Chapter 036. Edema (Part 2)

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Reduction of Effective Arterial Volume In many forms of edema, the effective arterial blood volume, a parameter that represents the filling of the arterial tree, is reduced. Underfilling of the arterial tree may be caused by a reduction of cardiac output and/or systemic vascular resistance. As a consequence of underfilling, a series of physiologic responses designed to restore the effective arterial volume to normal are set into motion. A key element of these responses is the retention of salt and, therefore, of water, ultimately leading to edema. Renal Factors and the Renin-Angiotensin-Aldosterone (RAA) System (See also Chap. 336) In the final...

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Chapter 036. Edema (Part 2) Reduction of Effective Arterial Volume In many forms of edema, the effective arterial blood volume, a parameter that represents the filling of the arterial tree, is reduced. Underfilling of the arterial tree may be caused by a reduction of cardiac output and/or systemic vascular resistance. As a consequence of underfilling, a series of physiologic responses designed to restore the effective arterial volume to normal are set into motion. A key element of these responses is the retention of salt and, therefore, of water, ultimately leading to edema. Renal Factors and the Renin-Angiotensin-Aldosterone (RAA) System (See also Chap. 336) In the final analysis, renal retention of Na + is central to the development of generalized edema. The diminished renal blood flow
characteristic of states in which the effective arterial blood volume is reduced is translated by the renal juxtaglomerular cells (specialized myoepithelial cells surrounding the afferent arteriole) into a signal for increased renin release (Chap. 336). Renin is an enzyme with a molecular mass of about 40,000 Da that acts on its substrate, angiotensinogen, an α2-globulin synthesized by the liver, to release angiotensin I, a decapeptide, which is broken down to angiotensin II (AII), an octapeptide. AII has generalized vasoconstrictor properties; it is especially active on the efferent arterioles. This efferent arteriolar constriction reduces the hydrostatic pressure in the peritubular capillaries, while the increased filtration fraction raises the colloid osmotic pressure in these vessels, thereby enhancing salt and water reabsorption in the proximal tubule as well as in the ascending limb of the loop of Henle. The RAA system has long been recognized as a hormonal system; however, it also operates locally. Intrarenally produced AII contributes to glomerular efferent arteriolar constriction, and this "tubuloglomerular feedback" causes salt and water retention. These renal effects of AII are mediated by activation of AII type 1 receptors, which can be blocked by specific antagonists [angiotensin receptor blockers (ARBs)]. The mechanisms responsible for the increased release of renin when renal blood flow is reduced include: (1) a baroreceptor response in which reduced renal perfusion results in incomplete filling of the renal arterioles and diminished stretch
of the juxtaglomerular cells, a signal that increases the elaboration and/or release of renin; (2) reduced glomerular filtration, which lowers the NaCl load reaching the distal renal tubules and the macula densa, cells in the distal convoluted tubules that act as chemoreceptors and that signal the neighboring juxtaglomerular cells to secrete renin; and (3) activation of the β-adrenergic receptors in the juxtaglomerular cells by the sympathetic nervous system and by circulating catecholamines, which also stimulates renin release. These three mechanisms generally act in concert to enhance Na+ retention and, thereby, contribute to the formation of edema. AII that enters the systemic circulation stimulates the production of aldosterone by the zona glomerulosa of the adrenal cortex. Aldosterone, in turn, enhances Na+ reabsorption (and K+ excretion) by the collecting tubule. In patients with heart failure, not only is aldosterone secretion elevated but the biologic half- life of aldosterone is prolonged, which increases further the plasma level of the hormone. A depression of hepatic blood flow, especially during exercise, is responsible for reduced hepatic catabolism of aldosterone. The activation of the RAA system is most striking in the early phase of acute, severe heart failure and is less intense in patients with chronic, stable, compensated heart failure. Increased quantities of aldosterone are secreted in heart failure and in other edematous states, and blockade of the action of aldosterone by spironolactone (an aldosterone antagonist) or amiloride (a blocker of epithelial Na+ channels) often
induces a moderate diuresis in edematous states. Yet, persistently augmented levels of aldosterone (or other mineralocorticoids) alone do not always promote accumulation of edema, as witnessed by the lack of striking fluid retention in most instances of primary aldosteronism (Chap. 336). Furthermore, although normal individuals retain some NaCl and water with the administration of potent mineralocorticoids, such as deoxycorticosterone acetate or fludrocortisone, this accumulation is self-limiting, despite continued exposure to the steroid, a phenomenon known as mineralocorticoid escape. The failure of normal individuals who receive large doses of mineralocorticoids to accumulate large quantities of extracellular fluid and to develop edema is probably a consequence of an increase in glomerular filtration rate (pressure natriuresis) and the action of natriuretic substance(s) (see below). The continued secretion of aldosterone may be more important in the accumulation of fluid in edematous states because patients with edema secondary to heart failure, nephrotic syndrome, and hepatic cirrhosis are generally unable to repair the deficit in effective arterial blood volume. As a consequence, they do not develop pressure natriuresis. Arginine Vasopressin (AVP) (See also Chap. 334) The secretion of AVP occurs in response to increased intracellular osmolar concentration, and by stimulating V2 receptors, AVP increases the reabsorption of free water in the renal distal tubule and collecting duct, thereby increasing total-body water. Circulating AVP is elevated in many
patients with heart failure secondary to a nonosmotic stimulus associated with decreased effective arterial volume. Such patients fail to show the normal reduction of AVP with a reduction of osmolality, contributing to edema formation and hyponatremia.