Clinical Note

Functional Hypovolemia

Congestive heart failure, liver disease with ascites (ECF accumulation in the peritoneal cavity), and the nephrotic syndrome are all characterized by avid renal retention of NaCl and water despite the presence of often-dramatic edema. The preceding Clinical Note presented situations in which edema could be present but in which the plasma volume is diminished. In these situations, decreased vascular filling is an appropriate signal for salt and water retention. However, in the three conditions considered here, most typically both the interstitial and vascular components of the ECF volume are increased as evidenced by edema and venous congestion (neck vein distension, increased central venous pressure).

In congestive heart failure, the underlying problem is usually a reduced cardiac output that provides inadequate perfusion of the tissues, including the kidneys. However, heart failure can also occur in a situation of normal or increased cardiac output due to an arteriovenous (AV) anastomosis such as a fistula, in which case most of the cardiac output is shunted to the venous side without perfusing the organs.

In liver disease, AV anastomoses are also the primary cause of poor tissue perfusion. These anastomoses occur in the liver, possibly because of hypertension in the portal circulation, but they also occur for unknown reasons in the skin and other organs. In the skin, the anastomoses form spiderlike angiomas characteristic of liver disease. The hypoproteinemia of liver disease can contribute to the edema as a result of the decreased colloid osmotic pressure of the plasma as discussed in the earlier Clinical Note on edema, but this effect is neutralized by increasing tissue hydrostatic pressure as the tissues are distended by edema.

In the nephrotic syndrome, NaCl and water retention appear to be an intrinsic response of the kidney to the disease process and directly result in the expansion of ECF volume and edema. Again one might reason that the edema occurs as a consequence of the loss of plasma proteins in the urine, but it is found that if steroid administration is effective in countering the autoimmune response, salt and water excretion increase dramatically before plasma proteins are restored.

In each of the three diseases, the characteristic sign is the presence of low urine Na+ concentration (<25 mmol/L) in a hypertonic urine, together with marked edema. In each situation, the mechanisms regulating Na+ and water excretion are responding as if the patient were volume depleted (both Na+ and water are being retained) despite the edema and vascular congestion. For this reason they are referred to collectively as examples of functional hypovolemia.

Changes in Glomerular Filtration Rate

Changes in the GFR result in a proportional change in the filtered load of Na+. Normally, renal blood flow (RBF) and GFR are maintained relatively constant by autoregulation and by the tubuloglomerular feedback mechanism. However, as discussed in Chapter 24, renal blood flow and GFR can be reduced by increased sympathetic nerve input to the kidney, circulating catecholamines, and angiotensin II. It is important to recognize that small changes in GFR that would not normally be detectable can result in marked changes in the rate of Na+ excretion.

When GFR changes, the proximal tubule reabsorbs a constant fraction of the filtered load of salt and water. In other words, the rate of proximal tubule salt and water reabsorption increases with increasing GFR so that the fraction of the filtered load that is reabsorbed remains constant. This response is referred to as glomerulotubular balance (GT balance). Under normal conditions, 60-66% of the filtered load of Na+ is reabsorbed in the proximal tubule. However, we need to consider the rate at which salt and water are passed on to the loop of Henle and distal nephron when the GFR changes. Because the proximal tubule acts like a mass reabsorber that adjusts its rate of reabsorption to match the rate of filtration, it delivers a constant fraction of the filtered Na+ to the loop of Henle. However, the absolute amount of this filtered salt and water that leaves the proximal tubule increases as the filtered amount increases. Considering Fig. 1, let us assume that the GFR increases by 10%. This would increase the filtered load of Na+ from 25,000 to 27,500 mmol/day. The proximal tubule would increase its rate of reabsorption so that a constant fraction of about 64% would be reabsorbed. Thus, reabsorption would increase from 16,000 to 17,600 mmol/day. However, this would leave an unreabsorbed Na+ flow of (27,500 - 17,600) = 9900 mmol/day that would be passed on to the loop of Henle. Thus, despite the increased Na+ reabsorption by the proximal tubule in response to the increased rate of filtration, a larger amount of Na+ flows out of the proximal tubule.

