whether to increase or minimize sodium excretion? There is no mechanism for the body to assay sodium content per se. Instead the detection of sodium content is indirect, based on a combination of assessing sodium concentration and vascular pressures. Glial cells in regions of the brain called the circumventricular organs (described later in this chapter) have sensory channels (Na_x) that respond to and act as detectors of extracellular sodium concentration. The glial cells modulate the activity of nearby neurons involved in the control of body sodium. There are also neurons in the hypothalamus containing Na_x channels that respond to the sodium concentration in the cerebrospinal fluid. Thus cells in or near the hypothalamus monitor extracellular sodium concentration.

As described above, ECF volume varies with sodium content at any given concentration. Volume affects pressures in different regions of the vasculature. Because vascular pressures are so important in regard to sodium excretion we will briefly review CV pressure regulation before describing its role in sodium excretion.

Vascular pressures are assessed by baroreceptors—cells that deform in response to changes in local intravascular pressure. Three sets of baroreceptors are important for controlling sodium excretion (Figure 7–2). These are (1) arterial baroreceptors, nerve cells that mediate the classic baroreceptor reflex, (2) cardiopulmonary baroreceptors that are also nerve cells and work in parallel with the arterial baroreceptors, and (3) intrarenal baroreceptors, which are not nerve cells. We will describe their operation shortly. Arterial baroreceptors are located in the carotid arteries and arch of the aorta and sense pressure on a beat-by-beat basis. The cardiopulmonary baroreceptors have sensory endings located in the cardiac atria and parts of the pulmonary vasculature. They, like the arterial baroreceptors, send afferent neural information to the central nervous system. They are often called low-pressure baroreceptors because they assess pressures in regions of the vascular tree where pressures are much lower than in the arteries. The cardiopulmonary baroreceptors serve as de facto blood volume detectors in the sense that pressures in the atria and pulmonary vessels rise when blood volume increases and fall when blood volume decreases.

The information from neural baroreceptors is directed to a control center for vascular pressures consisting of nuclei in the medulla oblongata (lower region of the brainstem close to where the brainstem merges with the spinal cord). Collectively these nuclei are called the vasomotor center. The vasomotor center stimulates vascular tone (vasoconstriction) throughout the body via the sympathetic nervous system. In the arterioles of the peripheral vasculature this sympathetic tone maintains total peripheral resistance, and in the peripheral venous system it maintains central venous pressure via its ability to lower the compliance of large veins. By altering venous constriction in different vascular beds the vasomotor center can shift blood volume between different organs. The vasomotor center also sends both sympathetic stimulatory and parasympathetic inhibitory signals to the heart.

Arterial baroreceptors exert tonic inhibition of the medullary vasomotor center, resulting in a brake on sympathetic drive. An increase in arterial pressure causes greater firing of the baroreceptors, more inhibition and therefore less sympathetic drive to the periphery, whereas a decrease in arterial pressure reduces firing in the baroreceptors and less inhibition, allowing more sympathetic drive. The resulting changes in vascular tone alter total peripheral resistance and help stabilize arterial pressure. The cardiopulmonary baroreceptors act in the same way, but respond, not to arterial pressure, but rather to pressures in the cardiac atria and pulmonary vessels.

The kidneys, being part of the peripheral vasculature, respond to changes in sympathetic drive and contribute to changes in total peripheral resistance. However, as we will describe later, changes in sodium excretion in response to sympathetic drive are even more important than the renal contribution to total peripheral resistance.

The amount of sympathetic drive on the heart, arterioles, and large veins changes very rapidly when pressure begins to change as a result of muscle activity or simple changes in posture. The result is to stabilize arterial pressure at its set point, the mean arterial pressure, which for most people is slightly less than 100 mm Hg. The set point is not rigidly fixed, however; it varies during the day, depending on activity and levels of excitement, and decreases approximately 20% during sleep.²

The baroreceptor/sympathetic drive system described above is very effective in maintaining arterial pressure at the set point. A major complication and area of uncertainty lies in the long-term control of blood pressure. The question of “what sets the set point” cannot be answered with confidence.³ However, it is clear that malfunction in the renal handling of sodium or malfunction in renal signaling can lead to hypertension. Any consideration of the long-term control of blood pressure must include renal actions.

Sympathetic Stimulation

Many signals exert control over sodium excretion. Given the preceding discussion, it should be clear that most signals directly or indirectly relate to events in the CV system. The major cardiovascular-related signaling systems are the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS).

The sympathetic nervous system is capable of an emergency “fight-or-flight” response, but its normal operation is a differential modulation of various functions within different organs. The vasculature and tubules of the kidney are innervated by postganglionic sympathetic neurons that release norepinephrine. In most regions of the kidney, norepinephrine is recognized by α-adrenergic receptors. In the renal vasculature activation of α₁-adrenergic receptors causes vasoconstriction of afferent and efferent arterioles. This reduces RBF and GFR.

Quite obviously, GFR is a crucial determinant of sodium excretion. Without filtration there is no excretion. However, except in body emergencies such as hypovolemic shock, GFR is kept within rather narrow limits due to autoregulatory processes detailed later. Thus although neural control does affect GFR, this component of sympathetic control is probably less important in normal circumstances than its effect on sodium reabsorption. Neural control of the renal vasculature is exerted primarily on blood flow in the cortex, allowing preservation of medullary perfusion even when cortical blood flow is reduced.

