Regulation Of Extracellular Fluid Volume And Nacl Balance

“What is the regulation of extracellular fluid volume?”

The major solutes of the extracellular fluid (ECF) are the salts of Na⁺. Of these, sodium chloride (NaCl) is the most abundant.

Because NaCl is also the major determinant of ECF osmolality, alterations in Na⁺ balance commonly are assumed to disturb ECF osmolality.
However, under normal circumstances, this is not the case because the arginine vasopressin (AVP) and thirst systems maintain body fluid osmolality within a very narrow range.
For example, the addition of NaCl to the ECF (without water) increases the Na+ concentration and osmolality of this compartment (intracellular fluid osmolality also increases because of osmotic equilibration with the ECF).

“Understanding the role of NaCl in fluid balance”

This increase in osmolality in turn stimulates thirst and the release of AVP from the posterior pituitary.

The increased ingestion of water in response to thirst, together with the AVP-induced decrease in water excretion by the kidneys (so-called antidiuresis), quickly restores ECF osmolality to normal.
However, the volume of the ECF increases in proportion to the amount of water ingested, which in turn depends on the amount of NaCl added to the ECF.
Thus in the new steady state, the addition of NaCl to the ECF is equivalent to adding an isosmotic solution, and the volume of this compartment increases. Conversely, a decrease in the NaCl content of the ECF lowers the volume of this compartment.

The kidneys are the major route for the excretion of NaCl from the body. Only about 10% of the Na⁺ lost from the body each day is lost by nonrenal routes (for example., in perspiration and feces).

Regulation Of Extracellular Fluid Volume And Nacl Balance The AVP System In Maintaining A Normal Body Flid Osmolality

“How does the body regulate ECF volume and NaCl balance?”

Thus the kidneys are critically important in regulating the volume of the ECF.

Under normal conditions, the kidneys keep the volume of the ECF constant by adjusting the excretion of NaCl to match the amount ingested in the diet.
If ingestion exceeds excretion, ECF volume increases above normal, whereas the opposite occurs if excretion exceeds ingestion.
It has been observed that the kidneys excrete sodium chloride (NaCl) more quickly when the NaCl is administered orally versus by an intravenous infusion.

This observation has led to the search for factors within the gastrointestinal tract that might modulate the renal excretion of NaCl. Indeed, neuroendocrine cells that produce the peptide hormones uroguanylin and guanylin in response to NaCl ingestion have been identified in the intestine.

These hormones increase NaCl and water excretion by the kidneys (uroguanylin > guanylin) by inhibiting Na⁺ reabsorption in both the proximal tubule and collecting duct.
Interestingly, the kidneys also produce uroguanylin and guanylin, suggesting that they also might play a paracrine role in the intrarenal regulation of NaCl excretion.
The potential importance of these peptides in regulating renal NaCl excretion is seen in mice lacking the uroguanylin gene. These mice have a blunted natriuretic response to an oral NaCl load, and they also have increased blood pressure.

The typical diet contains approximately 140 mEq/ day of Na⁺ (8 g of NaCl), and thus daily Na⁺ excretion is also about 140 mEq/day. However, the kidneys can vary the excretion of Na⁺ over a wide range.

Excretion rates as low as 10 mEq/day can be attained when persons are placed on a low-salt diet. Conversely, the kidneys can increase their excretion rate to more than 1000 mEq/day when challenged by the ingestion of a high-salt diet.
These changes in Na+ excretion can occur with only modest changes in the ECF volume and steady-state Na⁺ content of the body.
The response of the kidneys to abrupt changes in NaCl intake typically takes several hours to several days, depending on the magnitude of the change. During this transition period, the intake and excretion of Na⁺ are not matched as they are in the steady state.

“Importance of maintaining extracellular fluid volume”

Thus the individual experiences either positive Na⁺ balance (intake > excretion) or negative Na⁺ balance (intake < excretion). However, by the end of the transition period, a new steady state is established, and intake once again equals excretion.

Provided that the AVP and thirst systems are intact and normal, alterations in Na+ balance change the volume, but not the Na⁺ concentration, of the ECF. Changes in ECF volume can be monitored by measuring body weight because 1 L of ECF equals 1 kg of body weight.
In this chapter, the physiology of the receptors that monitor ECF volume is reviewed and the various signals that act on the kidneys to regulate NaCl excretion and thereby ECF volume are explained.
In addition, the responses of the various portions of the nephron to these signals are considered. Finally, the pathophysiologic mechanisms involved in the formation of edema are presented, with emphasis on the role of NaCl handling by the kidneys.

Concept Of Effective Circulating Volume

As described, the ECF is subdivided into two compartments: blood plasma and interstitial fluid. Plasma volume is a determinant of vascular volume and thus blood pressure and cardiac output.

The maintenance of Na⁺ balance, and thus ECF volume, involves a complex system of sensors and effector signals that act primarily on the kidneys to regulate the excretion of NaCl.
As can be appreciated from the dependence of vascular volume, blood pressure, and cardiac output on ECF volume, this complex system is designed to ensure adequate tissue perfusion.
Because the primary sensors of this system are located in the large vessels of the vascular system, changes in vascular volume, blood pressure, and cardiac output are the principal factors regulating renal NaCl excretion (described later in this chapter).

In a healthy person, changes in ECF volume result in parallel changes in vascular volume, blood pressure, and cardiac output. Thus a decrease in ECF volume, a situation termed volume contraction, results in reduced vascular volume, blood pressure, and cardiac output.

Conversely, an increase in ECF volume, a situation termed volume expansion, results in increased vascular volume, blood pressure, and cardiac output.
The degree to which these cardiovascular parameters change depends on the degree of volume contraction or expansion and the effectiveness of cardiovascular reflex mechanisms.
When a person is in a negative Na⁺ balance, ECF volume is decreased and renal NaCl excretion is reduced. Conversely, with a positive Na⁺ balance, an increase in ECF volume occurs, which results in enhanced renal NaCl excretion (i.e., natriuresis).

However, in some pathologic conditions (for example., congestive heart failure and hepatic cirrhosis), the renal excretion of NaCl is not reflective of the ECF volume.

In both of these situations, the volume of the ECF is increased. However, instead of increased renal NaCl excretion, as would be expected, a reduction in the renal excretion of NaCl occurs.
To explain renal Na+ handling in these situations, it is necessary to understand the concept of effective circulating volume (ECV). Unlike the ECF, the ECV is not a measurable and distinct body fluid compartment.
The ECV refers to the portion of the ECF that is contained within the vascular system and is “effectively” perfusing the tissues (effective blood volume is another commonly used term).

“Common mechanisms of NaCl balance regulation explained”

More specifically, the ECV reflects the perfusion of those portions of the vascular system that contain the volume sensors (described later in this chapter).

In healthy persons, ECV varies directly with the volume of the ECF and, in particular, the volume of the vascular system (arterial and venous), the arterial blood pressure, and cardiac output.
However, as noted, this is not the case in certain pathologic conditions. In the remaining sections of this chapter, the relationship between ECF volume and renal NaCl excretion in healthy adults, where changes in ECV and ECF volume occur in parallel, is examined.
Patients with congestive heart failure frequently have an increase in the volume of the extracellular fluid (ECF), which is manifested as an accumulation of fluid in the lungs (pulmonary edema) and peripheral tissues (peripheral edema).

