Renal regulation of extracellular fluid volume and osmolality.
Discuss the mechanism by which the kidney integrates signals from other body systems to control extracellular fluid volume and osmolality.
1. Describe the mechanisms by which sodium and water input and output are controlled.
2. Outline the neurological and endocrine effects on sodium and water homeostasis.
3. Compare and contrast the mechanisms for sodium, chloride and water transport in the proximal tubule, the thick ascending limb and the collecting duct.
Proper functioning of the cells of the body requires that their environment, the extracellular fluid (ECF), contain the fluid and electrolyte balance within narrow limits. All body systems, principally the cardiovascular, nervous and endocrine systems, contribute to maintaining fluid and electrolyte homeostasis. This article describes the mechanisms by which the kidneys integrate signals from other body systems to control the ECF volume and osmolality.
Paramount in the control of the ECF volume and osmolality is the regulation of sodium and water. The osmolality is set by the ratio of solute to water so that controlling either the amount of solute or water can set the extracellular osmolality to the optimal level. The osmolality and ionic composition of ECF are controlled within very narrow limits, as illustrated by the observation that a rise in body osmolality of as little as 1% to 2% results in a conscious desire to drink mad near maximal renal water conservation.
Body Requirements for Sodium and Water
Table 1 shows the typical routes of water gain and loss in adults in steady state. The majority of water gain comes from fluid and food intake, in addition, oxidation of food produces a small amount of water, primarily as a result of carbohydrate metabolism. While water loss is primarily in the form of urine, a sizable, insensible component of fluid loss occurs through evaporation from the skin and respiratory tract. This can be significantly augmented by evaporative loss from the skin in environments that induce sweating for thermal regulation. There is also a small fecal water loss. The major ways that fluid balance is controlled and maintained are through fluid intake (stimulated by thirst) and urine output.
Table 1 also shows the normal routes for the intake and output of sodium chloride (NACl). The majority of sodium ([Na.sup.+]) and chloride ([Cl.sup.-]) intake, which averages 10.5 grams per day, is through food ingestion. Sodium balance is controlled primarily by renal excretion of [Na.sup.+] and [Cl.sup.-]. The small amount of fluid lost through sweating is normally hypotonic. Sodium chloride loss via this route is modest except in situations that produce prolonged, copious sweating.
Homeostatic Control of Sodium and Water
Renal control and excretion of sodium, chloride, and water ([H.sub.2]O) is the most important contributor to the control of ECF volume and osmolality. There is no minimum requirement for sodium intake to maintain extracellular fluid homeostasis unless there are significant changes in body water osmolality due to [Na.sup.+] losses. In contrast, there is an obligatory water loss, and thus an obligatory water intake, to allow excretion of daily waste products (e.g., urea, sulfates, and phosphates). The typical daily production of these waste products requires a urine volume of at least 400-500 ml/day with a maximal osmolality of 1400 mOsm/L to allow for excretion.
The renal regulation of total body sodium simultaneously achieves regulation of the ECF. This is because sodium is essentially an extracellular solute so that changes in total body sodium are accompanied by virtually identical changes in the extracellular sodium. Since sodium and its associated anions account for more than 90% of all osmotically active ECF solutes, the amount of sodium in the ECF is the major determinant of the ECF volume. Thus ECF and plasma volume normally change in the same direction as total body sodium. Plasma volume, in turn, is a major determinant of cardiovascular pressures, which control total body sodium by acting directly on the kidneys and by stimulating reflexes that alter sodium and water excretion. The term effective circulating volume (ECV) is used to describe the vascular space of the ECF that perfuses tissues throughout the body. In normal states, the volume of the ECF and ECV, blood pressure, and cardiac output will increase as sodium levels rise and decrease as sodium levels fall. The kidneys respond to these changes through adjustment of sodium chloride excretion. In certain disease states (for example, congestive heart failure), blood pressure, cardiac output, and ECF and ECV volumes may not function as in normal states. In any case, the kidneys will adjust sodium excretion according to the ECV. The overall regulation of sodium and water excretion is highly complex with many interactions among neurological and hormonal stimuli. The major determinants of sodium and water excretion are depicted in Figure 1 and outlined in Table 2, but are described more fully in the text.
