EXTRACELLULAR FLUID VOLUME HOMEOSTASIS

1)Glomerular filtration rate

With a GFR of 120 ml/min (180 L/day) 25,000 mEq of sodium are filtered per day. In theory, small changes in GFR might be a powerful controlled mechanism for sodium conservation. However, recall that GFR is “autoregulated” to remain nearly constant in response to varying blood pressure. Moreover, a poorly understood phenomenon, glomerular-tubular balance, tends to keep fractional reaborption of sodium constant. Thus, changes in GFR are not the primary factor in maintaining extracellular fluid volume homeostasis.

Before considering the effector mechanism that acts on the kidneys, we will consider some quantitative aspects of regulation of sodium excretion by individual nephrons.

Consider a normal individual of stable weight whose dietary intake of sodium is 200 mEq/day. Urinary excretion will also be 200 mEq/day.

If his GFR is 125 ml/min (hence 180 1/day) and each liter of plasma contains 140 mEq of sodium (this is the normal value of plasma sodium), then 180 x 140 mEq of sodium will be filtered each day (25,000 mEq). This is known as the filtered load of sodium.

If 25,000 mEq is filtered and 200 mEq excreted, then the fraction of the filtered load excreted (the FENa) will be : (200/25,000) x 100 = 0.8%

This term is noted here because it is used frequently in clinical medicine and will be discussed again later in the course.

Hence the vast quantity of filtered sodium reabsorbed along the nephron. It is also clear from this simple example that even very small changes in the filtered load or sodium or that fraction that is reabsorbed along the nephron will exert a profound cumulative influence on sodium balance.

Two-thirds of the glomerular filtrate is reabsorbed in the proximal tubule without changing the osmolarity or sodium concentration of the unreabsorbed fraction. Through the Na reabsorption is active, it is strongly influenced by the oncotic and hydostatic pressure of the surrounding interstitium which is in turn influenced by events occurring in the glomerular capillary.

The decending limb of Henle’s loop is largely impermeable to sodium though the concentration of sodium increases due to abstraction of H₂O into the hypertonic interstitium. In the ascending limb of Henle’s loop there is a concentration gradient of sodium to passively leave the tubule so that the concentration of sodium at the junction of the thick and thin ascending limb is the same as the leaving the proximal tubule.

In the thick ascending limb there is an active reabsorption of NaCl – a process that makes the luminal fluid hypotonic and which pumps solute into the interstitium. The delivery of an appropriate quantity of NaCl from the proximal nephron to the thick ascending limb is an essential first step in the proccess of ordinary concentration and dilution and its clinical importance will become evident during discussion of disorders of sodium concentration. In the distal tubule, Na reabsorption continues and here may occur in exchange for potassium and hydrogen and may be influenced by aldosterone. The role of sodium reabsorption in the distal collecting duct is difficult to assess, but is probably more important than originally thought. The normal nephron is capable of making urine virtually Na-free when dietary sodium is very low and during severe volume contraction.

The collecting duct is probably important in the fine adjustment of sodium excretion.

1) Tubular reabsorption of sodium

A) Physical factors

The so-called “pump leak model” has been developed to explain sodium reabsorption in the proximal nephron (see figure). Sodium is actively transported, in part by a sodium-potassium ATPase, from tubular lumen to intercellular space.

There it may undergo two fates, either reabsorption into the peritubular capillary or diffusion back into the lumen. Reabsorption into the peritubular capillary is controlled by the same physical factors as any other capillary bed, oncotic and hydrostatic pressure, anything that increases oncotic pressure or reduces hydrostatic pressure will promote, tubular reabsorption of sodium.

Recall that in hypotension or volume contraction, GFR is in part maintained by efferent arteriolar constriction. This increases the filtration fraction (GFR/RBF), which are normally about 20%. Since albumin is not filtered, the increased filtration fraction will lead to an increased protein content and oncotic pressure in the peritubular capillary. Moreover, the increased efferent arteriolar constriction will reduce hydrostatic pressure in the peritubular capillary. Both of these effects will promote sodium reabsorption in the proximal tubule in states of decreased effective circulating volume.

B) Humoral factors:

1) Renin-angiotensin-aldosterone

A decreased in blood pressure or cardiac output will be sensed by the high-pressure intrarenal baroreceptor; renin is then released by the juxtaglomerular apparatus. Renin is a proteolytic enzyme which acts on its substrate, angiotensinogen, to produce the decapeptide angiotensin I. Angiotensin converting enzyme, converts angiotensin I to the active octapeptide angiotensin II. Angiotensin II has 3 primary actions in regard to sodium balance:

a) Increased systemic vascular resistance and maintain blood pressure.

b) Increased efferent arteriolar resistance, which increases GFR and promotes proximal reabsorption of sodium by its effect to increase filtration fraction and thus alter “physical factors”. (Increased oncotic pressure, reduce hydrostatic pressure).

c) Increased adrenal production of aldosterone by the zona glmerulosa.