This excess fluid is the result of sodium chloride (NaCl) and water retention by the kidneys. The kidneys’ response (i.e., retention of NaCl and water) appears paradoxical because the ECF volume is increased.

However, because of poor cardiac performance, perfusion of the portions of the vascular system that contain the volume sensors is reduced (i.e., decreased effective circulating volume).
Therefore the volume sensors misinterpret these signals as indicative of ECF volume contraction and respond by increasing NaCl and water retention by the kidneys, thereby exacerbating a vicious cycle of impaired cardiac function and increased NaCl and water reabsorption.
Large volumes of fluid accumulate in the peritoneal cavity of patients with advanced hepatic cirrhosis. This fluid, called ascites, is a component of the ECF and results from NaCl and water retention by the kidneys.

Again, the response of the kidneys in this situation seems paradoxical if only ECF volume is considered.

With advanced hepatic cirrhosis, blood pools in the splanchnic circulation (i.e., the damaged liver impedes the drainage of blood from the splanchnic circulation by the portal vein).
Thus volume and pressure are reduced in the portions of the vascular system where the volume sensors are found and, as in the case of congestive heart failure, the volume sensors interpret reduced effective circulating volume as decreased ECF volume and respond accordingly.
Hence the kidneys respond as they normally would to ECF volume contraction, resulting in NaCl and water retention and an increase in ECF volume, which results in the accumulation of ascites fluid.

“Role of aldosterone in regulating NaCl balance”

Volume Sensing Systems

The ECF volume (or ECV) is monitored by multiple sensors. A number of the sensors are located in the vascular system, and they monitor its fullness and pressure.

These receptors typically are called volume receptors; because they respond to pressure-induced stretch of the walls of the receptor (for example., blood vessels or cardiac atria), they also are referred to as baroreceptors.
The sensors within the liver and central nervous system (CNS) are less well understood and do not seem to be as important as the vascular sensors in monitoring the ECF volume.

Volume Sensors In The Low-Pressure Cardiopulmonary Circuit:

Volume sensors (i.e., baroreceptors), which are located within the walls of the cardiac atria, right ventricle, and large pulmonary vessels, respond to the distention of these structures.

Because the low-pressure venous side of the circulatory system has high compliance, these sensors respond mainly to the “fullness” of the vascular system.
These baroreceptors send signals to the brainstem through afferent fibers in the glossopharyngeal and vagus nerves. The activity of these sensors modulates both sympathetic nerve outflow and AVP secretion.
For example, a decrease in the filling of the pulmonary vessels and cardiac atria increases sympathetic nerve activity and stimulates AVP secretion. Conversely, distention of these structures decreases sympathetic nerve activity.

In general, 5% to 10% changes in blood volume and pressure are necessary to evoke a response.

The cardiac atria possess an additional mechanism related to the control of renal NaCl excretion. The myocytes of the atria synthesize and store a peptide hormone.
This hormone, termed atrial natriuretic peptide (ANP), is released when the atria are distended, which, by mechanisms outlined later in this chapter, reduces blood pressure and increases the excretion of NaCl and water by the kidneys.
The ventricles of the heart also produce a natriuretic peptide termed brain natriuretic peptide (BNP), so named because it was first isolated from the brain. Like ANP, BNP is released from the ventricular myocytes by distension of the ventricles. Its actions are similar to those of ANP.

“How does ADH affect extracellular fluid volume?”

Volume Sensors In The High-Pressure Arterial Circuit:

Baroreceptors also are present in the arterial side of the circulatory system; they are located in the wall of the aortic arch, carotid sinus, and afferent arterioles of the kidneys.

The aortic arch and carotid barorecep- tors send input to the brainstem through afferent fibers in the glossopharyngeal and vagus nerves. The response to this input alters sympathetic outflow and AVP secretion.
Thus a decrease in blood pressure increases sympathetic nerve activity and AVP secretion. An increase in pressure tends to reduce sympathetic nerve activity (and activate parasympathetic nerve activity).
The sensitivity of the high-pressure baroreceptors is similar to that in the low-pressure side of the vascular system; 5% to 10% changes in pressure are needed to evoke a response.

The juxtaglomerular apparatus of the kidneys, particularly the afferent arteriole, responds directly to changes in pressure. If perfusion pressure in the afferent arteriole is reduced, renin is released from the myocytes.

Renin secretion is suppressed when perfusion pressure is increased. As described later in this chapter, renin determines blood levels of angiotensin II and aldosterone, both of which play an important role in regulating renal NaCl excretion.
Of the two classes of baroreceptors, those on the high-pressure side of the vascular system appear to be more important in influencing sympathetic tone and AVP secretion.
For example, patients with congestive heart failure often have an increased vascular volume with dilation of the atria and ventricles, which would be expected to decrease sympathetic tone and inhibit AVP secretion via the low-pressure baroreceptors.

Constriction of a renal artery by an atherosclerotic plaque, for example, reduces perfusion pressure to that kidney.

This reduced perfusion pressure is sensed by the afferent arteriole of the juxtaglomerular apparatus and results in the secretion of renin.
The elevated renin levels increase the production of angiotensin II, which in turn increases systemic blood pressure by its vasoconstrictor effect on arterioles throughout the vascular system.
The increased systemic blood pressure is sensed by the juxtaglomerular apparatus of the contralateral kidney (i.e., the kidney without stenosis of its renal artery), and renin secretion from that kidney is suppressed.

“Impact of renin-angiotensin-aldosterone system (RAAS) on ECF volume”

In addition, the high levels of angiotensin II act to inhibit renin secretion by the contralateral kidney (negative feedback).

The treatment of patients with constricted renal arteries includes surgical repair of the stenotic artery, administration of angiotensin 2 receptor blockers, or administration of an inhibitor of angiotensin-converting enzyme.
The angiotensin-converting enzyme inhibitor blocks the conversion of angiotensin 1 to angiotensin 2.
However, the sympathetic tone often is increased and AVP secretion often is stimulated in these patients (the renin-angiotensin-aldosterone system also is activated).
This phenomenon reflects the activation of baroreceptors in the high-pressure arterial circuit in response to reduced blood pressure and cardiac out-put secondary to the failing heart (i.e., the high-pres-sure baroreceptors detect a reduced ECV and misinterpret this signal as indicative of reduced ECF volume).

Hepatic Sensors:

The liver also contains volume sensors that can modulate renal NaCl excretion, although they are not as important as the vascular sensors.

One type of hepatic sensor responds to pressure within the hepatic vasculature and therefore functions in a manner similar to the baroreceptors in the low- and high-pressure vascular circuits.
A second type of sensor also appears to exist in the liver. This sensor responds to [Na⁺] of the portal blood entering the liver.
Afferent signals from both types of sensors are sent to the same area of the brainstem where afferent fibers from both the low- and high-pressure circuit baroreceptors converge.
Increased pressure within the hepatic vasculature or an increase in portal blood [Na⁺] results in a decrease in efferent sympathetic nerve activity.