[FIGURE 1 OMITTED]
Control of sodium filtration. The kidneys play the major role in the maintenance of body sodium and water content. Because they are small and not bound to protein, sodium, chloride and water are all freely filtered at the glomerulus and are reabsorbed throughout most of the nephron. Since sodium is not also secreted, the amount that is finally excreted depends on filtration and reabsorption alone:
Amount [Na.sup.+] excreted = amount [Na.sup.+] filtered--amount [Na.sup.+] reabsorbed
The amount of [Na.sup.+] that is filtered is equal to the glomerular filtration rate (GFR) times the plasma concentration of sodium (P[Na.sup.+]). It is theoretically possible then to alter sodium excretion by altering GFR, P[Na.sup.+], and/or sodium reabsorption. Under normal conditions the plasma concentration of sodium does not vary greatly and therefore contributes little to the regulation of sodium excretion. GFR, on the other hand, is influenced by volume sensors, osmoreceptors, and arterial oncotic pressure.
Antidiuretic hormone (ADH), also known as vasopressin, is the primary regulator of the volume and osmolality of the urine, it is a small peptide (9 amino acids long) that is made in the hypothalamus. From there it is transported down the axon and stored in the nerve terminals located in the posterior pituitary gland. Hypothalamic synthesis and pituitary secretion of ADH occurs rapidly in response to hemodynamic and osmolality changes.
Volume sensors. Sodium reabsorption and GFR are controlled by extrarenal and intrarenal sensors. Extrarenal sensors located in the vascular system respond to changes in volume (stretch). High pressure sensors are located in the aortic arch and carotid sinus. A rise in vascular pressures (secondary to increased plasma volume, for example) stimulates these extrarenal baroreceptors to transmit signals to the brainstem via the vagus and glossopharyngeal afferent nerve fibers. Ultimately, the signal is transmitted to the ADH-producing cells of the hypothalamus to decrease ADH production and secretion. Low pres sure sensors are located in the walls of the cardiac atria and pulmonary vessels. Signals from the low volume sensors are transmitted to the ADH- producing cells of the hypothalamus to increase ADH production and secretion. Generally, a 5%-10% decrease in blood volume is necessary to stimulate ADH secretion.
Intrarenal solute sensors in the juxtaglomerular apparatus (JGA) sense changes in GFR via NaC1 concentration in the tubular fluid of the macula densa. Increased NaC1 concentration is associated with increased GFR, whereas decreased NaCl concentration is associated with de creased GFR. Signals from the JGA are transmitted to either dilate or constrict renal arterioles; this process is known as tubuloglomerular feedback. Dilation of the renal arterioles allows renal blood flow to increase, leading to a reduction in the normal rise of osmotic pressure along the glomerular capillary. The decreased osmotic pressure contributes to a higher net filtration pressure and consequently an increase in GFR. At the same time, increased vascular pressure within the kidneys stimulates intrarenal baroreceptors, decreasing renin secretion and angiotensin II. This also contributes to the vasodilation of the afferent and efferent arterioles, supporting the rise in GFR (and consequently, a rise in the amount of sodium filtered). In contrast, reduced stimulation of extrarenal and intrarenal baroreceptors leads to constriction of afferent and efferent arterioles and a reduction in renal blood flow. This results in a faster rise of osmotic pressure, which leads to filtration pressure equilibrium prior to the efferent end of the glomerular capillary bed. The consequence of this is that glomerular filtration stops earlier in the capillary bed, resulting in a reduction in GFR (and consequently, a fall in the amount of sodium filtered).
Osmoreceptors. Within the hypothalamus, osmoreceptor cells sense changes in ECF osmolality. The receptors selectively sense changes in the concentration of effective osmoses. These are solutes able to exert an osmotic pressure sufficient to balance the pressure exerted by intracellular solutes, thus resisting permeation of the cell membrane. Increases in effective ECF osmolality stimulate osmoreceptors to send signals to the hypothalamus to stimulate ADH synthesis and secretion. Conversely, decreases in effective ECF osmolality result in ADH inhibition. The osmoreceptors are highly sensitive, responding to osmolality changes in the ECF of as little as 1%.
Arterial oncotic pressure. A last contributor to GFR is arterial oncotic pressure (the pressure due to plasma protein concentration). As plasma protein concentration rises (secondary to severe sweating for example), GFR decreases; as the protein concentration falls, GFR increases. These changes have the effect of decreasing or increasing sodium and water excretion respectively, thereby correcting the initial change in oncotic pressure.
