Water electrolyte exchange disorders, Edema

Volume Control

Protection of the intravascular volume is paramount to normal survival. Maintenance of the

extracellular fluid (ECF) volume involves the integration of factors that
(1) control thirst (e.g., increased plasma osmolarity (POsm) and angiotensin II [ATII]);
(2)activate the renin-angiotensin-aldosterone (RAA) system (e.g., reduced renal blood flow,
sympathetic nervous system stimulation);
(3) stimulate the baroreceptors in the arterial circulation (e.g., decreased effective arterial blood
volume);
(4) increase free water reabsorption to concentrate the urine (e.g., antidiuretic hormone); and
(5) increase renal reabsorption of Na+ and water.

Effective Arterial Blood Volume Effective arterial blood volume (EABV) is a conceptual term that
refers to the portion of the ECF that is in the vascular space. In most instances, it correlates directly
with the ECF volume.

Baroreceptors and the Renin-Angiotensin-Aldosterone System Control of the EABV is monitored

by the pressure impacting upon the high pressure arterial baroreceptors located in the aortic
arch and carotid sinus, and the flow of blood to the renal arteries. When the baroreceptors are
activated by a decreased EABV, signals are sent to the medulla to increase sympathetic tone,
leading to release of catecholamines. The release of catecholamines causes vasoconstriction of
peripheral resistance arterioles (increases diastolic blood pressure), venoconstriction (increases
venous return to the heart), an increase in heart rate (chronotropic effect), and an increase in
cardiac contractility (inotropic effect).

Signals are also sent to the supraoptic and paraventricular nuclei in the hypothalamus to synthesize
and release antidiuretic hormone (ADH; vasopressin) from nerve endings located in the posterior
pituitary. ADH enhances the reabsorption of free water (fH2O; water without electrolytes) from
the collecting tubules. in the kidneys and is a potent vasoconstrictor of the peripheral resistance
vessels.

Finally, the RAA system is activated owing to reduced blood flow to the juxtaglomerular (JG)
apparatus located in the afferent arterioles and by direct sympathetic stimulation of the JG
apparatus with subsequent release of the enzyme renin. Renin initiates the following reaction
sequence: it cleaves renin substrate (angiotensinogen) into angiotensin I (ATI), which is converted
by pulmonary angiotensin-converting enzyme (ACE) into angiotensin II (ATII).

ATII has four functions:

1. Vasoconstriction of peripheral resistance arterioles
2. Stimulation of aldosterone synthesis and release from the zona glomerulosa (aldosterone
increases Na+ reabsorption)
3. Direct stimulation of the thirst center in the brain
4. Enhances activity of the Na+/H+ antiporter in the proximal renal tubule.

All of these events are an attempt to increase the EABV before medical intervention. In
contradistinction, when there is an increase in EABV, there are many counterregulatory
mechanisms that act to eliminate the excess fluid before medical intervention. An increase in
EABV is associated with a corresponding increase in cardiac output. This stretches the arterial
baroreceptors, which triggers cessation of sympathetic outflow from the medulla. This, in turn,
leads to inhibition of ADH synthesis and release, vasodilation of peripheral resistance arterioles,
decreased cardiac contraction, inhibition of the RAA system, and decreased renal retention of Na+
and water.
Other counterregulatory factors include atrial natriuretic peptide (ANP), prostaglandin E2,
and brain natriuretic peptide (BNP). ANP is released from the left and right atria in response to
atrial distention (e.g., left- and/or right-sided heart failure). ANP has multiple functions, including
(1) suppression of ADH release,
(2) inhibition of the effect of ATII on stimulating thirst and aldosterone secretion,
(3) vasodilation of the peripheral resistance vessels,
(4) direct inhibition of Na+ reabsorption in the kidneys (diuretic effect), and
(5) suppression of renin release.

Prostaglandin E2
(1) inhibits ADH,
(2) blocks Na+ reabsorption in the kidneys, and
(3) is a potent intrarenal vasodilator that offsets the vasoconstrictive effects of ATII and the
catecholamines.
BNP (brain natriuretic peptide) increases in the blood when the right and/or left ventricles
experience volume overload (e.g., left- and/or right-sided heart failure).