The thick ascending limb of the loop of Henle responds to the increased load by increasing its rate of Na+ reabsorption, but it too does not completely compensate. Consequently, increased amounts of salt and water are passed on to the distal nephron, which has a fixed rate of reabsorption unless this is altered by aldosterone. Therefore, the extra amount of filtered Na+ that is passed on to the distal nephron by a small increase in GFR can represent a large amount of Na+ in comparison with the usual rate of excretion of 25-250 mmol/day. For this reason, subtle changes in GFR can produce quite marked changes in Na+ excretion merely by delivering more Na+ to the distal nephron. Unfortunately, it is experimentally extremely difficult to reliably detect GFR changes of less than 10%, even though such changes could result in significant changes in Na+ excretion. Other than the changes with eating described next, it is thought that the GFR is relatively constant in humans. Nevertheless, changes that would not normally be detectable could regulate Na+ excretion.

GFR in humans increases with the ingestion of food, particularly a high-protein meal. GFR increases begin 30-60 minutes after the meal and reach a peak 20-50% above baseline within 1-2 hr. This increase in GFR can last for 3-6 hr, depending on the rate of gastric emptying and the size of the meal. The reason for this postprandial increase in GFR is not known. It could result from the effects of intestinal hormones on the renal circulation, the direct effect of an increased concentration of circulating amino acids, or from neurally mediated changes in afferent and efferent arterial resistance. Nevertheless, this increase in GFR can produce natriuresis and diuresis.

Natriuresis and diuresis are also known to be associated with increases in systemic blood pressure, a phenomenon referred to as pressure natriuresis. A 50% increase in systolic blood pressure can lead to a three- to fivefold increase in both urine flow and Na+ excretion. Nevertheless, as discussed in Chapter 24, GFR and RBF are not observed to change as blood pressure rises because of the phenomenon of autoregulation. However, it is difficult to state with certainty that a GFR increase could not explain the pressure natriuresis. As noted earlier, even relatively subtle changes in the GFR lead to substantial changes in the rate of Na+ excretion. Alternatively, blood pressure may affect the relative influence of other local hormones on the rate of Na+ reabsorption in the nephron.

Renin, Angiotensin, and Aldosterone

In Chapter 27, we considered the mechanisms involved in regulating ion transport in the connecting tubule and the collecting duct by aldosterone. Aldoste-rone is known to increase Na+ reabsorption by increasing Na+ entry across the luminal membrane of CNT and principal cells, by increasing the number of Na+,K+-ATPase pumps, and by increasing metabolism in these cells. However, aldosterone normally regulates the excretion of Na+ only in the range of 0.1-2.0% of the filtered load. As noted in Chapter 27, even in the complete absence of aldosterone, only about 2% of the filtered Na+ load is excreted.

Aldosterone also has a relatively slow effect on Na+ reabsorption by the connecting tubule and collecting duct. It normally takes at least 2 hr to see an effect of a change in the plasma aldosterone level, and the full effect is not experienced for 12-24 hr. Consequently, it is unlikely that aldosterone is involved in the rapid regulation of Na+ excretion as occurs, for example, when a large bolus of isotonic saline is infused intravenously or after a hemorrhage. In these circumstances, the rate of Na+ excretion is altered rapidly and dramatically with immediate effects that cannot be attributed to aldosterone. Thus, it appears that aldosterone is more important in regulating the day-to-day excretion of Na+ to match variations in Na+ intake in the diet.

In Chapter 27, the various stimuli that increase aldosterone secretion by the adrenal cortex were presented in Table 1. Which of these factors would be involved in increasing aldosterone production in the face of a falling extracellular volume? As discussed earlier, a decrease in ECF volume is not usually accompanied by a change in either the plasma Na+ or K+ concentration because the vasopressin mechanism maintains a constant plasma osmolality and, thus, constant concentrations of the constituent solutes. In most cases of clinical importance, changes in aldosterone secretion by the adrenal cortex are produced by changes in the circulating angiotensin II levels.

Figure 3 shows the feedback mechanism that regulates renin secretion by the juxtaglomerular (JG) cells in the afferent arterioles, as discussed previously in Chapter 24. Renin secretion by the JG cells is increased by a variety of factors, but the common denominator for all of them is decreased vascular volume, blood pressure, or poor tissue perfusion (e.g., functional hypovolemia). As expected, this feedback mechanism responds to a decrease in ECF volume by decreasing renal Na+ and water excretion. Conversely, expansion of ECF volume diminishes renin secretion. The increased plasma angio-tensin II that is produced by renin secretion increases Na+ reabsorption in both the proximal and distal

29. Regulation of Sodium Balance and Extracellular Fluid Volume TABLE 1 Factors That Alter Renin Release from Juxtaglomerular Cells


Factors promoting renin release

# Blood volume or# ECF volume

"Functional hypovolemia" (edematous states: congestive heart failure, nephrotic syndrome, cirrhosis of the liver) PGE2 and PGI2