The proximal tubule epithelial cells are innervated by α₁- and α₂-adrenergic receptors. Stimulation of these receptors in the proximal tubule by norepinephrine activates both components of the main transcellular sodium reabsorptive pathway, that is, the sodium–hydrogen antiporter NHE3 in the apical membrane and the Na-K-ATPase in the basolateral membrane. This pathway is activated in situations in which it is appropriate to reduce sodium excretion, for example, volume depletion or low blood pressure.

The effects of sympathetic stimulation on cells in the distal nephron are less straightforward. Other agonists are coreleased with norepinephrine and affect other receptor types (eg, ATP acting on purinergic receptors). However, the overall outcome of sympathetic stimulation of the kidney is clearly reduced sodium excretion.

The Renin-Angiotensin System

Even more important to the control of sodium excretion than sympathetic input by itself is the renin-angiotensin system. We will soon see that the renin-angiotensin system and the sympathetic nervous system are interacting systems and cannot be viewed as separate controllers. What is traditionally described as the renin-angiotensin system is really a set of renin-angiotensin systems. There is both a systemic circulating renin-angiotensin system, and separate organ specific renin-angiotensin systems in many tissues, including, but not limited to, the heart, sex organs, brain, and the kidneys. In addition, the circulating renin-angiotensin system is intimately involved in controlling the steroid hormone aldosterone. The circulating renin-angiotensin system can appropriately be called the RAAS.

Renin-angiotensin systems are peptide-signaling systems that regulate multiple processes in the kidney and elsewhere. They consist of a protein substrate (angiotensinogen), the enzyme renin that splits off a 10 amino acid peptide (angiotensin I) from angiotensinogen, several additional enzymes that split angiotensin I into smaller peptides, and finally receptors for the peptides that activate cellular actions upon binding. The most important of these smaller peptides is the 8 amino acid peptide angiotensin II (AII). It is formed from angiotensin I by the action of angiotensin converting enzyme (ACE). AII is a mediator of multiple effects in the kidneys and elsewhere.

In the circulating RAAS, angiotensinogen is synthesized in the liver (Figure 7–3). Plasma angiotensinogen levels are normally high and do not limit the production of AII. Furthermore, ACE, which is expressed on the endothelial surfaces of the vascular system, particularly the pulmonary vessels, avidly converts most of the angiotensin I into AII. Therefore, the major determinant of circulating AII is the amount of renin available to form angiotensin I. As outlined in Chapter 1 and shown in Figure 7–4, renin is produced by the juxtaglomerular (jg) apparatus. The renin-secreting cells are located in the late afferent arteriole just before the glomerulus, and are referred to as juxtaglomerular granular cells (because renin can be visualized as secretory granules). The secretion of renin by the granular cells is under the control of 3 primary regulators described below.

KEY ACTIONS OF AII

Vasoconstriction—

AII is a potent vasoconstrictor, acting on the vasculature of many peripheral tissues, the effect of which is to raise arterial pressure. It also vasoconstricts both cortical and medullary vessels in the kidney. This reduces total RBF and reduces GFR, thus decreasing the filtered load of sodium. A number of drugs for the treatment of hypertension either reduce the production of AII (ACE inhibitors) or block the peripheral receptors for AII (see later discussion).

Stimulation of sodium tubular reabsorption—

AII stimulates sodium reabsorption in both the proximal tubule and distal nephron. In the proximal tubule it stimulates the same transcellular transport pathway as does norepinephrine, namely the NHE3 sodium/hydrogen antiporter in the apical membrane and the Na-K-ATPase in the basolateral membrane. In the distal tubule and connecting tubule, it stimulates the activity of sodium/chloride symporters and sodium channels (ENaC) that reabsorb sodium.

Stimulation of the CNS: salt appetite, thirst, and sympathetic drive—

AII stimulates behavioral actions in response to fluid loss that increase salt appetite and thirst. AII acts on the circumventricular organs in the brain that are described later in this chapter. These function as detectors of many substances in the blood and convey information to various areas of the brain. In situations of volume depletion and low blood pressure, when circulating levels of AII are high, a key effect, in addition to vascular and tubular actions is increased thirst and salt appetite. These pathways also increase sympathetic drive.

Stimulation of aldosterone secretion—

Aldosterone is a major stimulator of sodium reabsorption in the distal nephron, that is, regions of the tubule beyond the proximal tubule and loop of Henle. Aldosterone-stimulated sodium retention is an effector system that is vital in correcting prolonged reductions in body sodium, blood pressure, and volume. We focus here on the role of aldosterone in sodium reabsorption, but aldosterone has many other important actions, including stimulation of potassium excretion and acid excretion (see Chapters 8 and 9).

The most important physiological factor controlling secretion of aldosterone is the circulating level of AII, which stimulates the adrenal cortex to produce aldosterone. This targets the distal nephron to increase sodium reabsorption and thus increase total body sodium and blood volume to produce a long-term correction to total body sodium content and mean blood pressure.