As described later in this chapter, this decreased sympathetic nerve activity leads to an increase in renal NaCl excretion.

Central Nervous System Na⁺ Sensors:

As with the hepatic sensors, the CNS sensors do not appear to be as important as the vascular sensors in monitoring the ECF volume and controlling renal NaCl excretion.

Nevertheless, alterations in the [Na⁺] of blood carried to the brain in the carotid arteries or the [Na⁺] of the cerebrospinal fluid modulate renal NaCl excretion.
For example, if the [Na⁺] in either the carotid artery blood or the cerebrospinal fluid is increased, a decrease in renal sympathetic nerve activity occurs, which in turn leads to an increase in renal NaCl excretion.
The hypothalamus appears to be the site where these sensors are located. Angiotensin II and natriuretic peptides are generated in the hypothalamus.

These locally generated signals, together with systemically generated angiotensin II and natriuretic peptides, appear to play a role in modulating the CNS Na⁺-sensing system.

Of the volume and Na+ sensors just described, those located in the vascular system are better understood. Moreover, their function in health and disease explains quite effectively the regulation of renal NaCl excretion.
Therefore the remainder of this chapter focuses on the vascular volume sensors (i.e., baroreceptors) and their role in regulating renal NaCl excretion.

“Biomechanics of sodium reabsorption in the nephron”

Volume Sensor Signals:

When the vascular volume sensors have detected a change in ECV, which under normal conditions reflects ECF volume, they send signals to the kidneys, which result in appropriate adjustments in NaCl and water excretion.

Accordingly, when the ECF volume is expanded, renal NaCl and water excretion are increased.
Conversely, when the ECF volume is concentrated, renal NaCl and water excretion are reduced.
The signals involved in coupling the volume sensors to the kidneys are both neural and hormonal. These signals are summarized, as are their effects on renal NaCl and water excretion.

Renal Sympathetic Nerves:

As described, sympathetic nerve fibers innervate the afferent and efferent arterioles of the glomerulus, as well as the nephron cells.

With negative Na⁺ balance (i.e., ECF volume contraction), baroreceptors in both the low- and high-pressure vascular circuits stimulate the sympathetic input to the kidneys.

This stimulation has the following effects:

The afferent and efferent arterioles constrict in response to a-adrenergic stimulation.

This vaso-constriction predominantly affects the afferent arteriole, effectively reducing hydrostatic pressure within the glomerular capillary lumen and decreasing glomerular filtration.
The resulting reduction in the glomerular filtration rate (GFR) reduces the filtered load of Na⁺ to the nephrons.
Renin secretion is stimulated by the cells of the afferent arterioles in response to p-adrenergic receptor stimulation. As described later, renin ultimately increases the circulating levels of angiotensin II and aldosterone.

NaCl reabsorption along the nephron is directly stimulated by a-adrenergic stimulation, effectively reducing the fraction of filtered Na⁺ that is ultimately excreted.

Quantitatively, the most important segment influenced by sympathetic nerve activity is the proximal tubule.
As a result of these combined actions, increased renal sympathetic nerve activity decreases net NaCl excretion, an adaptive response that works to restore ECF volume to normal, which is a state termed euvolemia.
With positive Na⁺ balance (i.e., ECF vol-ume expansion), renal sympathetic nerve activity is reduced, which generally reverses the effects just described.

Volume Sensing Systems At The Cellular Level:

A new “renal hormone” has been discovered recently, a flavin adenine dinucleotide-dependent amine oxidase named renalase.

Renalase is similar in structure to monoamine oxidase and breaks down catechol amines (for example., epinephrine and norepinephrine).
Several tissues (for example., skeletal muscle, heart, and small intestine) express renalase, but the kidneys secrete the enzyme into the circulation.

Because persons with chronic renal failure have very low levels of renalase in their plasma, the kidney is probably the primary source of the circulating enzyme.

In experimental animals, infusion of renalase decreases blood pressure and heart contractility.
Although the precise role of renalase in cardiovascular function and blood pressure regulation is not known, it may be important in modulating the effects of the sympathetic nervous system and especially the effects of the sympathetic nerves on the kidney.

“Steps in restoring NaCl balance during dehydration”

Renin-Angiotensin-Aldosterone System

Cells in the afferent arterioles (juxtaglomerular cells) are the site of synthesis, storage, and release of the proteolytic enzyme renin. Three factors are important in stimulating renin secretion:

Perfusion pressure. When perfusion pressure to the kidneys is reduced, renin secretion by the afferent arteriole is stimulated. Conversely, an increase in perfusion pressure inhibits renin release by the afferent arteriole.
Sympathetic nerve activity. Activation of the sympathetic nerve fibers that innervate the afferent arterioles increases renin secretion via P-adrenergic receptor stimulation. Renin secretion is decreased as renal sympathetic nerve activity is decreased.
Delivery of NaCl to the macula densa. Delivery of NaCl to the macula densa regulates the GFR by a process termed tubuloglomerular feedback.
- In addition, the macula densa plays a role in renin secretion. When NaCl delivery to the macula densa is decreased, renin secretion is enhanced. Conversely, an increase in NaCl delivery inhibits renin secretion.
- It is likely that macula densa-mediated renin secretion helps to maintain systemic arterial pressure under conditions of a reduced intravascular volume.
- For example, when intravascular volume is reduced, perfusion of body tissues (including the kidneys) decreases, which in turn decreases the GFR and the filtered amount of NaCl.
- The reduced delivery of NaCl to the macula densa then stimulates renin secretion, which acts through angiotensin II (a potent vasoconstrictor) to increase blood pressure and thereby maintain tissue perfusion.

Although many tissues express renin (for example., brain, heart, and adrenal gland tissues), the primary source of circulating renin is the kidneys. Renin is secreted by juxtaglomerular cells located in the afferent arteriole.

At the cellular level, renin secretion is mediated by the fusion of renin-containing granules with the luminal membrane of the cell.
This process is stimulated by a decrease in intracellular [Ca⁺⁺], a response opposite to that of most secretory cells where secretion is normally stimulated by an increase in intracellular [Ca⁺⁺].
Renin release is also stimulated by an increase in intracellular cyclic adenosine monophosphate levels.

Thus anything that increases intracellular [Ca⁺⁺] inhibits renin secretion, which includes stretch of the afferent arteriole (myogenic control of renin secretion), angiotensin 2 (feedback inhibition), and endo- thelin.

Conversely, anything that increases intracellular cyclic adenosine monophosphate stimulates renin secretion, which includes norepinephrine acting through p-adrenergic receptors and prostaglandin E₂.
Increases in intracellular cyclic guanosine monophosphate have been shown to stimulate renin secretion in some situations and inhibit secretion in others.
Notably, two substances that increase intracellular cyclic guanosine monophosphate are natriuretic peptides and nitric oxide.
Nitric oxide stimulates renin secretion, whereas atrial natriuretic peptide and brain natriuretic peptide are inhibitory.