Control of sodium reabsorption. Changes in tubular sodium reabsorption have a greater effect on sodium excretion than do changes in the amount of sodium filtered. This is because the changes in GFR are small and these changes automatically induce proportional changes in sodium reabsorption by the proximal tubule, a phenomenon known as glomerulotubular balance. That is, if GFR decreases by 25%, the rate of sodium reabsorption also decreases by close to 25% in the proximal tubule. Glomerulotubular balance is maintained because sodium reabsorption in the proximal tubule is by cotransport with glucose, amino acids, and other substances. The higher the GFR filtered load of these substances, the higher the sodium reabsorption. Glomerulotubular balance is also influenced by oncotic and hydrostatic pressures between renal capillaries (Starling forces).
Homeostatic control of sodium excretion is achieved via changes in sodium reabsorption in the late distal and collecting tubules. This requires some explanation since more than 90% of the filtered sodium is reabsorbed before the filtrate even reaches these nephron segments. Aldosterone is the single most important controller of sodium excretion, despite the fact that only 2% of the total filtered sodium is dependent on it for reabsorption. Although this seems small, it is actually quite large because of the large amount of sodium that is filtered. Each day the total filtered sodium is equal to the GFR times the concentration of sodium in the plasma. This equals approximately 180 L/day times 145 mmol/L, or 26,100 mmol of sodium each day. Aldosterone controls the reabsorption of 2% of this or 522 mmol/day. This sums to approximately 30 g NaCl per day or 3 times more than the average NaCl intake (see Table 1).
Aldosterone is secreted by the adrenal cortex in response to adrenocorticotropic hormone (ACTH) released from the anterior pituitary gland, high levels of potassium, and angiotensin II. The latter stimulator of aldosterone is the most important in regard to sodium-regulating reflexes and is mediated by the renin angiotensin system. The factors that regulate renin secretion (intrarenal baroreceptors, the macula densa, and the renal sympathetic nerves) also regulate aldosterone secretion, in response to low plasma volume (due to low sodium intake or hemorrhage, for example), the kidney releases renin. Renin is a proteolytic enzyme that catalyzes the splitting of angiotensin I from a plasma protein known as angiotensinogen, which is produced mainly by the liver and is present in the plasma in high concentration. Next, the terminal two amino acids are split from the relatively inactive angiotensin I to yield the highly active octapeptide angiotensin II. This is catalyzed by angiotensin converting enzyme (ACE), found primarily within the pulmonary capillaries.
Although angiotensin II acts directly on the tubular cells to stimulate sodium reabsorption, it has two major additional effects: (a) it causes vasoconstriction, thereby raising blood pressure; and, (b) it stimulates the release of aldosterone from the adrenal cortex. Aldosterone travels via the blood stream to the late distal tubule and collecting ducts. Being a fat-soluble steroid, aldosterone enters the cells where it combines with intracellular receptors and stimulates the synthesis of mRNA within the cell nucleus. The mRNA mediates translation of specific proteins that increase the activity and/or number of the luminal membrane sodium channels and basolateral membrane [Na.sup.+]/[K.sup.+] ATPase pumps. These proteins cause more [Na.sup.+] to be reabsorbed and more [K.sup.+] to be secreted. In contrast, ingestion of a high sodium diet results in a reduction of renin secretion, plasma angiotensin II, and aldosterone secretion. Ultimately sodium and water excretion increase.
In addition to stimulating renin secretion, the renal sympathetic nerves stimulate sodium reabsorption by directly acting on proximal tubular cells. When impulses traveling through these nerves are very high, afferent and efferent arteriolar constriction occurs, resulting in a decrease in renal blood flow and GFR. Ultimately, proximal sodium reabsorption rises. The resulting decrease in fluid delivered to the macula densa is accompanied by decreased sodium and chloride concentrations in the macula densa lumen and decreased NaCl reabsorption by the macula densa cells. While the pathway by which this occurs is unclear, the decreased reabsorption by the macula densa stimulates renin secretion. The rise in renin ultimately results in vasoconstriction (due to angiotensin II) and increased sodium reabsorption (due to aldosterone). Conversely, when flow, and hence, NaCl concentration in the macula densa are high, renin secretion is inhibited.
Another hormone affecting sodium reabsorption is atrial natriuretic hormone (ANH), also known as atrial natriuretic peptide, atrial natriuretic factor, or atriopeptin. ANH is secreted from the cells in the cardiac atria in response to distention of the atria, secondary to plasma volume expansion. Its ultimate effects are opposite to those of aldosterone, inhibiting sodium, mad therefore water, reabsorption. ANH acts directly on the medullary collecting ducts and indirectly on other tubular segments (by inhibiting several steps in the renin-angiotensin-aldosterone pathway) to inhibit sodium reabsorption. It inhibits renin and aldosterone secretion, and causes an increase in GFR (via its effects on the renal arterioles), all of which increase sodium and water excretion.