The main cellular targets of aldosterone are the principal cells in the cortical connecting tubule and principal cells in the cortical collecting duct. An action on this late portion of the nephron is what one would expect for fine-tuning the output of sodium, because more than 90% of the filtered sodium has already been reabsorbed by the time the filtrate reaches the collecting-duct system.

As a molecule, aldosterone has enough lipid character to freely cross principal cell membranes, after which it combines with mineralocorticoid receptors in the cytoplasm. After being transported to the nucleus, the receptor acts as a transcription factor that promotes gene expression of specific proteins. The effect of these proteins is to increase the activity or number of luminal membrane sodium channels (ENaCs) and basolateral membrane Na-K-ATPase pumps. Thus, the 2 major elements in transcellular sodium reabsorption are stimulated (Figure 7–5).

The percentage of sodium reabsorption dependent on the influence of aldosterone is approximately 2% of the filtered load. Thus, all other factors remaining constant, in the complete absence of aldosterone, a person would excrete 2% of the filtered sodium, whereas in the presence of high plasma concentrations of aldosterone, virtually no sodium would be excreted. Two percentage of the filtered sodium may seem trivial but is actually a significant amount because so much sodium is filtered:

Thus, aldosterone controls the reabsorption of 0.02 × 25,200 mmol/day = 504 mmol/day. In terms of sodium chloride, the form in which most sodium is ingested, this amounts to the control of almost 30 g NaCl/day, an amount considerably more than the average person consumes. Therefore, by control of the plasma concentration of aldosterone between minimal and maximal, the excretion of sodium can be finely adjusted to the intake so that total body sodium remains constant.

Aldosterone also stimulates sodium transport by other epithelia in the body, namely, sweat and salivary ducts and the intestine. The net effect is the same as that exerted on the kidney: movement of sodium from lumen to blood. Thus, aldosterone is an all-purpose stimulator of sodium retention.

AII produced by the circulating RAAS system is the main stimulator of aldosterone secretion. Since levels of AII are controlled by renin, this emphasizes the importance of renin in the control of sodium reabsorption. Both renin and aldosterone have relatively short plasma half-lives (∼15 minutes), whereas the half-life of AII is very short (<1 minute). Therefore, prolonged action of aldosterone requires the continuous stimulation of renin secretion.

Although we have emphasized the importance of AII as a stimulator of aldosterone secretion, there are other aldosterone controllers that play significant roles also. A complication in the operation of the RAAS is the role of AII and aldosterone in potassium and acid excretion. An elevated plasma potassium concentration is a stimulator of aldosterone secretion, and depletion of potassium is an inhibitor and may in some cases counteract the stimulating effect of AII. We will address this topic in Chapter 8. The atrial natriuretic factors (discussed later) also inhibit aldosterone secretion.

From all of the preceding discussion it should be clear that AII is a hugely important agent to preserve blood volume and blood pressure. It does so by retaining sodium, both through its own actions and via aldosterone, and by causing general vasoconstriction. The major actions of AII that lead to sodium retention and increased blood pressure are shown in Table 7–1. We will describe its influence on potassium excretion in Chapter 8.

Control of the circulating RAAS—

The activity of the circulating RAAS is governed by the amount of renin secreted by the granular cells of the jg apparatus. There are 3 major controllers of renin secretion. The first controller is sympathetic input. Norepinephrine released from postganglionic sympathetic neurons acts on β₁-adrenergic receptors in the granular cells. This activates a c-AMP-mediated pathway that causes the release of renin. The granular cells are quite sensitive to norepinephrine and respond to low levels of sympathetic activity that may have minimal direct effect on the renal vasculature or sodium transport. As described earlier, sympathetic drive is highly influenced by feedback detected by vascular pressures. Low pressures lead to increased sympathetic drive to the granular cells and increased release of renin.

The second controller of renin secretion is pressure in the afferent arteriole. The granular cells not only respond to vascular pressures indirectly via adrenergic stimulation, they respond directly to changes in afferent arteriolar pressure. When pressure in the afferent arteriole decreases, renin production increases. Except in cases of major renal arterial blockage, pressure in the arteriolar lumen at the granular cells is close to systemic arterial pressure and changes in parallel with it. Because the granular cells respond to vascular pressure, they are acting as baroreceptors. In fact, the granular cells are the intrarenal baroreceptors mentioned previously. Even though they are not neurons and do not send afferent feedback, they are baroreceptors nevertheless. Consider what happens when arterial pressure drops. The intrarenal baroreceptors (the granular cells) sense the drop in pressure and increase their secretion of renin. Simultaneously, the drop in pressure is also sensed by the arterial baroreceptors in the carotid arteries and aorta. The fall in their afferent signaling allows the vasomotor center to increase sympathetic drive to the granular cells, resulting in a huge combined stimulation of renin secretion.

The third controller of renin release originates from another component of the jg apparatus; namely the macula densa. The operation of the macula densa is somewhat complicated, but serves as a fascinating example of negative feedback in biological systems.