The control of renin secretion by the macula densa may involve paracrine factors such as prostaglandin E₂ (which stimulates renin secretion when NaCl delivery to the macula densa is decreased) and adenosine (which inhibits renin secretion when NaCl delivery to the macular densa is increased).

Regulation Of Extracellular Fluid Volume And Nacl Balance Schematic Representation Of Angiotensin Aldosterone System

“Mechanisms of sodium reabsorption in the nephron”

Summarizes the essential components of the renin-angiotensin-aldosterone system. Renin alone does not have a physiological function; it functions as a proteolytic enzyme.

Its principal substrate is a circulating protein, angiotensinogen, which is produced by the liver. Angiotensinogen is cleaved by renin to yield a 10-amino-acid peptide, angiotensin 1.
Angiotensin 1 also has no known physiological function, and it is further cleaved to an 8-amino-acid peptide, angiotensin 2, by a converting enzyme (angiotensin-converting enzyme [ACE]) found on the surface of vascular endothelial cells.

Pulmonary and renal endothelial cells are important sites for the bioconversion of angiotensin 1 to angiotensin 2. ACE also degrades bradykinin, a potent vasodilator. Angiotensin 2 has several important physiologic functions, including:
Stimulation of aldosterone secretion by the adrenal cortex
Arteriolar vasoconstriction, which increases blood pressure
Stimulation of AVP secretion and thirst
Enhancement of NaCl reabsorption by the proximal tubule, thick ascending limb of Henle’s loop, the distal tubule, and even the collecting duct; of these segments, the effect on the proximal tubule is quantitatively the largest

Angiotensin 2 is an important secretagogue for aldosterone. An increase in the plasma K⁺ concentration is the other important stimulus for aldosterone secretion.

Aldosterone is a steroid hormone produced by the glomerulosa cells of the adrenal cortex. Aldosterone acts in a number of ways on the kidneys.
With regard to the regulation of the ECF volume, aldosterone reduces NaCl excretion by stimulating its reabsorption by the thick ascending limb of the loop of Henle, portions of the distal tubule, and the collecting duct.
(The portions of the distal tubule that functionally respond to aldosterone together with the collecting duct are referred to as the aldosterone-sensitive distal nephron [ASDN].)

The effect of aldosterone on renal NaCl excretion depends mainly on its ability to stimulate Na+ reabsorption in the ASDN.

Aldosterone has many cellular actions in cells of the ASDN.
Notably, it increases the abundance of the apical membrane Na⁺– Cl^– symporter in the cells of the distal tubule (DCT2 segment; see previous
At the Cellular Level box) and the abundance of the epithelial Na+ channel in the apical membrane of principal cells in the late portion of the distal tubule and collecting duct.

Volume Sensing System At The Cellular Level:

The distal tubule can be divided into three distinct segments based on the presence of specific membrane transporters.

The first segment after the macula densa (DCT1) expresses a Na⁺-Cl^– symporter, which is specifically inhibited by the thiazide class of diuretics.
The next segment (DCT2) expresses the Na⁺-Cl^– symporter and the epithelial Na⁺ channel. The last segment of the distal tubule (connecting tubule), like the collecting duct, expresses only the epithelial Na+ channel.
Aldosterone selectivity and sensitivity are conferred by the presence of mineralocorticoid receptors, as well as the presence of the enzyme 11 β-hydroxysteroid dehydrogenase 2 (11β-HSD2).

Because the mineralocorticoid receptor also binds glucocorticoids, 11β- HSD2 is required for aldosterone specificity because it metabolizes glucocorticoids and thus prevents them from binding to the mineralocorticoid receptor.

The mineralocorticoid receptor is found throughout the distal tubule and collecting duct. However, 11β- HSD2 is only found in the DCT2, the connecting tubule, and the collecting duct.
Thus the aldosterone-sensitive distal nephron consists of the DCT2 and connecting tubule (collectively termed the late distal tubule) and the collecting duct. Accordingly, the DCT1 segment is referred to as the early distal tubule.
By this action, Na⁺ entry into the cells across the apical membrane is increased. Extrusion of Na+ from the cell across the basolateral membrane occurs via the Na⁺-K⁺-adenos- ine triphosphatase (ATPase) pump, the abundance of which is also increased by aldosterone.

Thus aldosterone increases net reabsorption of Na+ from the tubular fluid by ASDN segments, and reduced levels of aldosterone decrease the amount of Na+ reabsorbed by these segments.

As noted, aldosterone also enhances Na⁺ reabsorption by cells of the thick ascending limb of the loop of Henle.
This action probably reflects the increased entry of Na⁺ into the cell across the apical membrane (probably by the apical membrane Na⁺-K⁺-2Cl^– symporter) and increased extrusion from the cell by the basalt- eral membrane Na⁺-K⁺-ATPase pump.
Diseases of the adrenal cortex can alter aldosterone levels and thereby impair the ability of the kidneys to maintain Na⁺ balance and euvolemia.

“How do the kidneys maintain ECF volume balance?”

With decreased secretion of aldosterone (hypoaldosteronism), the reabsorption of Na⁺ by the aldosterone-sensitive distal nephron (late distal tubule and collecting duct) is reduced, and sodium chloride (NaCl) is lost in the urine.

Because urinary NaCl loss can exceed the amount of NaCl ingested in the diet, negative Na⁺ balance ensues, and the extracellular fluid (ECF) volume decreases.
In response to the ensuing ECF volume contraction, sympathetic tone is increased, and levels of renin, angiotensin 2, and arginine vasopressin are elevated.
With increased aldosterone secretion (hyperaldosteronism), the opposite effects are observed: Na⁺ reabsorption by the aldosterone-sensitive distal nephron is enhanced and excretion of NaCl is reduced.

Consequently, ECF volume is increased, sympathetic tone is decreased, and the levels of renin, angiotensin 2, and arginine vasopressin are decreased.

As described later in this chapter, atrial natriuretic peptide and brain natriuretic peptide levels also are elevated in this setting.
As summarized, activation of the renin-angiotensin-aldosterone system, as occurs with ECF volume depletion, decreases the excretion of NaCl by the kidneys.
Conversely, this system is suppressed by ECF volume expansion, thereby enhancing renal NaCl excretion.

Natriuretic Peptides

The body produces a number of substances, including ANP and BNP, that act on the kidneys to increase Na⁺ excretion.

Of these substances, natriuretic peptides produced by the heart and kidneys are best understood and are the focus of the following discussion.
The heart produces two natriuretic peptides. Atrial myocytes primarily produce and store the peptide hormone ANP, and ventricular myocytes primarily produce and store BNP.
Both peptides are secreted in response to myocardial wall stretch (i.e., during cardiac dilatation that accompanies volume expansion and/or heart failure), and they act to relax vascular smooth muscle and promote NaCl and water excretion by the kidneys.
The kidneys also produce a related natriuretic peptide termed urodilatin. Its actions are limited to promoting NaCl excretion by the kidneys.
In general, the actions of these natriuretic peptides, as they relate to renal NaCl and water excretion, antagonize those of the renin-angiotensin-aldosterone system.