Other hormones also influence sodium reabsorption, but are not reflexly controlled specifically for the homeostatic regulation of sodium balance. Cortisol, estrogen, growth hormone, thyroid hormone, and insulin all increase sodium reabsorption. In contrast, glucagon, progesterone, and parathyroid hormone decrease sodium reabsorption.
Control of water excretion. Like sodium, water excretion is the difference between the amount filtered and the amount reabsorbed. Similarly, the baroreceptor-initiated reflexes controlling GFR have the same effects on water filtration as on sodium filtration described earlier so that the major regulated determinant of water excretion is the rate of water reabsorption. Changes in ECF volume simultaneously elicit reflex changes in the excretion of both sodium and water. This works well since alterations in ECF volume are normally associated with loss or gain of sodium and water in approximately proportional amounts.
In situations whereby total body water increases without a proportional rise in total body sodium, the kidneys must be able to increase water excretion without increasing sodium excretion. The action of ADH is very important in managing such situations. As noted earlier, the ADH secreting hypothalamic cells receive two inputs, from baroreceptors and from osmoreceptors. An increase in plasma volume accompanied by a decrease in osmolality inhibits ADH secretion, while a decrease ha plasma volume accompanied by an increase in osmolality increase ADH secretion (see Table 2). In other cases, baroreceptor and osmoreceptor inputs oppose each other, if, for example, volume and osmolality are both decreased. Such situations wherein water and sodium balance are dissociated from one another occur in rare clinical conditions (for example, diabetes insipidus).
ADH acts on principal cells within the late distal tubule and the cortical and medullary collecting ducts and markedly increases the water permeability of the luminal membrane. Receptors located in the basolateral membrane of these tubular segments bind ADH, eliciting a second messenger that leads to the insertion of protein channels into the luminal membrane through which water can move. ADH also increases sodium reabsorption by the cortical collecting duct, appearing to synergize the effect of aldosterone in dais segment. If high enough concentrations of ADH result, ADH exerts direct vasoconstrictor effects on arteriolar smooth muscle, resulting in a rise in blood pressure. Concurrent constriction of renal arterioles and mesangial cells in the glomerular membrane lowers GFR, also promoting sodium and water retention.
Taken together, the interactions of various hormones and changes in renal vessel diameter allow the kidneys to maintain the ECF within very narrow limits conducive to optimal cell functioning. These effects are summarized in Table 2. In addition, homeostatic balance of salt and water may also be affected by altering the intake of these substances, as shown in Table 1. The centers that mediate thirst are located in the hypothalamus and are stimulated by reduced plasma volume and increased body fluid osmolality (the same stimuli that increase ADH secretion). Although salt craving does occur in humans who are severely salt depleted, its contribution to sodium homeostasis is probably minimal since, on a daily basis, we ingest 20 times the amount of salt needed.
General Renal Reabsorptive Mechanisms
As described earlier, alterations in reabsorption are the primary renal mechanism for regulation of sodium and water. The magnitude of sodium and water reabsorption can be appreciated in that approximately 180 liters of water and 630 grams of sodium are filtered every day by the kidney. In spite of this impressive filtered load, only about 0.5% to 1.0% of the filtered amounts are normally excreted in the urine.
Several pathways exist for the movement of ions and water between the tubule and the peritubular capillaries. One route is the transcellular pathway in which a solute traverses through the epithelial cells lining the tubules, moving through both the luminal and basolateral membranes. Transcellular ionic movement generally requires the expenditure of energy. Another transport route is the paracellular pathway, between or around cells through cellular junctional complexes and lateral intercellular spaces. Ionic movement via the paracellular pathway occurs passively by diffusion along chemical and/or electrical gradients and does not require energy expenditure directly. The permeability of the junctional complexes varies among nephron segments. In those nephron sites where the permeability of the junctional complexes is high, the paracellular movement of solute may dissipate the concentration gradients between the tubular lumen and the interstitium. In contrast, in tubule segments with low permeability of the junctional complexes, large solute concentration differences may be generated between the lumen, tubular cells, and the capillaries.