Functions of the Macula Densa

The macula densa is a detection system and initiator of feedback that helps regulate (1) renin secretion and (2) GFR. Regulation of GFR by the macula densa is called tubuloglomerular feedback (TG feedback), meaning from the tubule to the glomerulus. TG feedback is a component of the autoregulation of GFR described in Chapter 2. How do these 2 feedback systems work? The macula densa is located at the end of the loop of Henle where the tubule passes between the afferent and efferent arterioles of Bowman's capsule. It is able to sense (1) flow and (2) salt content in the tubular lumen that are the net result of filtration and reabsorption in tubular elements preceding it, that is, it senses “everything done so far.” Flow is sensed by cilia that project into the tubular lumen from macula densa cells. Bending of the cilia initiates intracellular signaling that leads to release of paracrine mediators. Tubular sodium chloride is sensed by uptake via Na-K-2Cl multiporters whose action changes ionic concentrations within the macula densa cells and also causes release of paracrine mediators. When tubular flow and sodium content are high it is as if “the body has too much sodium” and “GFR is too high.” The mediators released by the macula densa reduce the secretion of renin (thereby allowing more sodium excretion) and decrease GFR (restoring GFR to an appropriate level). The immediate mediator is ATP, which is converted extracellularly to adenosine. One or both bind to purinergic receptors on the nearby granular cells. This has the effect of increasing intracellular calcium and reducing the release of renin.⁴ In turn, the reduction in renin secretion reduces the levels of AII and allows the kidneys to excrete more of the filtered sodium. Simultaneously, the adenosine binds to purinergic receptors on afferent arteriole smooth muscle. The subsequent rise in calcium in these cells stimulates contraction, thus reducing pressure and flow through the glomerular capillaries and reducing GFR.

What happens in the opposite case, that is, when there is low flow and low salt content flowing past the macula densa? Now “the body has too little sodium” and “GFR is too low.” This initiates the release of different mediators, specifically prostaglandins (eg, PGE₂) and nitric oxide (NO). In the granular cells the prostaglandins stimulate or prolong the lifetime of c-AMP, thereby stimulating the release of renin. The now-activated RAAS reduces sodium excretion. In the afferent arteriole NO is a dilator of smooth muscle. The effect is to raise flow and pressure in the glomerular capillaries, and restore GFR to an appropriate level. The operation of the macula densa in feedback control of the RAAS and GFR autoregulation is shown in Figure 7–6.

The TG feedback mechanism helps autoregulate GFR in individual nephrons, keeping filtration within an acceptable range while allowing other controllers to modify how much of the filtered sodium is reabsorbed. TG feedback doesn't initiate overall changes in GFR or prevent changes; rather, it dampens changes originating from other signaling systems, for example, sympathetic control, so that GFR doesn't vary “too much.” Keep in mind that changes in GFR affect not only sodium, but every other filtered substance, and the kidneys have to maintain appropriate filtration in order to avoid deleterious effects on the excretion of those other substances.

Finally, descriptions of the RAAS quite naturally focus on its activation and subsequent stimulation of sodium reabsorption. This is because retention of sodium is crucial during hypovolemic emergencies and in unusual circumstances when dietary sodium is not plentiful. However, on typical Western diets the salt content of meals is often in excess, and it is imperative to let the kidneys excrete salt loads promptly. The main way this is accomplished is by decreasing the activity of the RAAS. Figure 7–7 summarizes control of renin secretion.

Modulation of Sodium excretion: Dopamine

The major regulators described in the preceding sections, that is, sympathetic input, AII and aldosterone all serve to increase sodium reabsorption. Another major regulator is dopamine, but its action is different—namely it inhibits sodium reabsorption. Dopamine is generally known as a neurotransmitter in the central nervous system that participates in multiple functions including the control of body movement. The dopamine that acts in the kidney is not released from neurons; rather it is synthesized in proximal tubule cells from the precursor l-DOPA (the same substance employed in the treatment of Parkinsonism). l-DOPA is taken up from the renal circulation and glomerular filtrate and converted to dopamine in the proximal tubule epithelium, and then released to act in a paracrine manner on nearby cells. Although the signaling path is not clear, it is known that increases in sodium intake lead to increased production of intrarenal dopamine. Dopamine has 2 actions, both of which reduce sodium reabsorption. First, it causes retraction of NHE antiporters and Na-K-ATPase pumps into intracellular vesicles, thereby reducing transcellular sodium reabsorption. Second, it reduces the expression of AII receptors, thereby decreasing the ability of AII to stimulate sodium reabsorption. Therefore dopamine, in combination with sympathetic input and the RAAS, comprises a true push-pull system that exerts bidirectional control over sodium reabsorption.

Other Regulators and Influences on Sodium Excretion

Changes in GFR, sympathetic input, the RAAS and dopamine are the most important means of regulating sodium excretion. As should be clear from the previous discussion, these processes influence each other, together yielding a final rate of sodium excretion that meets the goals outlined in the beginning of this chapter. There are still many other signals and processes that contribute to regulation, some of which are outlined below.

ADH

We previously described the role of ADH in regulating the reabsorption of water in the collecting duct system and will address this topic again later in the chapter. ADH also plays a direct role in regulating sodium excretion. When ADH binds to V2 receptors in tubular cells, it increases the production of c-AMP. This results in increased activity of the NKCC multiporter in the thick ascending limb and increased sodium channel (ENaC) presence in principal cells of the distal nephron, thereby increasing the uptake of sodium that, in both regions, is actively transported into the interstitium by the Na-K-ATPase. Interestingly, in the distal nephron the mechanism proceeds, not by moving ENaCs into the membrane, but rather by decreasing their removal and degradation. As mentioned in Chapter 4, transport proteins have a finite lifetime in membranes before being degraded. A process that slows degradation of a transport protein has the same effect as increasing the expression and insertion of the protein.