Aldosterone is a steroid hormone, which binds to its cytosolic receptor in the late distal tubule

and collecting duct. Aldosterone increases mRNA and protein synthesis, and promotes sodium reabsorption either by direct stimulation of the active sodium transport mechanism or by increasing sodium permeability at the luminal membrane. The corollary of increased sodium transport a this nephron site is increased potassium and hydrogen ion secretion. To the left is a model of glomerulus showing the close approximation of the juxta glomerular apparatus including the macula densa to the afferent and efferent arteriole.

FACTORS REGULATING RENIN SECRETION

Factor	Effect
Renal Perfusion pressure
Increase	Inhibit
Decrease	Stimulate
NaCl delivery to the macula densa
Increased	Inhibit
Decreased	Stimulate
Angiotensin II	Inhibit
Plasma electrolytes
Potassium	Inhibit
Calcium	Inhibit
Prostaglandins (PgI2)	Stimulate
Sympathetic nervous system
b adrenergic stim	Stimulate
a adrenergic stim	Inhibit
Natruretic Factors
Dopamine	Inhibit
ANF	Inhibit
Other factor
Vasopressin	Inhibit
ACTH	Stimulate

The renin angiotensin system is tightly controlled by physical and hormonal signals. It is closely regulated by the build up of the product ang II which is a negative feedback inhibitor of renin release.

Dietary sodium closely controls renin release. Low sodium diet increased renin release while a high sodium diet suppresses renin release. In some hypertensive patients the release of renin is no longer controlled.

In these patients the renin angiotensin system may be important in the pathogenesis of the hypertension. This system will be discussed in greater detail in the section on hypertension.

Aldosterone is a powerful sodium-retaining hormone, which acts on the distal nephron (particularly in the cortical collecting duct) and leads to sodium reabsorption in exchange for potassium and hydrogen. Levels of aldosterone are affected by numerous factors including the “fullness” of the circulation. Thus, it is clearly a volume-sensitive hormone. These levels may also be increased by tumorous production from the adrenal glad – a phenomenon referred to as “primary hyperaldosteronism”.

The effect of aldosterone in sodium reabsorption can, however, be overridden.

This is illustrated by the so-called “escape phenomenon”. The escape phenomenon is not due to failure of an aldosterone effect in the nephron since potassium excretion remains high. The aldosterone effect is overcome by other factors that recognize the increased ECF volume and reduce sodium reabsorption elsewhere along the nephron.

2) Other hormonal factors – “Atriopeptin” of “Atrial Natriuretic Factors”

For many years the term “third factor” was used to express the concept that a further mechanism (in addition to GFR and aldosteorne) was critical in the control of sodium excretion. The sympathetic nervous system, through renal nerves, catecholamine hormones and intrarenal protstaglandins were shown to have a role in volume control.

There is much evidence suggesting the presence of a “natriuretic hormone” whose identify was controversial. ATRIOPEPTIN or ATRIAL NATRIURETIC FACTOR is a newly discovered peptide hormone that is intimately involved in the regulation of fluid homeostasis. Its function is illustrated in the figure below. Basal level of atriopeptin exist in the circulation, however plasma levels increase when the atria are stretched by volume expansion (as induced by high salt diet, atreal tachycardia, water immersion). Atriopeptin produces a variety of effects that induce loss of sodium and water from the body. The presence of an important volume regulating system in the atria is consistent with the concept of “central blood volume” discussed above.

Above is an overview of the factors involved in the regulation sodium excretion.

II. EDEMA. SODIUM DEPLETION

Edema is the accumulation of excess interstitial fluid, that is, extracellular fluid (ECF) not in vessels. This fluid resembles plasma in electrolyte content although protein content may vary. Edema may be localized due to local vasular or lymphatic injury of it may be generalized as in congestive heart failure.

FORCES GENERATING EDEMA

Edema is generated by an alteration in the physical forces described by Starling that determine the movement of fluid across the capillary endothelium. These forces and their magnitudes are displayed in the diagram. Alterations in these forces can explain the development of both localized and generalized edema. The two major events that can lead to accumulation of plasma ultrafiltrate in the interstitial space and the general mechanisms responsible are listed.

