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Sodium and Water Physiology


Introduction

It is important to understand the physiology of sodium (Na + ) and of water homeostasis to determine the pathophysiology that leads to alteration in the extracellular fluid (ECF) volume and/or the concentration of sodium ions (Na + ) in plasma (P Na ), and what is the optimal therapy to deal with these disorders.

This chapter is divided into four sections. The first section deals with the factors that determine the distribution of water between the ECF and intracellular fluid (ICF) compartments, and factors that determine the distribution of ECF volume between its vascular and interstitial subcompartments. The second and third sections deal with the physiology of how balances for Na + ions and water, respectively, are achieved. In the final section, we provide a more in-depth look at selected aspects of the integrative physiology of Na + ions and water homeostasis.

Abbreviations

  • ECF, extracellular fluid

  • ICF, intracellular fluid

  • P Na , concentration of sodium ions (Na + ) in plasma

  • P K , concentration of potassium ions (K + ) in plasma

  • P Cl , concentration of chloride ions (Cl − ) in plasma


  • P HCO 3     , concentration of bicarbonate ions (
    HCO 3 −     ) in plasma

  • NKCC-1, Na + , K + , 2 Cl − cotransporter 1

  • NHE-3, sodium hydrogen cation exchanger-3

  • P Albumin , concentration of albumin in plasma

  • P Aldosterone , concentration of aldosterone in plasma

  • ANP, atrial natriuretic peptide

  • EABV, effective arterial blood volume

  • AQP, aquaporin water channel

  • GFR, glomerular filtration rate

  • PCT, proximal convoluted tubule

  • DtL, descending thin limb (of the loop of Henle)

  • AtL, ascending thin limb (of the loop of Henle)

  • mTAL, medullary thick ascending limb (of the loop of Henle)

  • cTAL, cortical thick ascending limb (of the loop of Henle)

  • DCT, distal convoluted tubule

  • CCD, cortical collecting duct

  • MCD, medullary collecting duct

  • CDN, cortical distal nephron, which consists of the late DCT, the connecting segment, and the CCD

  • NKCC-2, Na + , K + , 2 Cl − cotransporter 2

  • ROMK, renal outer medullary K + channel

  • NCC, Na + , Cl − cotransporter

  • ENaC, epithelial Na + channel

  • Ca-SR, calcium-sensing receptor

  • SPAK, STE20-related proline-alanine-rich-kinase

  • OSR1, oxidative stress response kinase type 1

  • SGK-1, serum and glucocorticoid-regulated kinase-1

  • K sp , solubility product constant for the activity of ions in a solution

Objectives

  • ▪

    To emphasize that the number of effective osmoles in the ECF and ICF compartments determines their respective volume.

  • ▪

    To emphasize that the hydrostatic pressure in capillaries and the concentration of albumin in plasma (P Albumin ) are the two major factors that determine the distribution of the ECF volume between its two subcompartments: the plasma volume and the interstitial fluid volume.

  • ▪

    To emphasize that, with some exceptions, the P Na determines the ICF volume. The ICF volume is expanded in patients with hyponatremia and is contracted in patients with hypernatremia.

  • ▪

    To point out that Na + ion homeostasis and water homeostasis are regulated by different control systems.

  • ▪

    To emphasize that the content of Na + ions in the ECF compartment is regulated by modulation of the rate of the reabsorption of Na + ions by the kidneys.

  • ▪

    To describe the mechanisms for Na + ion handling in the different nephron segments and how they are regulated.

  • ▪

    To emphasize that water balance is primarily the result of the interplay of thirst and renal actions of vasopressin. When vasopressin acts, the volume of urine is dependent on the rate of excretion of effective urine osmoles and the effective osmolality in the renal papillary interstitial compartment. When actions of vasopressin are absent, the urine volume is determined by the volume of distal delivery of filtrate and the volume of water reabsorbed in the inner medullary collecting duct (MCD) via residual water permeability.