GLOMERULOTUBULAR BALANCE

Glomerulotubular balance (not to be confused with TG feedback described previously) refers to the phenomenon whereby sodium reabsorption in the proximal tubule varies in parallel with the filtered load, such that approximately two thirds of the filtered sodium is reabsorbed even when GFR varies. As an example, consider what happens when GFR rises 20%. The filtered load rises 20%, but the absolute amount of sodium reabsorbed also rises 20%, and the fractional reabsorption remains at two thirds. Note that although two thirds of the larger filtered load is reabsorbed, the remaining one third of the larger filtered load is not reabsorbed, and the increased GFR still increases the absolute amount of sodium passed on to elements beyond the proximal tubule. The mechanism by which reabsorption varies with filtered load appears to be via mechanotransduction by the microvilli on the apical surface of the proximal tubule cells, similar in principle to mechanotransduction by primary cilia in the macula densa. As flow changes, the amount of bending of the microvilli changes, and this is converted by cellular mechanisms into changes in transport. Be aware that two thirds is only a rough approximation. The various controllers of sodium excretion operating in the proximal tubule are still functioning. In other words, sometimes exactly two thirds of the filtered load is reabsorbed. At other times, it might be somewhat more or somewhat less.

PRESSURE NATRIURESIS AND DIURESIS

Because the kidneys are responsive to arterial pressure, there are situations in which elevated blood pressure can lead directly to increased excretion of sodium, particularly if the body contains excess fluid. This phenomenon is called pressure natriuresis, and because natriuresis is usually accompanied by water (see later discussion), it is often called pressure diuresis. This is an intrarenal phenomenon, not requiring external signaling. However, external signals normally override pressure natriuresis, as occurs, for example, in aerobic exercise when arterial pressure is somewhat increased, but sodium excretion is decreased. In addition, a common cause of hypertension is renal pathology that inappropriately activates the intrarenal RAS. In these cases the elevated arterial pressure fails to increase sodium excretion.

NATRIURETIC PEPTIDES

Several tissues in the body synthesize members of a hormone family called natriuretic peptides, so named because they promote excretion of sodium in the urine. Key among these are atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP; named as such because it was first discovered in the brain). The main source of both natriuretic peptides is the heart. The natriuretic peptides have both vascular and tubular actions. They relax the afferent arteriole, thereby promoting increased filtration, and act at several sites in the tubule. They inhibit release of renin, inhibit the actions of AII that normally promote reabsorption of sodium, and act in the medullary collecting duct to inhibit sodium absorption. The major stimulus for increased secretion of the natriuretic peptides is distention of the atria, which occurs during plasma volume expansion. This is probably the stimulus for the increased natriuretic peptides that occurs in persons on a high-salt diet. Although most experts assume that these peptides play some physiological role in the regulation of sodium excretion in this and other situations in which plasma volume is expanded, it is not currently possible to quantitate precisely their contribution, although it is surely less than aldosterone. These peptides are greatly elevated in patients with heart failure and can serve as diagnostic indicators.

Summary of the Control of Sodium Excretion

Sodium excretion is controlled by an array of interacting control systems relating to the CV system, the most important of which are sympathetic outflow, the RAAS system and dopamine (Figure 7–8). Some controllers increase sodium excretion; others decrease it. Intrarenal signaling is bidirectional. The main goal of control is to preserve a total mass of sodium in the extracellular fluid that maintains appropriate osmotic content for the CV system. The important detection systems include baroreceptors in various locations and cells in the CNS that detect sodium concentration. Neural baroreceptors respond to pressures in the arterial system, and in the heart and pulmonary circuit, thereby providing information about volume, whereas intrarenal baroreceptors give additional information about arterial pressure. Control systems alter vascular resistances and the activity of renal transport proteins. Although changes in GFR contribute to the regulation of sodium excretion, changes in rates of sodium reabsorption are more important. Sodium deficits elicit strong responses to conserve sodium, mostly by increasing tubular reabsorptive processes in all nephron segments. Excess sodium is excreted primarily by decreasing tubular reabsorption. Under all circumstances, even with considerable excess dietary sodium, the vast majority of filtered sodium (over 98%) is reabsorbed, but because so much sodium is filtered, even small adjustments in reabsorption result in large cumulative changes in total body sodium.

Water excretion, as with sodium excretion, is regulated in partnership with the CV system. Central goals in regulating both salt and water excretion are to (1) preserve vascular volume and (2) maintain plasma osmolality at a level that is healthy for tissue cells. The main regulators of water excretion, not surprisingly, relate to osmolality and volume.

Quantitatively, renal water excretion is determined by 2 values: (1) the amount of solute in the urine and (2) the osmolality of the urine.