Natriuretic Peptide Actions Include:

Afferent arteriolar vasodilation and efferent arteriolar vasoconstriction within the glomerulus, increase the GFR and the filtered amount of Na⁺.
Inhibition of renin secretion by the juxtaglomerular cells of the afferent arterioles.
Inhibition of aldosterone secretion by the glomerulus cells of the adrenal cortex. This inhibition occurs by two mechanisms:
- Inhibition of renin secretion by the juxtaglomerular cells, thereby reducing angiotensin II-induced aldosterone secretion, and
- Direct inhibition of aldosterone secretion by the glomerulosa cells of the adrenal cortex.
Inhibition of NaCl reabsorption by the collecting duct, which also is caused in part by reduced levels of aldosterone. However, the natriuretic peptides also act directly on the collecting duct cells.
- Through the second messenger, cyclic guanosine monophosphate, natriuretic peptides inhibit Na⁺ channels in the apical membrane and thereby decrease Na⁺ reabsorption.
- This effect occurs predominantly in the medullary portion of the collecting duct.
Inhibition of AVP secretion by the posterior pituitary and AVP action on the collecting duct. These effects decrease water reabsorption by the collecting duct and thus increase the excretion of water in the urine.

Regulation Of Extracellular Fluid Volume And Nacl Balance Response To Step Increases And Decreases In NaCl Intake

“Role of the loop of Henle in NaCl concentration”

These effects of the natriuretic peptides increase the net excretion of NaCl and water by the kidneys.
Hypothetically, a reduction in the circulating levels of these peptides would be expected to decrease NaCl and water excretion, but convincing evidence for this effect has not been reported.

Arginine Vasopressin:

As discussed, a decreased ECF volume stimulates AVP secretion by the posterior pituitary.
The elevated levels of AVP decrease water and NaCl excretion by the kidneys, which serve to reestablish euvolemia.

Control Of Renal Nacl Excretion During Euvolemia

The maintenance of Na⁺ balance and therefore euvolemia requires the precise matching of the amount of NaCl ingested and the amount excreted from the body.

As already noted, the kidneys are the major route for NaCl excretion. Accordingly, in a euvolemic person, we can equate daily urine NaCl excretion with daily NaCl intake.
The amount of NaCl excreted by the kidneys can vary widely. Under conditions of salt restriction (i.e., a low NaCl diet), virtually no Na⁺ appears in the urine.
Conversely, in persons who ingest large quantities of NaCl, renal Na⁺ excretion can exceed 1000 mEq/day. The kidneys require several days to respond maximally to variations in dietary NaCl intake.

During the transition period, excretion does not match intake, and the person is in either positive (intake > excretion) or negative (intake < excretion) Na⁺ balance.

This phenomenon is illustrated. When Na⁺ balance is altered during these transition periods, the ECF volume changes in parallel.
Water excretion, regulated by AVP, also is adjusted to keep plasma osmolality constant, effectively resulting in isosmotic changes in ECF volume.
Thus with positive Na⁺ balance, the ECF volume expands, whereas with negative Na⁺ balance, the ECF volume contracts. In both cases, no change in plasma [Na⁺] occurs.

These changes in ECF volume can be detected by monitoring changes in body weight. Ultimately, renal excretion reaches a new steady state and NaCl excretion once again is matched to intake.

The time course for the adjustment of renal NaCl excretion varies (from hours to days) and depends on the magnitude of the change in NaCl intake.
Adaptation to large changes in NaCl intake requires a longer time than adaptation to small changes in intake.
The general features of Na⁺ handling along the nephron must be understood to comprehend how renal Na⁺ excretion is regulated. (for the cellular mechanisms of Na⁺ transport along the nephron.)

Regulation Of Extracellular Fluid Volume And Nacl Balance Segmental Na Plus Reabsorption

“Impact of glomerular filtration rate (GFR) on ECF volume”

Most (67%) of the filtered amount of Na⁺ is reabsorbed by the proximal tubule. An additional 25% is reabsorbed by the thick ascending limb of the loop of Henle, and the remainder is largely reabsorbed by the distal tubule and collecting duct.

In a normal adult, the filtered amount of Na⁺ is approximately 25,000 mEq/day.

Filtered amount of Na⁺ = (GFR)(plasma [Na⁺])

= (180 L/day)(140 mEq/L)

= 25,200 mEq/day

With a typical diet, less than 1% of this filtered amount is excreted in the urine (approximately 140 mEq/day). Because of the large amount of filtered Na⁺, small changes in Na⁺ reabsorption by the nephron can profoundly affect Na⁺ balance and thus the volume of the ECF.

For example, an increase in Na⁺ excretion from 1% to 3% of the filtered amount represents an additional loss of approximately 500 mEq/day of Na⁺.
Because the ECF Na⁺ concentration is 140 mEq/L, such a Na⁺ loss would decrease the ECF volume by more than 3 L (i.e., water excretion would parallel the loss of Na⁺ to maintain body fluid osmolality constant: [500 mEq/day]/[140 mEq/L] = 3.6 L/ day of fluid loss).
Such fluid loss in a person weighing 70 kg would represent a 26% decrease in the ECF volume.

In euvolemic subjects, the nephron segments distal to the loop of Henle, namely the distal tubule and collecting duct, are the main nephron segments where Na⁺ reabsorption is adjusted to maintain excretion at a level appropriate for dietary intake.

However, this does not mean that the other portions of the nephron are not involved in this process.
Because the reabsorptive capacity of the distal tubule and collecting duct is limited, the upstream segments of the nephron (i.e., the proximal tubule and loop of Henle) must reabsorb the bulk of the filtered amount of Na⁺.

Thus during euvolemia, Na⁺ handling by the nephron can be explained by two general processes:

Na⁺ reabsorption by the proximal tubule and loop of Henle is regulated so that a relatively constant portion of the filtered amount of Na⁺ is delivered to the distal tubule.
- The combined action of the proximal tubule and loop of Henle reabsorbs approximately 92% of the filtered amount of Na⁺, and thus 8% of the filtered amount is delivered to the distal tubule.
Reabsorption of this remaining portion of the filtered amount of Na⁺ by the distal tubule and collecting duct is regulated so that the amount of Na⁺ excreted in the urine closely matches the amount ingested in the diet at a steady state.
- Thus these later nephron segments make final adjustments in Na⁺ excretion to maintain the euvolemic state.

Mechanisms For Maintaining Constant Na⁺ Delivery To The Distal Tubule:

A number of mechanisms maintain delivery of a constant fraction of the filtered amount of Na⁺ to the beginning of the distal tubule.

These processes are autoregulation of the GFR (a mechanism that keeps the filtered amount of Na⁺ constant), glomerulotubu-lar balance, and load dependence of Na⁺ reabsorption by the loop of Henle.
Autoregulation of the GFR allows maintenance of a relatively constant filtration rate over a wide range of perfusion pressures. Because the filtration rate is constant, the delivery of filtered Na⁺ to the nephrons also is kept constant.

Despite the autoregulatory control of the GFR, small variations in GFR occur. If these changes were not compensated for by an appropriate adjustment in Na⁺ reabsorption by the nephron, Na⁺ excretion would change markedly.

