Changes In Gt Balance

The three systemic mechanisms for regulating Na+ excretion just discussed (changes in GFR, plasma aldosterone levels, and circulating natriuretic factors) may not be responsible for the rapid changes in sodium excretion in response to sudden alterations in ECF volume. Changes in GFR hold promise as potential modulators of Na+ excretion, but they are extremely difficult to demonstrate. Aldosterone appears to be an appropriate hormone for the day-to-day regulation of Na+ excretion over a relatively modest range, but it cannot account for the rapid natriuresis observed with volume expansion. ANP at physiologic concentrations has a rather modest effect on Na+ excretion, and the physiologic role of OLF remains to be demonstrated.

As discussed earlier, the proximal tubule normally reabsorbs a constant fraction (60-66%) of the filtered load of salt and water. However, this GT balance can be disturbed dramatically under pathologic conditions. In nephrotic syndrome or liver disease (in which large amounts of plasma volume are lost to the interstitial fluid), severe dehydration, or cardiac failure, the proximal tubule can increase its rate of Na+ and water reabsorption to 90% of the filtered load. On the other hand, when the ECF volume is expanded by NaCl or plasma infusion, the proximal tubule can decrease its rate of Na+ and water reabsorption to <50% of the filtered load. These changes occur rapidly and result in dramatic changes in Na+ delivery to the distal nephron and, thus, in dramatic changes in Na+ excretion.

The hormones known to influence proximal tubular reabsorption are listed in Table 2. However, all of

TABLE 2 Hormones Affecting Volume Reabsorption in the Proximal Tubule

Renal Nerves

As discussed in Chapter 24, strong firing of the renal sympathetic nerves produces a fall in GFR and a corresponding decrease in Na+ excretion. However, these levels of sympathetic firing are usually found under relatively nonphysiologic circumstances. Thus, this mechanism may be important in severe volume depletion, as occurs with hemorrhage or under conditions of decreased cardiac output due to heart failure. Under these circumstances, RBF and GFR fall, resulting in a decrease in Na+ excretion and in expansion of the ECF volume.

The renal nerves also have effects on renal Na+ reabsorption. These effects are exerted directly on the nephron rather than indirectly by changes in GFR. Acute denervation of the kidneys results in decreased Na+ reabsorption. On the other hand, low-level stimulation of the renal nerves results in Na+ and water retention because of increased proximal tubule reabsorption. Adrenergic fibers have nerve endings that release catecholamines in the proximal tubule and portions of the distal nephron. Norepinephrine increases Na+ reabsorption by stimulating the Na+-H+ antiporter in the proximal tubule. Thereby, even low-level sympathetic stimulation decreases Na+ excretion by enhancing its reabsorption in the proximal tubule.

As discussed earlier (see Fig. 3), sympathetic firing to the kidney, produced, for example, by ECF volume contraction, increases renin release from JG cells by activating ^-adrenergic receptors on these cells. The resulting renin release, acting via angiotensin II, also enhances aldosterone production, which increases Na+ reabsorption by CNT and principal cells in the ARDN. Angiotensin II also acts like norepinephrine to increase proximal tubular Na+ reabsorption by stimulating the Na+-H+ antiporter in proximal tubules.

Proximal volume reabsorption # Proximal volume reabsorption

Norepinephrine Parathyroid hormone (PTH)

Angiotensin II Dopamine

Thyroid hormone

Insulin

Glucagon

Peritubular Factors

The rate of salt and water reabsorption by the proximal tubule may also be affected by the efficiency with which the reabsorbed fluid can be taken up into peritubular capillaries. As discussed in Chapter 24, the uptake of fluid from the cortical interstitial space into peritubular capillaries is favored by the Starling forces present there. As shown in Fig. 4, normal renal interstitial pressure is relatively high and the hydrostatic pressure in the peritubular capillaries is low because it has been reduced by both the afferent and efferent arterioles. Furthermore, the colloid osmotic pressure of the capillaries is increased because of the filtration of fluid at the glomerulus. All of these factors produce a net driving force that is normally quite high in favor of absorption of fluid from the interstitium.