Excreted solute consists mostly of organic waste and excess electrolytes. In a given metabolic state, the rate of organic waste excretion is more or less constant, and is not altered for purposes of controlling water excretion. Electrolyte excretion is highly regulated, but more to achieve balance of individual substances like sodium and potassium than to control water excretion per se. Given that solute excretion is so variable, the main way the body controls water excretion in normal circumstances is to control urine osmolality. In other words, given a certain amount of solute that is excreted, the body controls the amount of water accompanying it by controlling urine osmolality.

When the body excretes urine that is more dilute than plasma (osmolality below 285 mOsm/kg H₂O), the body is excreting “free water” (like adding pure water to otherwise isosmotic urine). Conversely, when the excreted urine is more concentrated than plasma, there is “negative free water” excretion. It is as if the body has reclaimed pure water from otherwise isosmotic urine.

As we already know from Chapter 6, the kidneys first generate hypo-osmotic tubular fluid in the loop of Henle. Then, as the fluid subsequently flows through the collecting duct system, variable amounts of water are reabsorbed by allowing the tubular fluid to equilibrate to varying degrees with the surrounding interstitium. The final osmolality, and hence final volume, depends on the peak medullary osmolality and how closely the tubular osmolality approaches that value. We also know that equilibration with the interstitium is a function of water permeability in the collecting ducts under the control of the hormone antidiuretic hormone (ADH). Therefore the regulation of water excretion, that is independent of solute excretion, focuses on controls over ADH secretion.

ADH (also called arginine vasopressin because of its role as a vasoconstrictor) is a small peptide (9 amino acids) synthesized by neurons in the hypothalamus. The cell bodies are located in the supraoptic and paraventricular nuclei of the hypothalamus. Their axons extend downward to the posterior pituitary gland, from which ADH is released into the blood. There is normally a moderate rate of ADH secretion, allowing considerable water reabsorption in the renal collecting ducts and resulting in urine that is more concentrated than plasma. ADH secretion can increase or decrease from this level, giving the control system a bidirectional responsiveness. And because the collecting ducts are very sensitive to ADH, this allows the body to control water excretion rate over a very wide range. There are many sources of synaptic input to the ADH-secreting neurons. The most important signals originate in osmoreceptors and CV baroreceptors.

Osmoreceptor Control of ADH Secretion

Plasma osmolality is one of the most tightly regulated variables in the body. Plasma osmolality is set mainly by the ratio of ECF sodium (plus its associated anions) to water. Other solutes (eg, glucose and potassium) make some contribution, but those other solutes are regulated for reasons other than plasma osmolality. Thus, except under unusual circumstances such as severe hyperglycemia, variations in plasma osmolality mostly reflect variations in sodium concentration. If the body keeps the inputs and outputs of sodium and water matched in lock step, osmolality remains constant. But inputs are often not matched. The major effect of gaining or losing water or salt without corresponding changes in the other is a change in the osmolality of the body fluids. When osmolality deviates from normal, strong reflexes come into play to change ADH secretion, and thus change the excretion of water.

Key receptors that initiate reflexes controlling ADH secretion are osmoreceptors, neurons responsive to changes in osmolality. Most osmoreceptors are located in tissues surrounding the third cerebral ventricle. These tissues, along with those surrounding the fourth cerebral ventricle, are known collectively as circumventricular organs. Although the vast majority of cerebral tissue is separated from direct contact with substances in the blood by impermeability of the vascular endothelium, the circumventricular organs contain fenestrated capillaries. The fenestrations allow rapid adjustment of local interstitial composition when plasma composition changes. Osmoreceptors shrink and swell in response to changes in local osmolality. This affects the activity of stretch-sensitive channels in their membranes, which thereby transduce osmotic changes into electrical signals. The hypothalamic cells that synthesize ADH receive synaptic input from osmoreceptors in the circumventricular organs. Via these connections, an increase in osmolality increases the rate of ADH secretion. In turn, this causes water permeability of the collecting ducts to increase, water reabsorption rises, and a small volume of concentrated (hyperosmotic) urine is excreted. By this means, relatively less filtered water than solute is excreted, which lowers body fluid osmolality toward normal. Conversely, decreased osmolality inhibits ADH secretion. For example, when a person drinks pure water, the excess water lowers the body fluid osmolality, which inhibits ADH secretion. As a result, water permeability of the collecting ducts becomes low, little water is reabsorbed from these segments, and a large volume of dilute (hypo-osmotic) urine is excreted. In this manner, the excess water is rapidly eliminated and plasma osmolality is increased (Figure 7–9).

Earlier, we mentioned specific sodium-detecting glial cells located in the circumventricular organs and hypothalamic neurons that contain Na_x channels. The amount of ADH that is secreted at a given level of plasma osmolality is modulated by information about sodium concentration detected in these cells. Most of the time, the influence on ADH secretion from sodium-detecting cells and osmoreceptors is synergistic (ie, both high sodium concentration and high osmolality stimulate ADH).

The osmoreceptor-ADH system is very sensitive, responding to an osmolality change of only 1 or 2 mOsm/kg. However, common perturbations are often a good deal greater than this. For example, if a 70 kg person consumes 1 L of pure water, ECF osmolality is reduced by approximately 7 mOsm/kg. And exercise for several hours on a warm day can increase ECF osmolality by 10 mOsm/kg or more. Such routine perturbations result in strong ADH responses that remain active until osmolality returns to its previous value. ADH has a plasma half-life of only a few minutes, so prolonged stimulation of water permeability in the kidneys requires continuous stimulation of the ADH-secreting neurons.