“How does the renal system respond to sodium imbalance?”

Fortunately, Na⁺ reabsorption in the euvolemic state, especially by the proximal tubule, changes in parallel with changes in the GFR. This phenomenon is termed glomerulotubular (G-T) balance.
Thus if the GFR increases, the amount of Na⁺ reabsorbed by the proximal tubule increases proportionately. The opposite occurs if the GFR decreases.

The final mechanism that helps maintain the constant delivery of Na⁺ to the beginning of the collecting duct involves the ability of the loop of Henle to increase its reabsorptive rate in response to increased delivery of Na⁺.

Regulation Of Distal Tubule And Collecting Duct Na⁺ Reabsorption:

When delivery of Na⁺ is constant, small adjustments in the distal tubule and, to a lesser degree, collecting duct Na⁺ reabsorption is sufficient to balance excretion with intake.

(As already noted, as little as a 2% change in fractional Na⁺ excretion produces more than a 3 L change in the volume of the ECF.) Aldosterone is the primary regulator of Na⁺ reabsorption by the distal tubule and collecting duct and thus of Na⁺ excretion under this condition.
When aldosterone levels are elevated, Na⁺ reabsorption by these segments is increased (excretion is decreased). When aldosterone levels are decreased, Na⁺ reabsorption is decreased (excretion is increased).

In addition to aldosterone, a number of other factors, including natriuretic peptides, prostaglandins, uroguanylin, adrenomedullin, and sympathetic nerves, alter Na⁺ reabsorption by the distal tubule and collecting duct.

However, the relative effects of these other factors on the regulation of Na⁺ reabsorption by these segments during euvolemia are unclear.
As long as variations in the dietary intake of NaCl are minor, the mechanisms previously described can regulate renal Na⁺ excretion appropriately and thereby maintain euvolemia.
However, these mechanisms cannot effectively handle significant changes in NaCl intake.
When NaCl intake changes significantly, ECF volume expansion or ECF volume contraction occurs.
In such cases, additional factors are invoked to act on the kidneys to adjust Na⁺ excretion and thereby reestablish the euvolemic state.

The excretion rate of Na⁺ by the kidneys can be quantitated in the following way:

⇒ \(\mathrm{U}_{\mathrm{Na}^{+}} \times \dot{\mathrm{V}}=\mathrm{GFR} \times \mathrm{P}_{\mathrm{Na}^{+}}-\mathrm{R}\)

where U_Na+ × V is the excretion rate in mEq/time (U_Na+ is the urine [Na⁺] and V is the urine flow rate), GFR X P_Na+ is the filtered amount of Na⁺ (GFR is the glomerular filtration rate and P_Na+ is the plasma [Na⁺]), and R is the amount of Na⁺ reabsorbed by the nephron.

“Pathophysiology of ECF volume imbalances explained”

Control Of Na⁺ Excretion With Volume Expansion

During ECF volume expansion, baroreceptors in both the high- and low-pressure vascular circuits send signals to the kidneys. These signals result in increased excretion of NaCl and water.

The signals acting on the kidneys include:

Decreased activity of the renal sympathetic nerves
Increased release of ANP and BNP from the heart and urodilatin by the kidneys
Inhibition of AVP secretion from the posterior pituitary and decreased AVP action on the collecting duct
Decreased renin secretion and thus decreased production of angiotensin 2
Decreased aldosterone secretion, which is a consequence of reduced angiotensin II levels, and elevated natriuretic peptide levels The integrated response of the nephron to these signals is illustrated.

Three general responses to ECF volume expansion occur (the numbers correlate with those circled:

Regulation Of Extracellular Fluid Volume And Nacl Integrated Response To Extracellular Flid Volume Expansion

“Emerging research on ECF volume regulation mechanisms”

The GFR increases. The GFR increases mainly as a result of the decrease in sympathetic nerve activity.

Sympathetic fibers innervate the afferent and efferent arterioles of the glomerulus and control their diameter. Decreased sympathetic nerve activity leads to arteriolar dilation.
Because afferent arteriolar dilation is greater than efferent dilation, the hydrostatic pressure within the glomerular capillary is increased, thereby increasing the filtration pressure and the GFR.
Note that the corresponding filtration fraction decreases because the renal plasma flow increases to a greater degree than the GFR.

Natriuretic peptides, which are increased during ECF volume expansion, also promote an increase in GFR via differential direct effects on the afferent (vasodilation) and efferent (vasoconstriction) arterioles.

With the increase in the GFR, the filtered amount of Na⁺ increases. The reabsorption of Na⁺ decreases in the proximal tubule and loop of Henle.
Several mechanisms act to reduce Na⁺ reabsorption by the proximal tubule, but the precise role of each of these mechanisms remains unresolved.
Because activation of the sympathetic nerve fibers that innervate this nephron segment stimulates Na⁺ reabsorption, the decreased sympathetic nerve activity that results from ECF volume expansion decreases Na⁺ reabsorption.

In addition, angiotensin 2 directly stimulates Na⁺ reabsorption by the proximal tubule. Because angiotensin 2 levels also are reduced by ECF volume expansion, proximal tubule Na⁺ reabsorption decreases accordingly.

Increased hydrostatic pressure within the glomerular capillaries also increases the hydrostatic pressure within the peritubular capillaries.
In addition, the decrease in filtration fraction reduces the peritubular oncotic pressure.
These alterations in the capillary Starling forces reduce the absorption of solute (for example., NaCl) and water from the lateral intercellular space and thus reduce proximal tubular reabsorption.

Both the increase in the filtered amount of NaCl and the decrease in NaCl reabsorption by the proximal tubule result in the delivery of more NaCl to the loop of Henle.

Because activation of the sympathetic nerves and aldosterone stimulates NaCl reabsorption by the loop of Henle, the reduced nerve activity and low aldosterone levels that occur with ECF volume expansion serve to reduce NaCl reabsorption by this nephron segment.
Thus the fraction of the filtered amount delivered to the distal tubule is increased.
Na⁺ reabsorption decreases in the distal tubule and collecting duct. As noted, the amount of Na⁺ delivered to the distal tubule exceeds that observed in the euvolemic state (the amount of Na⁺ delivered to the distal tubule varies in proportion to the degree of ECF volume expansion).

This increased amount of delivered Na⁺ can overwhelm the reabsorptive capacity of the distal tubule and the collecting duct, an effect heightened by the reduced reabsorptive capacity of these segments associated with increased circulating natriuretic peptides and decreased circulating aldosterone levels.

The final component in the response to ECF vol-ume expansion is the excretion of water. As Na⁺ excretion increases, plasma osmolality begins to fall, which decreases the secretion of AVP.
AVP secretion also is decreased in response to the elevated levels of natriuretic peptides. In addition, these natriuretic peptides inhibit the action of AVP on the collecting duct.
Together, these effects decrease water reabsorption by the collecting duct and thereby increase water excretion by the kidneys.

Thus the excretion of Na⁺ and water occurs in concert; euvolemia is restored, and body fluid osmolality remains constant.