Edema
A. Definition
• Increased fluid in the interstitial space of the extracellular compartment
B. Types
1. Transudate
a. Protein-poor (<3 g/dL) and cell-poor fluid.
b. Clinically associated with dependent pitting edema and body cavity effusions. The lack
of significant amounts of protein and complete absence of cells allows a transudate to obey
the law of gravity and to settle in dependent areas of the body (e.g., ankles when
standing, sacral area when supine).
c. Always associated with an alteration in Starling forces.
2. Exudate
a. Protein-rich (>3 g/dL) and cell-rich (e.g., neutrophils) fluid.
b. Produces swelling of tissue but no pitting edema, because of increased viscosity due
to increased protein and cells.
3. Lymphedema
a. Protein-rich fluid
b. Increased viscosity prevents pitting edema.
4.Myxedema
a. Primarily due to an increase in hyaluronic acid (a glycosaminoglycan)
b. Increased viscosity prevents pitting edema.

Approximately 60% of lean body weight is water, two thirds of which is intracellular. Most of the
remaining water is found in extracellular compartments in the form of interstitial fluid, the fluid
may be protein-poor (transudate) or protein-rich (exudate); only 5% of the body’s water is in blood
plasma.
Edema is an accumulation of interstitial fluid within tissues. Extravascular fluid can also collect in
body cavities such as the pleural cavity (hydrothorax), the pericardial cavity (hydropericardium),
or the peritoneal cavity (hydroperitoneum, or ascites). Anasarca is severe, generalized edema
marked by profound swelling of subcutaneous tissues and accumulation of fluid in body cavities.
Edema may be caused by:

• Increased hydrostatic pressure (e.g., heart failure)

• Increased vascular permeability (e.g., inflammation)
• Decreased colloid osmotic pressure, due to reduced plasma albumin
• Decreased synthesis (e.g., liver disease, protein malnutrition)
• Increased loss (e.g., nephrotic syndrome)
• lymphatic obstruction (e.g., inflammation or neoplasia)
• Sodium retention (e.g., renal failure)

The mechanisms of inflammatory edema are largely related to increased vascular permeability; the
noninflammatory causes are detailed in the following discussion. Fluid movement between the
vascular and interstitial spaces is governed mainly by two opposing forces—the vascular
hydrostatic pressure and the colloid osmotic pressure produced by plasma proteins. Normally,
the outflow of fluid produced by hydrostatic pressure at the arteriolar end of the microcirculation is
neatly balanced by inflow due to the slightly elevated osmotic pressure at the venular end; hence
there is only a small net outflow of fluid into the interstitial space, which is drained by lymphatic
vessels. Either increased hydrostatic pressure or diminished colloid osmotic pressure causes
increased movement of water into the interstitium. This in turn increases the tissue hydrostatic
pressure, and eventually a new equilibrium is achieved. Excess edema fluid is removed by
lymphatic drainage and returned to the bloodstream by way of the thoracic duct. The edema fluid
that accumulates owing to increased hydrostatic pressure or reduced intravascular colloid typically
is a protein-poor transudate; it has a specific gravity less than 1.012. By contrast, because of
increased vascular permeability, inflammatory edema fluid is a protein-rich exudate with a specific
gravity `usually greater than 1.020.
Increased Hydrostatic Pressure

Local increases in intravascular pressure can result from impaired venous return—for example, a
deep venous thrombosis in the lower extremity can cause edema restricted to the distal portion of
the affected leg. Generalized increases in venous pressure, with resultant systemic edema, occur
most commonly in congestive heart failure. Several factors increase venous hydrostatic pressure in
patients with congestive heart failure. The reduced cardiac output leads to hypoperfusion of the
kidneys, triggering the renin-angiotensin-aldosterone axis and inducing sodium and water
retention (secondary hyperaldosteronism). In patients with normal heart function, this adaptation
increases cardiac filling and cardiac output, thereby improving renal perfusion. However, the
failing heart often cannot increase its cardiac output in response to the compensatory increases in
blood volume. Instead, a vicious circle of fluid retention, increased venous hydrostatic pressures,
and worsening edema ensues. Unless cardiac output is restored or renal water retention is reduced
(e.g., by salt restriction or treatment with diuretics or aldosterone antagonists) this downward spiral
continues. Because secondary hyperaldosteronism is a common feature of generalized edema,
salt restriction, diuretics, and aldosterone antagonists also are of value in the management of
generalized edema resulting from other causes.