In general, primary active transport of sodium provides the energy for subsequent reabsorption of chloride and water. The [Na.sup.+]/[K.sup.+] ATPase pumps found on the basolateral membrane of all tubular segments are the primary active transport mechanism. Using ATP, they work diligently to exclude [Na.sup.+] from the cell while bringing [K.sup.1] into the cell. The low intracellular sodium provides the driving force for [Na.sup.+] movement across the luminal membrane. Depending on the tubular segment, the movement of [Na.sup.+] down this concentration gradient into the cell may be as a sodium ion alone, in cotransport with other organic substances such as amino acids and glucose or ions such as chloride, or in a countertransport mechanism with ions such as hydrogen. Transporters that do not require ATP directly, but are driven by the extracellular to intracellular sodium concentration gradient are called secondary active transporters.
The mechanisms by which [Na.sup.+] reabsorption drives reabsorption of other substances are varied. The loss of [Na.sup.+] from the tubular lumen decreases the osmolality of the tubular fluid while increasing the intracellular osmolality. Depending on the water permeability, water crosses the luminal membrane to restore osmotic equilibrium between these two compartments. Movement of water out of the lumen concentrates other intraluminal substances such as urea, allowing these substances to diffuse out of the lumen along their concentration gradients. In some nephron segments, such as the collecting duct, water permeability is under hormonal control and varies according to the body's osmolality. This reabsorption of water into the peritubular capillaries is dependent upon the presence of ADH and the hypertonic medullary interstitium, as described in an earlier article of this series.
Similarly, [Cl.sup.-] reabsorption occurs passively as a consequence of chemical and/or electrical concentration gradients between the tubular lumen, tubular cells, and the peritubular capillaries. The movement of sodium from the tubular lumen to the cell leads to the development of a lumen negative transtubular potential difference that drives [C1.sup.-] movement. In addition water reabsorption from the tubular lumen increases the luminal C1 concentration, which establishes a chemical gradient favoring [C1.sup.-] movement. In many segments [C1.sup.-] diffuses passively via the paracellular pathway driven by both chemical and electrical gradients established secondary to the active reabsorption of [Na.sup.+].
Specific Tubular Reabsorptive Mechanisms
The actual transport mechanisms differ among the various nephron segments. The segments of primary interest in sodium, chloride and water reabsorption are the proximal tubule, the loop of Henle, the late distal tubule, and the collecting ducts, as shown in Figure 2.
[FIGURE 2 OMITTED]
Proximal tubule. Over the course of the convoluted and straight portions of the proximal tubules, approximately 67% of filtered [Na.sup.+], [Cl.sup-], and water is reabsorbed. The large reabsorptive capacity is facilitated by the high permeability of the junctional complexes. As shown in Figure 3, the active movement of 3 [Na.sup.+] and 2 [K.sup.+] across the basolateral membrane by the [Na.sup.+]/[K.sup.+] ATPase pump creates both a chemical gradient and an electrical gradient that provide the energy needed to move [Na.sup.+] across the luminal membrane. The luminal entry of sodium requires various carriers that transport sodium coupled or in countertransport with other solutes across the luminal membrane.
[FIGURE 3 OMITTED]
In the early proximal tubule, [Na.sup.+] leaves the lumen in cotransport with phosphate or organic solutes such as amino acids and glucose. As a result, the luminal concentration of these solutes decreases and the intracellular concentration increases. These solutes then diffuse passively across the basolateral membrane into the peritubular capillaries. In this segment, the transcellular transport rates of sodium and chloride are quite high, but because the paracellular pathway is highly permeable to water, high sodium and chloride concentration gradients between the lumen and the interstitium are not generated.
Although there is some transport of [C1.sup.-] that occurs via ration counter-transport in the luminal membrane and cotransport with potassium across the basolateral membrane (not depicted in Figure 3), most [C1.sup.-] is passively reabsorbed via the paracellular pathway secondary to the chemical and electrical gradients established by [Na.sup.+] movement. Luminal [C1.sup.-] concentration increases because water is reabsorbed along the proximal tubule. The loss of [Na.sup.+] from the luminal fluid leads to a lumen negative potential difference. The chemical and electrical gradients allow [C1.sup.-] to diffuse out of the lumen and into the interstitial space.
In the proximal tubule, [Na.sup.+]' also crosses the luminal membrane in countertransport with hydrogen ion ([H.sup.+]), thereby exchanging electropositive ions. The dissociation of [H.sub.2]C[O.sub.3] within the proximal cells and subsequent movement of [H.sup.+] into the lumen enhances the secondary active reabsorption of bicarbonate in cotransport with sodium across the basolateral membrane. Thus bicarbonate reabsorption is mostly sodium-coupled. Further information regarding renal acidification is described in an earlier article of this series.