Baroreceptor Control of ADH Secretion

There is another major influence on ADH secretion. This originates in systemic baroreceptors (the same ones that influence sympathetic drive to the kidneys). A decreased extracellular volume or major decrease in arterial pressure reflexively activates increased ADH secretion. The response is mediated by neural pathways originating in cardiopulmonary baroreceptors, and if arterial pressure decreases, from arterial baroreceptors.

Decreased CV pressures cause less firing by the baroreceptors, which relieves inhibition of stimulatory pathways and results in more ADH secretion. In effect, the low CV pressures are interpreted as low volume, and the response of increased ADH appropriately serves to minimize loss of water (Figure 7–10). Conversely, baroreceptors are stimulated by increased CV pressures, interpreted as excess volume, and this causes inhibition of ADH secretion. The decrease in ADH results in decreased reabsorption of water in the collecting ducts, and more excretion. The adaptive value of these baroreceptor reflexes is to help stabilize ECF volume and, hence, blood pressure.

There is a second adaptive value to this reflex: Large decreases in plasma volume, as might occur after a major hemorrhage, elicit such high concentrations of ADH—much higher than those needed to produce maximal antidiuresis—that the hormone is able to exert direct vasoconstrictor effects on arteriolar smooth muscle. The result is increased total peripheral resistance, which helps restore arterial blood pressure independently of the slower restoration of body fluid volumes. Renal arterioles and mesangial cells also participate in this constrictor response, and so a high plasma concentration of ADH, quite apart from its effect on water permeability and sodium reabsorption in the distal nephron, promotes retention of both sodium and water by lowering GFR.

We have described 2 different major afferent pathways controlling the ADH-secreting hypothalamic cells: 1 from baroreceptors and 1 from osmoreceptors. These hypothalamic cells are, therefore, true integrators, whose activity is determined by the total synaptic input to them. Thus, a simultaneous increase in plasma volume and decrease in body fluid osmolality causes strong inhibition of ADH secretion. Conversely, a simultaneous decrease in plasma volume and increase in osmolality produces very marked stimulation of ADH secretion. However, what happens when baroreceptor and osmoreceptor inputs oppose each other (eg, if plasma volume and osmolality are both decreased)? In general, because of the high sensitivity of the osmoreceptors, the osmoreceptor influence predominates over that of the baroreceptors when changes in osmolality and plasma volume are small to moderate. However, a dangerous reduction in plasma volume will take precedence over decreased body fluid osmolality in influencing ADH secretion; under such conditions, water is retained in excess of solute even though the body fluids become hypo-osmotic (for the same reason, plasma sodium concentration decreases). In essence, when blood volume reaches a life-threatening low level, it is more important for the body to preserve vascular volume and thus ensure an adequate cardiac output than it is to preserve normal osmolality.

The cells that synthesize ADH in the hypothalamus also receive synaptic input from many other brain areas. Thus, ADH secretion and, hence, urine flow can be altered by pain, fear, and a variety of other factors, including drugs such as alcohol, which inhibits ADH release. However, this complexity should not obscure the generalization that ADH secretion is determined over the long term primarily by the states of body fluid osmolality and plasma volume.

Figure 7–11 shows the major factors known to control renal sodium and water excretion in response to severe sweating. Sweat is mainly a hypo-osmotic salt solution. Therefore, sweating causes both a decrease in ECF volume and an increase in body fluid osmolality. This strongly activates the RAAS and secretion of ADH, leading to increased reabsorption of both sodium and water. These responses interact with each other. First, the high levels of ADH aid in the reabsorption of sodium. Second, reducing sodium excretion reduces the osmotic load in the urine that obligates water to accompany it

THIRST AND SALT APPETITE

Deficits of salt and water cannot be corrected by renal conservation, and ingestion is the ultimate compensatory mechanism. The subjective feeling of thirst, which drives one to obtain and ingest water, is stimulated both by reduced plasma volume and by increased body fluid osmolality. The adaptive significance of both is self-evident. Note that these are precisely the same changes that stimulate ADH production, and the receptors—osmoreceptors and the nerve cells that respond to the CV baroreceptors—that initiate the ADH-controlling reflexes are near those that initiate thirst. The thirst response, however, is significantly less sensitive than the ADH response.

There are also other pathways controlling thirst. For example, dryness of the mouth and throat causes profound thirst, which is relieved by merely moistening them. Also, when animals such as the camel (and humans, to a lesser extent) become markedly dehydrated, they will rapidly drink just enough water to replace their previous losses and then stop. What is amazing is that when they stop, the water has not yet had time to be absorbed from the gastrointestinal tract into the blood. Some kind of metering of the water intake by the gastrointestinal tract has occurred, but its nature remains a mystery. Neural afferents from the pharynx and upper gastrointestinal tract are likely to be involved.