Part A

Body Fluid Compartments

Case 9-1: A Rise in the P Na After a Seizure

A 20-year-old man experienced a generalized tonic–clonic seizure one day prior to presenting to the hospital. He had been well before and had no history of seizures prior to this episode. The physical examination was normal, and all the results of blood tests performed, including the P Na (140 mmol/L), were in the normal range. A few hours later, he had another generalized tonic–clonic seizure. A brachial venous blood sample was drawn immediately after the seizure; the results revealed the expected metabolic acidosis with a large increase in the P Anion gap because of accumulation of L-lactic acid. To everyone’s surprise, however, his P Na was 154 mmol/L after the seizure, but on a repeat measurement done on a brachial venous sample obtained few hours later, his P Na fell back to 140 mmol/L. Of note, there was no large increase in urine output prior to the development of hypernatremia, and he did not ingest a large volume of water nor was he given hypotonic fluids after the seizure.

Question

  • What is the basis for the acute rise in the patient’s P Na ?

Total Body Water

Water is the most abundant constituent of the body. Although it is said to constitute approximately 60% of body mass, the actual percentage of body weight due to water in any individual depends on the relative proportions of muscle and fat in the body. Skeletal muscle is the largest organ in the body, and about half of total body water is located in the ICF and ECF compartments of muscle. Because neutral fat does not dissolve in water, triglycerides are stored in fat cells without water. Accordingly, when relating total body water to body weight, one must consider the relative proportions of muscle and fat. For example, females tend to have a higher proportion of fat to body weight than males, and hence they have a lower percentage of water relative to body weight (typically 50% in females vs 60% in males). Obese individuals have less water per kg body weight. Similarly, older people have less water per kg body weight because they often have a relatively smaller proportion of muscle. Newborn infants, on the other hand, have less adipose tissue and therefore they have a higher proportion of water per kg body weight (∼70%).

Distribution of Water Across Cell Membranes

Water crosses cell membranes rapidly through aquaporin (AQP) water channels to achieve osmotic equilibrium. Not all compounds and ions are distributed equally in the ICF and ECF compartments, however, because there are active pumps and transporters that affect the distribution of individual solutes between the ECF and ICF compartments ( Table 9-1 ). Water distribution across cell membranes depends on the number of particles that are restricted to either the ICF or ECF compartment ( Fig. 9-1 ); these particles account for the effective osmolality, or the tonicity, in these compartments. The particles restricted to the ECF compartment are largely Na + ions and their attendant anions (chloride [Cl − ] and bicarbonate [
HCO 3 − ] ions). In contrast, the major cation in the ICF compartment is potassium ions (K + ); electroneutrality is maintained primarily by the anionic charge on organic phosphate esters inside the cells (RNA, DNA, phospholipids, phosphoproteins, adenosine triphosphate [ATP], and adenosine diphosphate [ADP]). These are relatively large molecules and hence exert little osmotic force. Other organic solutes contribute to the osmotic force in the ICF compartment. The individual compounds, however, differ from organ to organ. The organic solutes that have the highest concentration in skeletal muscle cells are phosphocreatine and carnosine; each is present at ∼25 mmol/kg. Other solutes include amino acids (e.g., glutamine, glutamate, taurine), peptides (e.g., glutathione), and sugar derivatives (e.g., myoinositol).

TABLE 9-1
Concentration of Ions in the EXTRACELLULAR FLUID and INTRACELLULAR FLUID Compartments
ECF ICF
Na + 150 10-20
K + 4.0 120-150
Cl − 113 ∼5

HCO 3 − 		25 10
Phosphate 2.0 (inorganic) ∼130 (organic in macromolecules)
Data are expressed as mEq/kg of water. Concentrations of ions in the ICF compartment are not known with certainty, because some of the water in the ICF compartment is held in a “bound form” and there are regions of cytoplasm where there appears to be less “solvent water.” Moreover, these concentrations differ from organ to organ. Values provided are approximations for the ICF in skeletal muscle. ECF , Extracellular fluid; ICF , intracellular fluid.