As a result of the tightly coupled reabsorption of sodium, chloride, and water over the course of the proximal tubule, tubular fluid undergoes little change in [Na.sup.+] concentration or osmolality. Luminal fluid bicarbonate concentration decreases to about 20% of filtered concentration and glucose falls to zero. In the presence of osmotic agents such as mannitol or high glucose concentration in the tubular fluid (often seen in patients with diabetes mellitus), water reabsorption may be sharply reduced, which leads to an osmotic diuresis. This situation can also lead to renal excretion of large quantities of [Na.sup.+] and [Cl.sup.-] because the retardation of water reabsorption leads to a drop in luminal [Na.sup.+] concentration, creating a concentration gradient favoring net diffusion of sodium into the tubular lumen and subsequent excretion.
Loop of Henle. The loop of Henle consists of several segments including the thin descending limb, the thin ascending limb of Henle, and the thick ascending limb. Together these segments reabsorb approximately 25% of filtered [Na.sup.+] and [Cl.sup.-] and about 15% of filtered water. The individual segments have important differences in [Na.sup.+] and water reabsorption. At the beginning of the thin descending limb where the tubular fluid has an osmolality of 300 mOsm/L, the interstitial osmolality is maintained at approximately 400 mOsm/L. At the tip of the loop, the interstitial osmolality may be as high as 1200 mOsm/L. The interstitial gradient is established by [Na.sup.+] and [C1.sup..-] reabsorption in the ascending limb of the loop and by urea reabsorption in the collecting ducts. Because the thin descending limb is highly permeable to water and relatively impermeable to [Na.sup.+] and [C1.sup.-], water moves out of the lumen into the hypertonic medullary interstitium. As a consequence, there is an increase in tubular fluid [Na.sup.+] and [Cl.sup.-] and urea concentrations as the tubular fluid travels through the descending limb.
In contrast, the thin and thick ascending limbs are highly permeable to [Na.sup.+] and [C1.sup.- ]while being impermeable to water. [Na.sup.+] and [C1.sup.-] are reabsorbed, contributing to the hypertonic medullary interstitium, and the tubular fluid becomes more dilute because water is not able to follow.
As tubular fluid moves into the thick ascending limb, more [Na.sup.+] and [C1.sup.-] than water has been reabsorbed leading to a relatively lower ion concentration and osmolality compared to plasma. As shown in Figure 4, [Na.sup.+] is moved across the basolateral membrane by the [Na.sup.+]/[K.sup.+] ATPase pump. Chloride moves out of the tubular cells into the interstitium in cotransport with potassium and via diffusion. The resulting low intracellular concentrations of sodium and chloride drive a luminal membrane carrier, known as a [Na.sup.+]/[K.sup.+]/2[C1.sup.-] cotransporter. Diffusion of potassium back across the luminal membrane (driven by the concentration gradient between the cell and the lumen) creates a lumen-positive voltage. The positive voltage favors passive sodium movement through paracellular pathways. In addition, this segment contains luminal [Na.sup.+]/[H.sup.+] counter-transport as previously described in the proximal tubule.
[FIGURE 4 OMITTED]
By the end of the ascending limb of the loop of Henle, more than 90% of filtered [Na.sup.+] and [C1.sup.-] and 80% of filtered water have been reabsorbed. Under normal homeostatic conditions, [Na.sup.+] and [C1.sup.-] reabsorption continues until the final urine contains less than 1% of the filtered [Na.sup.+] and [C1.sup.-] . However, the actual [Na.sup.+] and [C1.sup.-] reabsorption is under the physiologic control of aldosterone and varies as a function of the body's salt balance.
Early distal tubule. Although the early distal convoluted tubule also serves as a diluting segment, some of the transporters differ from those in the thick ascending limb. [Na.sup.+]/[K.sup.+] ATPase pumps are again located on the basolateral membrane, maintaining a low concentration of sodium intracellularly. Sodium crosses the luminal membrane in cotransport with [C1.sup.-] and by simple diffusion driven by the low intracellular sodium, and leaving behind a negative potential. [Cl.sup.-] reabsorption occurs via secondary active cotransport with [Na.sup.+] across the luminal membrane and passive diffusion across the basolateral membrane. Since the water permeability of the distal convoluted tubule is quite low, little or no water is reabsorbed in this nephron segment and the luminal fluid osmolality continues to decrease.