The peritubular capillary pressure depends on the resistances of the afferent and efferent arterioles. When these resistances increase, peritubular capillary pressure decreases, enhancing uptake of fluid into the peritubular capillaries, as shown in Fig. 4. On the other hand, dilation of these resistance vessels leads to an increased capillary pressure and decreased uptake.

Glomerular dynamics also influence the colloid osmotic pressure in peritubular capillaries and, thus, the force favoring fluid uptake. When the filtration fraction is increased, for example, by increased GFR at a constant renal blood flow, the increase in the filtration fraction elevates the colloid osmotic pressure in the peritubular capillaries, which increases their uptake of fluid. On the other hand, when the filtration fraction is low, peritubular colloid osmotic pressure is decreased.

The peritubular capillary and interstitial colloid osmotic pressures and the capillary and interstitial hydrostatic pressures are commonly referred to as peritubular factors. As discussed in Chapter 26 (see Fig. 7 of that chapter), the net driving force for uptake into the capillary may also change the permeability characteristics of the junctional complexes between cells. When peritubular capillary uptake is diminished, interstitial fluid pressure may rise, which may, in turn, distort junctions between the cells and increase the backflow of fluid from the interstitial space to the tubular lumen. This would decrease the net reabsorption of salt and water by the proximal tubule. These mechanisms could be responsible for the rapid natriuresis and diuresis observed when saline solutions are administered.

Prostaglandins, Bradykinin, and Dopamine

Cells within the kidney produce prostaglandins and bradykinin. In the plasma, bradykinin is also produced by the action of plasma kallikrein. Increased plasma kallikrein levels and renal kallikrein excretion is associated with natriuresis and diuresis. Infusion of prostaglandin E2 or I2, or of bradykinin, results in natriuresis and diuresis. These actions of the prosta-glandins and bradykinin appear to be due to their hemodynamic effects. They increase RBF with a lesser increase in the GFR. Thus, the filtration fraction falls and a lower colloid osmotic pressure favoring fluid uptake into the peritubular capillaries could lead to natriuresis and diuresis by the mechanisms discussed.

FIGURE 4 Effect of afferent and efferent arteriolar resistances on the Starling forces for fluid uptake in peritubular capillaries. With normal afferent and efferent arteriolar resistances (left panel), approximately 20% of the renal plasma flow is filtered at the glomerulus. The ultrafiltration of the protein-free fluid raises the average colloid osmotic pressure (COP) of the plasma and the peritubular capillaries. The resistance afforded by the two arterioles in series produces a lower hydrostatic pressure (P) in the peritubular capillaries. Both the increased colloid osmotic pressure and decreased hydrostatic pressure favor absorption of fluid from interstitial fluid space. With increasing afferent and efferent arteriolar resistances (right panel), total renal blood flow is reduced. A higher filtration fraction results in a higher average colloid osmotic pressure in the peritubular capillaries. Because of the higher resistances of the arterioles, hydrostatic pressure in the peritubular capillaries is reduced. The greater increase in colloid osmotic pressure and the greater decrease in hydrostatic pressure produce an increased driving force for fluid absorption.

FIGURE 4 Effect of afferent and efferent arteriolar resistances on the Starling forces for fluid uptake in peritubular capillaries. With normal afferent and efferent arteriolar resistances (left panel), approximately 20% of the renal plasma flow is filtered at the glomerulus. The ultrafiltration of the protein-free fluid raises the average colloid osmotic pressure (COP) of the plasma and the peritubular capillaries. The resistance afforded by the two arterioles in series produces a lower hydrostatic pressure (P) in the peritubular capillaries. Both the increased colloid osmotic pressure and decreased hydrostatic pressure favor absorption of fluid from interstitial fluid space. With increasing afferent and efferent arteriolar resistances (right panel), total renal blood flow is reduced. A higher filtration fraction results in a higher average colloid osmotic pressure in the peritubular capillaries. Because of the higher resistances of the arterioles, hydrostatic pressure in the peritubular capillaries is reduced. The greater increase in colloid osmotic pressure and the greater decrease in hydrostatic pressure produce an increased driving force for fluid absorption.