Figure 9-1, Factors Regulating Water Distribution Across Cell Membranes.

This difference in the concentrations of the major cations between the ECF and the ICF compartments is maintained because Na + ions that enter the ICF compartment are actively exported out of cells by the Na-K-ATPase, which are located in cell membranes. Particles such as urea are transported across cell membranes rapidly via urea transporters. Hence, the concentration of urea molecules is virtually equal in the ICF and ECF compartments, and therefore, urea molecules do not play a role in the distribution of water across cell membranes (i.e., urea is not an effective osmole).

The number of effective osmoles in each compartment determines that compartment’s volume. It is commonly stated that the ICF volume is twice as large as the ECF volume, so that 67% of body water is in the ICF compartment whereas 33% is in the ECF compartment. Hence, a 70-kg, nonobese male subject with a total body water of 60% of body weight (42 L) will have an ECF volume of 14 L and an ICF volume of 28 L. The data to support this conclusion are not robust and vary depending on the method used to estimate ECF volume. It has also been suggested that only slightly more than half of body water (55%) is in the ICF compartment and 45% is in the ECF compartment. Changes in ECF and ICF volumes after administering isotonic saline or the administration of water are illustrated in Figure 9-2 .

Figure 9-2, Changes in Volumes of Body Fluid Compartments After Administering Water or Saline.

The content of Na + ions and their attendant monovalent anions in the ECF compartment determine the ECF volume. Although macromolecular phosphate compounds in the ICF do not exert a large osmotic pressure (they do not represent a large number of particles), they nonetheless carry a large anionic net charge and as a result help retain a large number of cations (primarily K + ions) to achieve electroneutrality. Because particles in the ICF compartment are relatively “fixed” in number and charge, changes in the ratio of particles to water in the ICF compartment usually come about by changes in its content of water. The concentration of Na + ions in the ECF compartment is the most important factor that determines the ICF volume (except when the ECF compartment contains other effective osmoles [e.g., glucose in a patient with diabetes mellitus and relative lack of insulin, mannitol]). Hence, hyponatremia (because of a gain of water in or the loss of Na + ions from the ECF compartment) is associated with an increase in ICF volume; in contrast, hypernatremia (because of a loss of water from or the gain of Na + ions in the ECF compartment) is associated with a decrease in ICF volume.

Defense of Brain Cell Volume

Defense of brain cell volume is necessary because the brain is contained in a rigid box: the skull ( Fig. 9-3 ). When brain cells swell (as occurs when the P Na is low), the initial defense mechanism is to expel as much Na + and Cl − ions and water as possible from the interstitial space into the cerebrospinal fluid to prevent a large rise in intracranial pressure. If brain cells continue to swell, the intracranial pressure will rise, the brain will be pushed caudally, which may result in compression of the cerebral veins against the bony margin of the foramen magnum, and hence the venous outflow will be diminished. Because the arterial pressure is likely to be high enough to permit the inflow of blood to continue, the intracranial pressure rises further and abruptly. This may lead to serious symptoms (seizures, coma) and eventually herniation of the brain through the foramen magnum, causing irreversible midbrain damage and death.

Figure 9-3, Regulation of Brain Cell Volume.

In contrast, excessive shrinkage of brain cell volume (as occurs when the P Na is high) stretches the vessels coming from the inner surface of the skull, which may cause their rupture, leading to focal intracerebral and subarachnoid hemorrhages.

Because the large intracellular macromolecular anions are essential compounds for cell structure and function, defense of brain cell volume requires that small ions or nonelectrolyte osmoles be exported from swollen brain cells or be imported into shrunken brain cells to return their cell sizes close to normal in either case.