Late distal tubule and collecting duct. The late distal tubule is similar in function to the collecting duct. Two different cell types are involved in [Na.sup.+] and [C1.sup.-] reabsorption in these segments, principal cells and intercalated cells. As shown in Figure 5, [Na.sup.+] enters the principal cells through sodium channels and leaves the cells via the [Na.sup.+]/[K.sup.+] ATPase pump. Intercalated cells (not shown) reabsorb chloride. The luminal membrane contains [C1.sup.-]/HC[O.sup.3] counter-transporters; once inside the intercalated cell, [Cl.sup.-] diffuses passively across the basolateral membrane. In addition, some [C1.sup.-] reabsorption occurs by paracellular diffusion, driven by the lumen negative PD.
[FIGURE 5 OMITTED]
The final regulation of NaC1 and water reabsorption occurs by the late distal tubule and the collecting ducts under hormonal control. In the presence of aldosterone, the principal cells synthesize proteins that increase the activity and/or number of the luminal membrane sodium channels and the basolateral [Na.sup.+/[K.sup.+] ATPase pumps, ultimately increasing sodium reabsorption. In response to plasma volume expansion, ANH inhibits sodium reabsorption in the medullary collecting duct, resulting in natriuresis. The water permeability of these segments is under control of ADH secretion. Without ADH, the late distal tubule and collecting ducts are impermeable to water, and the water that is within the tubular fluid is excreted, resulting in a dilute urine. In contrast, in the presence of ADH, the late distal tubule and collecting ducts are permeable to water and water is reabsorbed in proportion to the interstitial fluid osmolality. A description of the mechanisms whereby the kidney is able to produce either a dilute or concentrated urine as needed is described in an earlier article of this series.
In summary, regulation of sodium, chloride, and extracellular fluid volume and osmolality is complex, but very efficient. The excretion of sodium and water is altered through changes in GFR and reabsorption. As summarized in Figure 1, these changes are stimulated by alterations in cardiovascular pressure and are mediated by the nervous system (signals passing through extrarenal and intrarenal baroreceptors) and the endocrine system (ADH, ANH, and aldosterone). Integration of the neural and hormonal signals by the kidney results in changes in filtration and reabsorption and, therefore, changes in sodium, chloride, and water excretion.
Ninety percent of the filtered sodium, chloride and water is reabsorbed by the proximal tubule, loop of Henle, and early distal tubule. Aldosterone, ADH, and ANH work primarily on the late distal tubule and collecting duct system to fine tune sodium reabsorption in accordance with our body's needs. In normal persons, the mechanisms for regulating sodium excretion are so precise that sodium balance does not vary by more than a small percentage despite marked changes in dietary intake or losses caused by sweating, vomiting, diarrhea, hemorrhage, or burns.
Table 1 Normal Routes for Water and NaCl Gain and Loss Water (ml/day) NaCl (g/day) Intake Fluid 1200 10.50 Food 1000 Metabolism 350 Total 2550 10.50 Output Insensible (skin & lungs) 900 Sweat 50 0.25 Feces 100 0.25 Urine 1500 10.00 Total 2550 10.50 Table 2 Major Determinants of Sodium and Water Excretion Renal Stimulus Signaling Pathway Response Net Effect [down arrow] [down arrow] stimulation [down arrow] [down arrow] plasma volume of extrarenal RBF & GFR [Na.sup.+] & baroreceptors [right [H.sub.2]O arrow] excretion [up arrow] renal sympathetic nerve activity [right arrow] afferent & efferent arteriole constriction [down arrow] stimulation [up arrow] of intrarenal [Na.sup.+] & baroreceptors [right [H.sub.2]O arrow] reabsorption [up arrow] renin [right arrow] [up arrow] angiotensin II [right arrow] [up arrow] aldosterone [down arrow] stimulation [down arrow] of intrarenal GFR baroreceptors [up arrow] renin [right arrow] [up arrow] angiotensin II [right arrow] vasoconstriction [down arrow] atrial [down arrow] distention [right arrow] GFR [down arrow] release of [up arrow] ANH [Na.sup.+] & [H.sub.2]O reabsorption [down arrow] [up arrow] ADH [up arrow] plasma volume [H.sub.2]O & [up arrow] reabsorption plasma osmolality [up arrow] stimulation of extrarenal [up arrow] [up arrow] plasma baroreceptors [right RBF & GFR [Na.sup.+] & osmolality arrow] [H.sub.2]O excretion [down arrow] renal sympathetic nerve activity [right arrow] afferent & efferent arteriole dilation stimulation of intrarenal [down arrow] baroreceptors [right [Na.sup.+] & arrow] [H.sub.2]O reabsorption [down arrow] renin [right arrow] [down arrow] angiotensin II [right arrow] [down arrow] aldosterone stimulation of intrarenal [up arrow] baroreceptors [right GFR arrow] [down arrow] renin [right arrow] [down arrow] angiotensin II [right arrow] vasodilation atrial distention [right [up arrow] arrow] [up arrow] release GFR of ANH [down arrow] [Na.sup.+] & [H.sub.2]O reabsorption [up arrow] [down arrow] ADH [down arrow] plasma volume [H.sub.2]O & [down reabsorption arrow] plasma osmolality
Koeppen, B.M., & Stanton, B.A. (2001). Renal physiology (3rd edition). St. Louis, MO: Mosby.