The time course of this response (hours to days) depends on the magnitude of the ECF volume expansion.
Thus if the degree of ECF volume expansion is small, the mechanisms just described generally restore euvolemia within 24 hours. However, with larger degrees of ECF volume expansion, the response can take several days.

In brief, the renal response to ECF volume expansion involves the integrated action of all parts of the nephron:

The filtered amount of Na⁺ is increased,
The proximal tubule and loop of Henle reabsorption is reduced (the glomerular filtration rate is increased and proximal reabsorption is decreased, and thus G-T balance does not occur under this condition), and
The delivery of Na⁺ to the distal tubule is increased. This increased delivery, along with the inhibition of distal tubule and collecting duct reabsorption, results in the excretion of a larger fraction of the filtered amount of Na⁺ and thus restores euvolemia.

“Case studies on ECF volume and NaCl balance outcomes”

Control Of Na⁺ Excretion With Volume Contraction

During ECF volume contraction, volume sensors in both the high- and low-pressure vascular circuits send signals to the kidneys that reduce NaCl and water excretion. The signals that act on the kidneys include:

Increased renal sympathetic nerve activity
Increased secretion of renin, which results in elevated angiotensin II levels and thus increased secretion of aldosterone by the adrenal cortex
Stimulation of AVP secretion by the posterior pituitary

The integrated response of the nephron to these signals is illustrated. The general response is as follows

Regulation Of Extracellular Fluid Volume And Nacl Extracellular Flid Volume Contraction

“Global prevalence of ECF volume disorders”

The GFR decreases. Afferent and efferent arteriolar constriction occurs as a result of increased renal sympathetic nerve activity.
The effect is greater on the afferent than on the efferent arteriole. This vasoconstriction causes the hydrostatic pressure in the glomerular capillary to fall and thereby decreases the GFR.
The filtration fraction increases because the renal plasma flow decreases more than the GFR, but the absolute decrease in the GFR reduces the filtered load of Na⁺.

Na⁺ reabsorption by the proximal tubule and loop of Henle is increased. Several mechanisms augment Na⁺ reabsorption in the proximal tubule.

For example, increased sympathetic nerve activity and angiotensin II levels directly stimulate Na⁺ reabsorption.
The decreased hydrostatic pressure within the glomerular capillaries also leads to a decrease in the hydrostatic pressure within the peritubular capillaries.
In addition, the increased filtration fraction results in an increase in the peritubular oncotic pressure.

These alterations in the capillary Starling forces facilitate the movement of fluid from the lateral intercellular space into the capillary and thereby stimulate the reabsorption of solute (for example., NaCl) and water by the proximal tubule.

The reduced amount of filtered Na⁺ and enhanced proximal tubule reabsorption decrease the delivery of Na⁺ to the loop of Henle.
Increased sympathetic nerve activity, as well as elevated levels of angiotensin 2 and aldosterone, stimulate Na⁺ reabsorption by the thick ascending limb.
Because sympathetic nerve activity is increased and angiotensin 2 and aldosterone levels are elevated during ECF volume contraction, increased Na⁺ reabsorption by this segment is expected. Thus less Na⁺ is delivered to the distal tubule.

Na⁺ reabsorption by the distal tubule and collecting duct is enhanced. The small amount of Na⁺ that is delivered to the distal tubule is almost completely reabsorbed because transport in this segment and the collecting duct is enhanced.

This stimulation of Na⁺ reabsorption by the distal tubule and collecting duct is induced by increased angiotensin 2 and aldosterone levels (increased sympathetic nerve activity also will stimulate Na⁺ reabsorption).
Finally, water reabsorption by the late portion of the distal tubule and the collecting duct is enhanced by AVP (AVP also stimulates limited Na⁺ reabsorption in the late distal tubule and collecting duct), the levels of which are elevated through activation of the low high-pressure vascular volume sensors and by the elevated levels of angiotensin 2.
As a result, water excretion is reduced.

Because both water and Na+ are retained by the kidneys in equal proportions, euvolemia is reestablished and body fluid osmolality remains constant.

The time course of this expansion of the ECF (hours to days) and the degree to which euvolemia is attained depend on the magnitude of the ECF volume contraction and the dietary intake of Na+.
Thus the kidneys reduce Na+ excretion and euvolemia can be restored more quickly if additional NaCl is ingested in the diet.

In brief, the nephron’s response to ECF volume contraction involves the integrated action of all its segments:

The filtered amount of Na+ is decreased,
Proximal tubule and loop of Henle reabsorption is enhanced (the GFR is decreased and proximal reabsorption is increased and thus G-T balance does not occur under this condition), and
The delivery of Na+ to the distal tubule is reduced. This decreased delivery, together with enhanced Na+ reabsorption by the distal tubule and collecting duct, virtually eliminates Na+ from the urine.

Edema

Edema is the accumulation of excess fluid within the interstitial space. As described, Starling forces across the capillary wall determine the movement of fluid into and out of the vascular compartment in exchange with the extravascular interstitial compartment.

Alterations of these forces under pathologic conditions can lead to increased movement of fluid from the vascular space into the interstitium, resulting in edema formation.
The role of the kidneys in the formation of edema can be appreciated by recognizing that the interstitial compartment typically must contain 2 to 3 L of excess fluid before edema is clinically evident (for example., swelling of the ankles).

The source of this fluid is the vascular compartment (i.e., plasma), which has a volume of 3 to 4 L in healthy persons.

Alterations in the Starling forces that would accompany a 2 to 3 L fluid shift out of the vascular compartment into the interstitial compartment would be predicted to limit such marked fluid movement and the decline in blood pressure that would attend such a marked fluid shift.
However, retention of NaCl and water by the kidneys maintains intravascular compartment volume, thereby maintaining the blood pressure and facilitating interstitial fluid redistribution and edema development.

Alterations In Starling Forces:

In the Starling forces and their effect on fluid movement across the capillary wall were explained.

Edema results from changes in the Starling forces that alter these fluid dynamics.
Recall that fluid movement across a capillary wall is driven by hydrostatic and oncotic pressure gradients:

Filtration rate = K_f[(P_c — P_i) — a( π_c —π_i)]

where K_f is the filtration coefficient of the capillary wall (a measure of the intrinsic wall permeability and the surface area available for fluid flow), and P_c and P_i are the hydrostatic pressures within the lumen of the capillary.

The interstitium, respectively, σ is the reflection coefficient for protein across the capillary wall (approximately 0.9 for skeletal muscle), and π_c and π_i are the oncotic pressures generated by protein within the capillary lumen and the interstitium, respectively.

Capillary Hydrostatic Pressure (P_c)

Increasing the Pc favors the movement of fluid out of the capillary or retards its movement into the capillary, thereby promoting edema formation.

Normally the resistance of the precapillary arteriole is well regulated such that changes in systemic blood pressure do not result in marked alterations in P_c.
However, postcapillary resistance is not regulated to the same degree, and thus alterations in the pressure within the venous side of the circulation have significant effects on P_c.
Consequently, an increase in the venous pressure elevates P_c, which increases the movement of fluid into the interstitium, resulting in the accumulation of edema fluid.
Common causes for increased venous pressure include venous thrombosis and congestive heart failure.