Reduced Plasma Osmotic Pressure

Under normal circumstances albumin accounts for almost half of the total plasma protein.
Therefore conditions in which albumin is either lost from the circulation or synthesized in
inadequate amounts are common causes of reduced plasma osmotic pressure. In nephrotic
syndrome, damaged glomerular capillaries become leaky, leading to the loss of albumin (and
other plasma proteins) in the urine and the development of generalized edema. Reduced albumin
synthesis occurs in the setting of severe liver disease (e.g., cirrhosis) and protein malnutrition.
Regardless of cause, low albumin levels lead in a stepwise fashion to edema, reduced intravascular
volume, renal hypoperfusion, and secondary hyperaldosteronism. Unfortunately, increased salt and
water retention by the kidney not only fails to correct the plasma volume deficit but also
exacerbates the edema, since the primary defect—low serum protein—persists.
Pathways leading to systemic edema resulting from heart failure,
renal failure, or reduced plasma osmotic pressure.

Lymphatic Obstruction

Impaired lymphatic drainage and consequent lymphedema usually result from a localized
obstruction caused by an inflammatory or neoplastic condition. For example, the parasitic infection
filariasis can cause massive edema of the lower extremity and external genitalia (so-called
elephantiasis) by engendering inguinal lymphatic and lymph node fibrosis. Infiltration and
obstruction of superficial lymphatics by breast cancer may cause edema of the overlying skin; the
characteristic finely pitted appearance of the skin of the affected breast is called peau d’orange
(orange peel). Lymphedema also may occur as a complication of therapy. One relatively common
setting for this clinical entity is in women with breast cancer who undergo axillary lymph node
resection and/or irradiation, both of which can disrupt and obstruct lymphatic drainage, resulting in
severe lymphedema of the arm.

Sodium and Water Retention

Excessive retention of salt (and its obligate associated water) can lead to edema by increasing
hydrostatic pressure (due to expansion of the intravascular volume) and reducing plasma osmotic
pressure. Excessive salt and water retention are seen in a wide variety of diseases that compromise
renal function, including poststreptococcal glomerulonephritis and acute renal failure. Edema is
easily recognized on gross inspection; microscopic examination shows clearing and separation of
the extracellular matrix elements.
Pathogenesis of Edema
1. Transudates are associated with an alteration in Starling forces.
a. Two Starling forces present in the vascular system (capillaries/venules) are
hydrostatic pressure (HP) and oncotic pressure (OP).
(1) HP favors movement of fluid (transudate) out of capillaries/venules.
(2) OP equates with the serum albumin level and opposes filtration of fluid out of
capillaries/venules.
(3) In normal circumstances, plasma OP is greater than HP .

b. Clinical examples of increased HP include:

(1) Pulmonary edema in left-sided heart failure
(2) Peripheral pitting edema in right-sided heart failure (RHF)
 (3) Portal hypertension (PH) in cirrhosis producing ascites

c. Clinical examples of decreased OP (hypoalbuminemia) producing peripheral pitting

edema and ascites include:
(1) Malnutrition with decreased protein intake
(2) Cirrhosis with decreased synthesis of albumin
(3) Nephrotic syndrome with increased loss of protein in urine (>3.5 g/24 hours)
(4) Malabsorption with decreased absorption of protein

d. Clinical example where both HP and OP are involved

• Ascites in cirrhosis—↑hydrostatic pressure (portal vein hypertension), ↓oncotic pressure
(hypoalbuminemia)

e. Renal retention of sodium and water

(1)This increases HP (increasesplasma volume) and decreases OP (dilutional effect
on albumin).
• Periorbital edema is a common finding due to the loose interstitial tissue in that area
(renal edema). (2) Examples — acute and chronic renal failure, glomerulonephritis
2. Lymphatic obstruction
a. It produces lymphedema.
b. Examples include:
(1) Lymphedema following modified radical mastectomy and radiation
(2) Lymphedema in filariasis (human parasitic worm).