Guthrie, D., & Yucha, C. (2004). Urinary concentration and dilution. Nephrology Nursing Journal, 37(3), 297-301.
Guyton, A.C., & Hall, J.E. (2000). Textbook of medical physiology (10th edition). Philadelphia: W.B. Saunders Company.
Yucha, C. (2004). Renal regulation of acid-base balance. Nephrology Nursing Journal, 31(2), 201-208.
Renal Regulation of Extracellulax Fluid Volume and Osmolality Lori Candela, EdD, RN, and Carolyn Yucha, PhD, RN Posttest--2.5 Contact Hours Posttest Questions (See posttest instructions on the answer form, on page 406.)
Ms. Smith, 77 years old, is brought to the clinic by her daughter. She states that her mother does not seem to be eating or drinking much. In fact over the past 24 hours, her mother has had only approximately 4 oz. of milk and 6 oz. of water.
1. If Ms. Smith's hormones levels were measured, which of the following would you expect to be elevated?
A. Aldosterone only
B. Aldosterone and antidiuretic hormone (ADH) only
C. Aldosterone, ADH and atrial natriuretic hormone (ANH) only
D. Aldosterone, ADH, ANH and progesterone
2. In order to excrete the waste products that are produced by normal metabolism, Ms. Smith must produce a urine volume of at least
A. 100 ml/day.
B. 400 ml/day.
C. 1000 ml/day.
D. 1400 ml/day.
3. Ms. Smith's plasma sodium level is 150 mEq/L. Her GFR is 100 mi/minute (0.1 L/min). Calculate the amount of sodium that is filtered in 24 hours.
A. 1500 mEq/day
B. 15,000 mEq/day
C. 20,000 mEq/day
D. 21,600 mEq/day
4. If Ms. Smith were to receive excessive fluid intake, intravenously, for example, which hormone would you expect to increase?
5. Ms. Smith's kidneys are conserving water by increasing
A. sodium reabsorption only.
B. sodium and water reabsorption only.
C. sodium and water reabsorption and GFR.
D. sodium and water reabsorption, GFR, and osmolality.
6. If 25,000 mEq/day of sodium were filtered, approximately how much would be reabsorbed by the proximal tubule in a euvolemic adult?
A. 2,500 mEq/day
B. 8,000 mEq/day
C. 16,750 mEq/day
D. 25,000 mEq/day
7. Approximately how much sodium reabsorption would be dependent on aldosterone?
B. 250 mEq/day
C. 500 mEq/day
D. All of it
8. The most important stimulator of aldosterone secretion in regard to sodium- regulating reflexes is
A. adrenecorticotropic hormone (ACTH)
B. high plasma levels of potassium
C. atrial natriuretic hormone (ANH)
D. angiotensin II
9. What would you expect to happen if the [Na.sup.+]/[K.sup.+] ATPase pump stopped working?
A. Intracellular sodium levels would rise.
B. Intracellular potassium levels would rise.
C. Sodium reabsorption would increase.
D. Water reabsorption would increase.
10. In a patient with severe burn, sodium absorption would be fine tuned in the
A. proximal tubules.
B. collecting ducts.
C. early distal tubules.
D. loops of Henle.
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|Title Annotation:||Continuing Education|
|Author:||Candela, Lori; Yucha, Carolyn|
|Publication:||Nephrology Nursing Journal|
|Date:||Jul 1, 2004|
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