Increased Formation	Decreased Removal
1. Increased capillary oncotic pressure	1. Decreased plasma	Hydrostatic pressure
2. Increased capillary permeability	2. Impaired lymphatic outflow
3. Increased filtration time due to decreased vasomotion

The major specific causes of edema may be classified according to the mechanism responsible.

Increased Hydrostatic Pressure	Decreased Oncotic Pressure
1. Venous/lumphatic obstruction	1. Nephrotic syndrome
2. Congestive heart failure	2. Malabsorption
3. Cirrhosis of the liver	3. Cirrhosis of the liver
4. Primary salt excess (ARF, CRF)	4. Primary salt excess
Increased Capillary Permeability	Defined Mechanisms
1. Trauma such as burns	1. Idiopathic cyclic edema
2. Allergic reactions	2. Pregnancy
3. Diabetes mellitus	3. Hypothyroidism

FORCES MAINTAINING GENERALIZED EDEMA

The following schema illustrates that the final common pathway maintaining generalized edema is renal retention of excess sodium and water.

All generalized edema states can be conceived of as being caused by a decreased in “effective circulatory volume”. Effective circulatory volume is a conceptual or functional blood volume and not a measured blood volume. Effective circulatory volume is that volume is that volume of blood which perfuses some critical area of the body in which the volume-sensing mechanisms reside. It may also be defined as the blood volume which maintains a normal state of sodium balance. In clinical practice we tend to rely on the state of sodium balance to tell us about the state of the effective circulatory volume. Thus, in states of sodium retention we infer that the effective circulatory volume is decreased, whereas, in natriuretic states we infer that the effective circulatory volume is increased.

The factors that comprise effective circulatory volume have previously been listed and the difference between the effective circulatory volume and the actual volume is shown in the following figure. This figure highlights that it is the functional element of the volume rather than the measured compartment which determines the response of the interstitial and intravascular compartments and the effective circulatory volume is shown as the dark area of the lower right hand corner. Salt depletion leads to volume contraction with a fall in body weight. All compartments of the ECF are contracted under these conditions as the EABV. Salt loading on the other hand increases the volume of all compartments and the EABV. In the lower part of the diagram are four edema forming states in which the retained fluid is confined to one or other compartment of the ECF volume. In D fluid is trapped within a pathological compartment such as in the peritoneal cavity. Although total ECF volume may be normal under these circumstances the fact that part of this volume is confined to a space which is not in functional communication with the rest of the ECF leads to a contraction of the effective circulatory volume. In nephrotic syndrome there is an increase in the interstitial fluid compartment and yet effective circulatory volume is still perceived as being contracted. Similarly for congestive heart failure or surgical AV fistula. The pathodgenesis of edema formation and salt retention in several of these states will be discussed below.

In a, b and c, effective circulatory volumes correlates well with total ECF volume. In d, e, f, and g, effective circulatory volume is not well correlated with total ECF volume because of derangements in fluid distribution.

These factors are displayed in more detail in the following figures. N.B. Do not be overwhelmed at first glance. We do not expect to take pencil or quill in hand and trace through each pathway.

TREATMENT OF EDEMA

Based on the above considerations, therapy of the edematous states should be primarily based on therapy of the underlying defect. Some general principles in the treatment of edematous disorders follow:

1. Evaluate the adequacy of treatment of primary disease responsible for edema.

2. Evaluate the level of salt and water intake.

3. Attempt to mobilize the edema with bed rest and supportive stockings.

4. Evaluate the need for diuretics. Indications include impaired respiratory function, impaired cardiovascular function secondary to fluid overload, excess fluid limiting physical activity and causing discomfort, inability to consume a palatable diet due to the need for severe sodium restriction, and cosmetic effect (a marginal indication).

Diuretic therapy is often a necessary undertaking in the edematous disorders. The primary nephron sites of the action of various diuretics and displayed below.

The localization of the site of action of diuretic agents has been determined by clearance techniques. Several examples will be given?

1. Acetazolamide (carbonic anhydrase inhibitor): causes massive bicarbonaturia (greater than 20% filtered load) and phosphaturia, clearly inhibiting proximal functions.

2. Furosemide: decreased urinary concentrating capacity during antidiuresis, a medullary thick ascending limb function.

3. Thiazides: decreased free water clearance during water loading, a cortical ascending limb and early distal function.

4. Spironolactone: decreased potassium excretion, increased bicarbonate excretion, both distal functions (competes with aldosterone for its receptor).

Such knowledge of the site of action becomes very important when it becomes necessary to combine diuretics to achieve natriuresis.

As with any medication you prescribe, you must recall both the beneficial and the adverse effects.