In the previously discussed pitting edema states, the cardiac output is decreased, because fluid is
trapped in the interstitial space and body cavities. A decrease in cardiac output causes the release
of catecholamines, activation of the renin-angiotensin-aldosterone system, stimulation of
antidiuretic hormone (ADH) release, and increased renal retention of Na+. This further exacerbates
the pitting edema and body cavity effusions. Unfortunately, the cardiac output will continue to be
decreased until the cause of the decreased cardiac output is corrected.

Subcutaneous edema can be diffuse but usually accumulates preferentially in parts of the body
positioned the greatest distance below the heart where hydrostatic pressures are highest. Thus,
edema typically is most pronounced in the legs with standing and the sacrum with recumbency, a
relationship termed dependent edema. Finger pressure over edematous subcutaneous tissue
displaces the interstitial fluid, leaving a finger-shaped depression; this appearance is called pitting
edema.

Edema due to renal dysfunction or nephrotic syndrome often manifests first in loose connective
tissues (e.g., the eyelids, causing periorbital edema – loose connective tissue) – periorbital
edema.

With pulmonary edema, the lungs often are two to three times their normal weight, and sectioning
reveals frothy, sometimes blood-tinged fluid consisting of a mixture of air, edema fluid, and
extravasated red cells.

• Brain edema can be localized (e.g., due to abscess or tumor) or generalized, depending on the
nature and extent of the pathologic process or injury. With generalized edema, the sulci are
narrowed while the gyri are swollen and flattened against the skull.

The Nephrotic Syndrome

The nephrotic syndrome refers to a clinical complex that includes:
• Massive proteinuria, with daily protein loss in the urine of 3.5 g or more in adults
• Hypoalbuminemia, with plasma albumin levels less than 3 g/dL
Generalized edema, the most obvious clinical manifestation
• Hyperlipidemia and lipiduria.
The nephrotic syndrome has diverse causes that share common mechanisms. In all there is
a derangement in the capillary walls of the glomeruli that results in increased permeability to
plasma proteins. Any increased permeability resulting from either structural or
physicochemical alterations in the glomerular basement membrane (GBM) allows protein to
escape from the plasma into the glomerular filtrate.
With long-standing or extremely heavy proteinuria, serum albumin is decreased, resulting in
hypoalbuminemia and a drop in plasma colloid osmotic pressure. The resulting decrease in
intravascular volume and renal blood flow triggers increased release of renin from renal
juxtaglomerular cells. Renin in turn stimulates the angiotensin-aldosterone axis, which
promotes the retention of salt and water by the kidney. These alterations further aggravate
the edema and if unchecked may lead to the development of generalized edema (anasarca).
The genesis of the hyperlipidemia is more obscure. Presumably, hypoalbuminemia triggers
increased synthesis of lipoproteins in the liver or massive proteinuria causes loss of an
inhibitor of their synthesis.
The most frequent systemic causes of the nephrotic syndrome in adults are diabetes, amyloidosis,
and systemic lupus erythematosus.
The most important of the primary glomerular lesions that characteristically lead to the nephrotic
syndrome are focal and segmental glomerulosclerosis. Membranous nephropathy and
membranoproliferative glomerulonephritis, also commonly produce the nephrotic syndrome.

The Nephritic Syndrome The nephritic syndrome is a clinical complex, usually of acute onset,
characterized by (1) hematuria with dysmorphic red cells and red cell casts in the urine; (2) some
degree of oliguria and azotemia; and (3) hypertension. Although proteinuria and even edema also
may be present, these usually are not as severe as in the nephrotic syndrome. The lesions that
cause the nephritic syndrome have in common proliferation of the cells within the glomeruli, often
accompanied by an inflammatory leukocytic infiltrate. This inflammatory reaction severely injures
the capillary walls, permitting blood to pass into the urine and inducing hemodynamic changes that
lead to a reduction in the GFR (Glomerular Filtration Rate). The reduced GFR is manifested
clinically by oliguria, fluid retention, and azotemia. Hypertension probably is a result of both the
fluid retention and some augmented renin release from the ischemic kidneys.