Plasma Oncotic Pressure (π_c):

A decrease in π_c would be expected to favor the movement of fluid out of the capillary lumen and inhibit its reabsorption from the interstitium.

Because albumin is the most abundant plasma protein, alterations in nc result primarily from changes in the plasma [albumin].
However, it is important to remember that changes in plasma protein concentration result in parallel changes in the protein concentration of the interstitial fluid.
This phenomenon reflects the fact that the reflection coefficient for protein is 0.9 and thus proteins can cross the capillary wall.
Because of the parallel changes in capillary and interstitial fluid protein concentration, the oncotic pressure gradient across the capillary wall (π_c – π_i) may not change appreciably.

Lymphatic Obstruction:

As noted , the lymphatic system serves to return interstitial fluid formed by capillary filtration to the vascular system.

Obstruction of a lymphatic duct interferes with this process, and as a result, interstitial fluid accumulates in the portion of the body drained by the obstructed duct (i.e., edema forms).
As this interstitial fluid accumulates, the interstitial hydro-static pressure increases, and eventually a new steady state is reached where the Starling forces are once again balanced and no additional fluid accumulates.
However, unless the obstruction is corrected, the area. Edema can be classified as localized or generalized.

Localized edema, as the name denotes, represents the abnormal accumulation of interstitial fluid in a specific area or region of the body.

Common causes of localized edema include insect stings and lymphatic obstruction.
The venom of many stinging or biting insects contains substances that either directly increase capillary permeability or cause the release of mediators of inflammation that have a similar effect.
In addition, the venom or inflammatory mediators may cause vasodilation. Increasing the permeability of the capillary, or in some cases the postcapillary venule, increases the filtration coefficient (Kf) and also can decrease the protein reflection coefficient.

Both effects can increase fluid movement out of the capillary, with the latter effect also altering the Starling forces by changing the protein oncotic pressure gradient.

Starling forces are further altered in response to the vasodilation (i.e., capillary hydrostatic pressure [Pc] is increased).
The net effect of these changes is that more fluid moves out of the capillary into the interstitium and localized swelling occurs.

Lymphatic obstruction often accompanies surgical treatment of tumors. For example, in some women with breast cancer, regional lymph nodes that drain the affected breast are surgically removed.

When those located in the axilla are removed, the draining of lymph from that arm may be impaired. As a result, edema may develop in the arm.
Generalized edema results when Starling forces across all capillary beds are altered. Edema may be present in the lungs (i.e., pulmonary edema) or throughout the systemic circulation (i.e., peripheral edema).

Peripheral edema is most commonly observed in the feet, ankles, and legs, where the force of gravity magnifies the changes in Starling forces (i.e., further increases P_c) and thereby causes more fluid to leave the capillary and enter the interstitium.

One of the most common causes of generalized edema is congestive heart failure.
In this condition, blood accumulates in the venous side of the circulation, raising P_c, which in turn causes fluid to move out of the capillary into the interstitium.

Generalized edema is also seen with renal diseases associated with the nephrotic syndrome.

In the nephrotic syndrome, glomerular capillary permeability is altered, allowing large quantities of albumin to be lost in the urine (albuminuria).
If the rate of loss exceeds the rate at which albumin is synthesized by the liver, the plasma [albumin] falls.

The reduction in plasma protein concentration, and thus nc, was thought to be the primary cause of edema formation in patients with nephrotic syndrome.

Because the oncotic pressure gradient across the capillary wall may not change appreciably (i.e., interstitial protein oncotic pressure also falls), it is likely that other factors are responsible for, or at least contribute to, the abnormal accumulation of fluid in the interstitial compartment.
Supporting this notion is the observation that edema does not spontaneously develop in rats deficient in albumin. It is now known that one of these other factors is primary NaCl retention by the distal tubule and collecting duct.

With damage to the glomerular filtration barrier, the serum protein plasminogen enters the renal tubules where it is cleaved to form plasmin by the serine protease urokinase (produced by proximal tubule cells).

Plasmin, also a serine protease, then cleaves the y-subunit of the epithelial Na⁺ channels present in the apical membrane of cells in the late distal tubule and collecting duct, thereby increasing the open time of these channels.
This phenomenon results in increased Na⁺ (and Cl^–) reabsorption. The ensuing retention of NaCl (along with water) increases vascular volume and thereby leads to an increase in P_c, increased movement of fluid into the interstitial compartment, and thus edema formation.

Drained by the obstructed lymphatic duct remains edematous even in this new steady state.

Capillary Permeability:

An increase in capillary permeability favors increased movement of fluid across the capillary wall and thus accumulation of excess fluid in the interstitial compartment.
The increased permeability also can alter the capillary reflection coefficient for protein(s), allowing more protein across the capillary and thus altering the protein oncotic pressure gradient
(π_c-π_i).

Role Of The Kidneys:

The role of the kidneys in edema-forming states is best illustrated by considering the situation that exists with heart failure. Because of decreased cardiac performance, venous pressure is elevated, and perfusion of the kidneys is impaired.

Regulation Of Extracellular Fluid Volume And Nacl Balance Mechanisms Involved In The Formation Of Generalized Edema

“Complications of ignoring ECF volume issues”

The increase in venous pressure alters the Starling forces (i.e., increased Pc) and causes fluid to accumulate in the interstitium.
At the same time, decreased cardiac performance (decreased cardiac output and blood pressure) reduces the ECV, which is misinterpreted by the body’s vascular volume sensors as a decrease in ECF volume.
The fall in ECF volume activates the renal sympathetic nerves and the renin-angiotensin-aldo-sterone system and causes AVP secretion. In response to these signals, the kidneys retain NaCl and water, as already described.

This retention of isotonic fluid expands the ECF volume and thus blood volume, thereby helping perpetuate a vicious cycle of fluid accumulation that can further exacerbate congestive heart failure.

Intravascular volume expansion also contributes to the increased Pc, increased interstitial fluid accumulation, and edema formation.
As fluid begins to accumulate in the interstitium, it is taken up by the lymphatics and returned to the systemic circulation. As noted, thoracic duct and right lymphatic duct flow is approximately 1 to 4 L/day.
The lymphatic system can increase this flow up to 20 L/day. Because a significant amount of lymph returns to the circulation at the level of regional lymph nodes, the actual amount of interstitial fluid returned to the systemic circulation by the lymphatic system can exceed 20 L/day.

Nevertheless, the capacity of the lymphatic system has a limit. When this limit is reached, edema fluid begins to accumulate.

The importance of NaCl retention by the kidneys in edema formation provides two approaches for treatment. The first involves dietary manipulation. The ultimate source of NaCl is the diet.
Thus if dietary intake of NaCl is restricted, the amount that can be retained by the kidneys is reduced and edema formation is limited. The second approach is to inhibit the kidneys’ ability to retain NaCl.
This inhibition is accomplished clinically by the use of diuretics, which, as described, inhibit Na⁺ transport mechanisms in the nephron. Thus NaCl excretion is increased and NaCl retention is blunted.