Some Adverse Effects to Diuretics

All Diuretics	Acetazolamide
Volume contraction	Hypokalemia
Hyponatremia	Metabolic acidosis
Hematological problems
Gastrointestinal problems	Thiazides
	Hypokalemia
Spironalactone	Metabolic alkalosis
Hyperkalemia	Glucose intolerance
Gynecomastia	Hyperiuricemia
Menstrual disturbances	Hyperlipidemia
	Hypercalcemia
Furosemide	Hypersensitivity nephritis
Hypokalemia
Metabolic alkalosis	Triamterene, amiloride
Ototoxicity	Hyperkalemia
Hypersensitivity nephritis

Additionally al diuretics stimulate the renin-angiotensin-aldosterone axis. Therefore, they should be tapered rather than abruptly discontinued to avoid rebound sodium retention. This “rebound” has been hypothesized as a cause of the poorly understood phenomenon of “cyclic edema” in-patients who may be surreptitious diuretic abusers.

In summary, the following contribute to the choice of which, if any, diuretic agent should be used in the treatment of edema.

Considerations in choice of diuretics:

1. Define the objective of therapy and utilize all other appropriate modes of therapy (i.e., bed rest, digitalis, salt restriction, etc.)

2. Consider the potency of the diuretic agent and its duration of action compared to the severity of the edema. Potent loop diuretics (e.g. furosemide) should be reserved for advanced cases of fluid retention.

3. Consider the metabolic side effects of each diuretic. Potent diuretics have potentially serious side effects when compared to milder agents. Vigorous treatment with potent diuretics is a common precipitating event associated with electrolyte imbalance and worsening renal function.

4. Consider the cost and dosing schedules for diuretics in the same class and among different classes.

Note that intravascular volume may be depleted by diuretics despite the persistence of edema or ascites. The altered hemodynamic state resulting form this causes organ hypoperfusion, including the kidneys. Factors favoring sodium and water retention will be enhanced. Thus, a state of apparent diuretics resistance may appear. If more diuretic medication is given, serious organ dysfunction may result.

SUMMARY

Edema is the accumulation of excess interstitial fluid generated by alterations in capillary fluid transport. Renal sodium and water retention maintains and enhances edema. A state of positive sodium and water balance is present although a new steady state may occur in which edema is not increased and a transient state of zero balance may occur. Thus, generalized edema always means excess total body sodium and water. However, this does not mean that intravascular volume is even adequate. Treatment is directed at the underlying disorder, the most common of which are congestive heart failure, cirrhosis, nephrotic syndrome, and renal failure. Diuretics should be used with respect.

III. SODIUM DEPLETION STATES

Sodium depletion means extracellular volume depletion and reduced effective circulatory volume. Thus the compensating mechanisms responsible for sodium retention is sodium-depleted states are similar to these in edematous disorders.

ADAPTATION TO SODIUM DEPLETION

In order to protect blood pressure and hence tissue perfusion during sodium depletion, several mechanisms are activated. These mechanisms are directed to 1) maintain blood pressure at normal, 2) reduce renal sodium excretion to a minimum, and 3) increase or at least maintain ECF volume.

Blood pressure is supported by activation of the autonomic nervous system and the renin-angiotensin system. This result is vasoconstriction and maintenance of mean arterial pressure.

Renal sodium excretion is minimized by both reducing the amount of sodium filtered and by increasing tuular sodium reabsorption. The decreased ECF volume due to sodium depletion includes decreased intravascular plasma volume. This causes decreased renal perfusion pressure and a variable decrease in glomerular filtration rate and thus sodium filtration. Note that autoregulation tends to protect renal blood flow and glomerular filtration rate. Of more importance are changes in three factors that affect renal tubular sodium reabsorption: 1) increased aldosterone due to increased renin-angiotensin activity due to sympathetic nervous system and renal baro- and chemoreceptor activation; 2) increased peritubular physical forces favoring sodium reabsorption due to increased renal vascular resistance (angiotensin and autonomic nervous system) and increased plasma oncotic pressures and hematocrit; and 3) suppression of natriuretic hormone due to stimulation of volume receptors.

Volume depletion stimulates aldosterone to conserve sodium and antidiuretic hormone to conserve water via renal effects. Thirst and salt appetite are stimulated to allow for repletion of deficits. Sweat and fecal sodium and water content fall to minimize volume losses. The net result depends on which factor is disrupted by the disease state that initiated the sodium/volume depletion.

The factors responsible for maintenance of blood pressure, renal sodium conservation, and extrarenal sodium conservation are summarized in the following fugures:

“Effective circulating volume”

Some Adverse Effects to Diuretics