FIGURE 5 Primary mechanisms that conserve Na+ and ECF volume in true or functional hypovolemia.

Dopamine is synthesized in the kidney and has local actions that are mediated by receptors in both the proximal tubule and the distal nephron. Dopamine synthesis and excretion is elevated in natriuresis, and dopamine infusion causes natriuresis and diuresis. Dopamine has been found to inhibit Na+ reabsorption by both the proximal tubule and the collecting duct, and it inhibits the action of vasopressin in the collecting duct. Dopamine is sometimes used clinically in conjunction with diuretics to treat edema.

INTEGRATED CONTROL OF Na+ EXCRETION: A SUMMARY

As noted in the introduction, the factors that regulate Na+ excretion are multiple and overlapping. It is easy, therefore, to lose track of the primary feedback mechanisms that preserve Na+ balance on a day-to-day basis. Figures 5 and 6 summarize the interactions of these mechanisms that regulate Na+ excretion and thus extracellular volume, in hypovolemia and hypervolemia, respectively.

As shown in Fig. 5, the effects of hypovolemia can be produced either by a true deficit in ECF volume or in response to a perceived deficit in ECF volume resulting from low cardiac output, poor tissue perfusion, or renal disease, that is, functional hypovolemia. The primary response to hypovolemia is the systemic release of the three hypovolemic hormones: vasopressin, renin, and norepinephrine. Angiotensin II generation in response to renin has three effects that decrease Na+ excretion. It acts directly on proximal tubule cells to increase Na+ reabsorption. Angiotensin II also increases the secretion of aldosterone, which in turn increases Na+ reabsorption by CNT and principal cells in the ARDN. Finally, angiotensin II also decreases the GFR, which, by decreasing Na+ and water delivery to the loop of Henle, decreases Na+ excretion.

Norepinephrine released by nerve endings and epinephrine, which is released by the adrenal medulla as a stress hormone in response to volume contraction, have two primary effects to conserve Na+. They decrease the GFR by their action on the afferent and efferent arterioles, and they directly stimulate Na+ reabsorption by the proximal tubule. As discussed in the previous chapter, a reduction of the ECF volume by 5% or more produces high plasma vasopressin levels regardless of the plasma osmolality, and the resulting water retention can lead to hyponatremia. Vasopressin also acts directly on the CNT and principal cells of the ARDN to increase Na+ reabsorption.

In hypervolemia (Fig. 6), the release of the three hypovolemia hormones is suppressed. Natriuretic hormones such as ANP and possibly OLF are released, and they increase GFR while inhibiting Na+ reabsorption. Volume expansion may also be accompanied by

FIGURE 6 Primary mechanisms that enhance Na+ and water excretion in hypervolemia.

dilution of plasma proteins, resulting in a fall of the plasma colloid osmotic pressure. There is also an increase in renal interstitial fluid pressure. Both of the latter effects diminish the net uptake of fluid into the peritubular capillaries and thus decrease Na+ and water reabsorption by the proximal tubule.

Suggested Readings

Humphreys MH, Valentin J-P. Natriuretic humoral agents. In Seldin DW, Giebisch G, eds. The kidney: Physiology and pathophysiology, Vol 1, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2000, pp 1371-1410.

Kirchner KA, Stein JH. Sodium metabolism. In Narins RG, ed. Maxwell & Kleeman's clinical disorders of fluid and electrolyte metabolism, 5th ed. New York: McGraw-Hill, 1994, pp 45-80.

Navar LG, Inscho EW, Majid DSA, Imig JD, Harrison-Bernard WM, Mitchell KD. Paracrine regulation of the renal microcirculation. Physiol Rev 1996;76:425-536.

Palmer BF, Alpern RJ, Seldin RW. Physiology and pathophysiology of sodium retention. In Seldin DW, Giebisch G, eds. The kidney: Physiology and pathophysiology, Vol 1, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2000, pp 1473-1518.

Rose BD, Post TW. Clinical physiology of acid-base and electrolyte disorders, 5th ed. New York: McGraw-Hill, 2001, pp 239-284.

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