Congestive Heart Failure and Hypertension: Cardiovascular Pathologies That Involve the Kidneys

We conclude this chapter with a brief description of congestive heart failure and hypertension, 2 very common pathologies, particularly in the geriatric population. They both directly or indirectly involve the kidneys and illustrate the connections between the renal and CV systems, not only in normal function, but pathology as well. This is brought home by the fact that primary therapies for both pathologies employ drugs that alter renal function. In congestive heart failure and in most cases of hypertension, the perturbed function lies in inappropriate signaling to or within the kidneys rather than pathology of renal transport mechanisms per se.

Congestive heart failure occurs when cardiac muscle is weakened (for any of several reasons) and the heart becomes less effective as a pump. It cannot increase cardiac output to meet the demands of exercise and, more importantly, can only provide adequate resting cardiac output in the presence of excessive neurohumoral drive (something like a car with a sputtering engine that can only keep up speed when the accelerator is pushed to the floor). The neurohumoral drive is characterized by high levels of renin, AII, aldosterone, catecholamines, and ADH. These signals stimulate the heart and cause the kidneys to retain sodium and water, which in principle should assist the heart by raising filling pressures. However, the increased fluid volume leads to edema in the lungs, and later, edema in peripheral tissues, which is why this is called congestive heart failure. Because of the high fluid volume, atrial pressures sensed by the cardiopulmonary baroreceptors are high. The high atrial pressures should lead to decreased ADH secretion and decreased sympathetic drive to the kidneys.⁵ Instead, sympathetic activity and ADH are increased, and the kidneys operate at a new set point in which normal sodium and water excretion occur only when there is excessive body fluid volume. Furthermore the plasma concentration of sodium actually falls, producing hyponatremia, because water retention exceeds sodium retention. If fluid volume is somehow restored to normal levels, renal excretion of sodium drops to very low levels. Another characteristic of congestive heart failure is high levels of natriuretic peptides. This is an appropriate response to the high atrial pressures and partially counteracts the sodium-retaining signals to the kidneys, but does not restore sodium output to a level that would occur in a healthy person who transiently developed a high fluid volume (a volume that exists chronically in the heart failure patient). The high fluid volume of congestive heart failure is deleterious to pulmonary function and over time often leads to structural changes in the heart (dilation) that only exacerbates the defective pumping. Therapy for congestive heart failure includes drugs that directly or indirectly interfere with sodium-retaining processes in the kidneys. Diuretics directly increase sodium excretion. Drugs that inhibit the generation of AII (ACE inhibitors) or block the actions of angiotensin II (angiotensin receptor antagonists) reduce the signals that cause sodium retention.

Hypertension is both more common than congestive heart failure, and more mysterious. In some cases the reason for the elevated blood pressure is clear. For example, renal glomerular disease often leads to inappropriate release of renin with subsequent increases in AII, aldosterone, collecting-tubule sodium reabsorption, and finally an increase in blood pressure. A tumor of the adrenal cortex can lead to excess production of aldosterone and increases in blood pressure; or a specific gain of function mutation in the sodium reabsorptive mechanism in the collecting duct also leads to excess sodium reabsorption and profound hypertension. These are all examples of secondary hypertension, that is, hypertension secondary to a known cause, whereas the vast majority of cases are called primary or essential hypertension, in which the cause is unknown. Research indicates that the intrarenal RAS is activated in essential hypertension, but there is debate whether this is the root of the problem or the result of inappropriate sympathetic stimulation. It is interesting that, unlike congestive heart failure, essential hypertension is not characterized by obvious signs of sodium retention such as swelling of the feet. However, current therapy employs most of the same drugs used to induce sodium loss, that is, diuretics, ACE inhibitors, AII receptor blockers and aldosterone receptor blockers. At first glance this may seem paradoxical, because it is natural to ascribe the effectiveness of these agents to their reduction of sodium retention. But we remind the reader that the RAS system has direct vascular actions, and inhibition of changes in peripheral resistance and vascular stiffness may account for their value. In addition, many drugs exhibit beneficial effects that cannot be accounted for on the basis of their known mechanisms of action, or the drugs are effective only with prolonged use.

• Sodium and water excretion are regulated primarily to meet the needs of the CV system via preservation of vascular volume and plasma osmolality.

• Extracellular volume varies directly with sodium content.

• Baroreceptors, at various sites, inform the kidneys of vascular pressures and volume status.

• Sympathetic stimulation is a major controller of sodium excretion.

• Angiotensin II, produced by local and systemic renin-angiotensin systems, is a crucial regulator of sodium excretion and blood pressure via its actions in the kidneys, peripheral vasculature and adrenal glands.

• Aldosterone stimulates sodium reabsorption in principal cells in the distal nephron.

• The 3 major controllers of renin secretion are sympathetic drive, pressure in the afferent arteriole and feedback from the macula densa.

• The macula densa blunts changes in GFR via tubuloglomerular feedback.

• Intrarenal dopamine plus several other mediators limit sodium reabsorption (increase excretion).

• Water excretion varies in proportion to solute excretion and inversely with urine osmolality.

• ADH secretion is regulated by plasma osmolality via osmoreceptors in the circumventricular organs, and by blood pressure via the baroreceptor-vasomotor center system.

• Most cases of heart failure and hypertension involve hyper-activation of the RAAS and are commonly treated with drugs that block components of the RAAS.