# NaCl delivery to the loop of Henle and distal nephron Factors inhibiting renin release

" Blood volume or" ECF

volume (even without " BP) Atrial natriuretic peptide (ANP; see next section of text) Cyclooxygenase inhibitors (NSAIDs)

" NaCl delivery to the loop of Henle and distal nephron ^-Adrenergic agonists

Intrinsic renal baroreceptor function of JG cells in afferent arteriole

Systemic baroreceptors and venous stretch receptors, via renal efferent nerves and

^-adrenergic effect of circulating catecholamines on JG cells to increase intracellular cAMP Above mechanisms augmented by decreased renal blood flow, and generalized poor tissue perfusion

Released by the kidney and act locally as paracrine and autocrine regulators of JG cells Macula densa cells sense decrease NaCl delivery; release ATP and/or adenosine to signal JG cells to release renin

Direct effect on JG cells in afferent arteriole to decrease renin release Decreased firing by systemic volume receptors such as stretch receptors in the veins and atria of the heart Circulating hormone from the atria of the heart directly inhibits renin release by JG cells

# Renal prostaglandin production, especially important in the setting of ECF

volume depletion, stress, or trauma Macula densa cells sense increased NaCl delivery and decrease ATP and/or adenosine release diminishing signal to JG cells Direct effect on JG cells to # cAMP

segments of the nephron. In the proximal tubule, angiotensin acts directly to augment the activity of the Na+-H+ exchanger. Angiotensin II indirectly stimulates Na+ reabsorption in the CNT and principal cells of the ARDN by stimulating zona glomerulus cells in the adrenal cortex to secrete aldosterone. As discussed in Chapter 24, angiotensin II also decreases RBF and GFR, which, in turn, decrease Na+ and water excretion for the reasons discussed earlier. Finally, angiotensin II also acts in the central nervous system to stimulate thirst.

Table 1 presents some of the most important factors that augment or diminish renin release as shown in Fig. 3. JG cells in the afferent arterioles function as stretch receptors and their intracellular Ca2+ concentration rises with increased wall stretch. When blood pressure falls, therefore, the intracellular Ca2+ concentration in the JG cells falls, resulting in increased renin secretion. Although renin secretion is the expected response to a decrease in blood pressure, the intracellular signaling system is unique because in most other secretory cells (e.g., the vasopressin secreting cells in the posterior pituitary) secretion is stimulated by a rise in intracellular Ca2+.

Decreased blood pressure and decreased vascular volume are sensed systemically by arterial baroreceptors and venous stretch receptors. Through central nervous system reflex mechanisms, the decreased blood pressure results in increased renal nerve activity resulting in ft-adrenergic stimulation of the JG cells. ^-Adrenoceptor stimulation increases cAMP levels in the JG cells, which also augments renin release. The JG cells also have ft-

adrenergic receptors, and ^-adrenergic agonists inhibit intracellular cAMP production and thus renin release.

Renin release by JG cells also responds to changes in NaCl delivery to the macula densa such that decreased NaCl delivery stimulates renin release and vice versa. As discussed in Chapter 24, the effect of NaCl delivery to the distal nephron on renin release is confusing in the context of the tubuloglomerular feedback mechanism. This feedback involves an increase in single nephron GFR in response to decreased NaCl delivery to the macula densa, which is opposite to what one would expect if angio-tensin II levels were raised by renin secretion. However, it is important to recognize that angiotensin II is not the mediator of the tubuloglomerular feedback mechanism. Furthermore, tubuloglomerular feedback operates on a local level to control the single nephron GFR, whereas the change in plasma renin levels in response to changes in NaCl and water flow to the macula densa occur as a generalized phenomenon in all nephrons. Although the macula densa cells are in proximity to the JG cells, no direct anatomic connection exists between the two. Recent evidence indicates that macula densa cells release ATP and/or adenosine, which stimulates JG cells to increase renin secretion as shown in Fig. 3.

The renin-angiotensin-aldosterone system is an important target of emerging drug therapy for hypertension because of its central role in the regulation of ECF volume. These drugs include inhibitors of the enzyme that converts angiotensin I to angiotensin II—so-called ACE inhibitors, as well as angiotensin II receptor blockers. Because there are at least two angiotensin II

1 pSssuIe \ i ECF v<*uw* I to macuTadensa

1 Tensron in t Sympalhetic Ucal release of

Srtfiriolfi • nonjo inn-iJl A atd wall nerve inpul ft circulating calechol amines

ATP and/or adenosine v

JG cells in afferent arteriole

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