Regulatory decrease in brain cell volume

In patients with hyponatremia, primary mechanism to return swollen brain cells toward their original size is to decrease the number of effective osmoles inside the cells. Close to half of this decrease in the number of effective osmoles is the result of exporting K + cations with an accompanying anion (other than organic phosphate) to maintain electroneutrality (see margin note). Another mechanism to cause water to exit from cells is to have some intracellular effective ions “disappear” and thereby lower the osmolality in this compartment. This could occur if ions were to become bound to intracellular macromolecules and hence become osmotically inactive; this, however, is not known to occur in neuronal cells. Organic solutes are extruded from brain cells as part of the regulatory decrease in volume. The major organic osmoles that are lost from brain cells are the amino acids glutamine, glutamate, and taurine, and the sugar derivative myoinositol.

Anions Exported From Brain Cells With K + Ions

  • The authors are not clear on which anions are exported from brain cells with K + ions during this regulatory decrease in brain cell volume.

  • One of these anions could be Cl − ions. The concentration of Cl − ions, however, is very low in the ICF compartment. Notwithstanding, it may be higher in nonneuronal brain cells (e.g., astrocytes).

  • It is unlikely that this volume defense mechanism involves the export of
    HCO 3 −     ions because changes in their concentration alter the pH in cells and thereby the net charge on intracellular proteins.

Regulatory increase in brain cell volume

In patients with hypernatremia, the mechanism to return of shrunken cells toward their original volume begins with an influx of Na + and Cl − ions (see margin note), which usually occurs via the furosemide-sensitive Na + , K + , 2 Cl − cotransporter-1 (NKCC-1), but it is also possible that this may be achieved by parallel flux through the Na + /H + cation exchanger and the
Cl − / HCO 3 − anion exchanger. The second mechanism for increasing the size of shrunken brain cells is via an increase in the number of organic compounds in brain cells (e.g., taurine and myoinositol), which seems to account for close to half of the increase in the number of effective osmoles in this adaptive process.

Increase in the Intracellular Concentration of Na + Ions

  • To permit a rise in the intracellular Na + ion concentration, the Na-K-ATPase either must have a lower affinity for Na + ions or there must be fewer active pump units in the cell membrane.

Distribution of Water in the ECF Compartment

The ECF compartment is subdivided into two subcompartments: the plasma fluid volume (∼4% of body weight, ∼3 L in a 70-kg nonobese male) and the interstitial fluid volume (i.e., fluid in tissues between the cells; ∼16% of body weight, ∼11 L in a 70-kg nonobese male). In certain disease states, fluid accumulates in the interstitial space of the ECF compartment to an appreciable degree, causing peripheral edema, ascites, or pleural effusion (see margin note). Because the interstitial fluid volume is much larger than the intravascular volume, whenever expansion of the interstitial space is detected (e.g., peripheral edema), the patient always has an expanded ECF volume even if the intravascular volume is reduced (e.g., in a patient with chronic hypoalbuminemia).

The major driving force for fluid movement from the intravascular space to the interstitial space is the hydrostatic pressure difference. The hydrostatic pressure at the venous end of the capillary is higher under conditions that lead to venous hypertension (e.g., venous obstruction, congestive heart failure).

The major driving force for inward flow of fluid (from the interstitial space to the intravascular space) is the colloid oncotic pressure difference. This difference is the result of a higher concentration of proteins in plasma than in the interstitial fluid. The osmotic pressure generated by plasma proteins (the plasma oncotic pressure) is attributed not only to the concentration of proteins in plasma (∼0.8 mmol/L) but also to their net negative charge (Gibbs–Donnan equilibrium; see the following).

Interstitial fluid returns to the venous system via the lymphatic system.

Third Space

  • This term is commonly used to refer to a space into which fluid may move and from which it is difficult to return to the intravascular space. Common situations in which this is said to occur include following abdominal surgery and in patients with pancreatitis.

Gibbs–Donnan equilibrium

The net negative valence on plasma proteins causes ions to redistribute between the intravascular and interstitial spaces, because it attracts cations (largely Na + ions) into, and repels anions (largely Cl − and
HCO 3 − ions) out of, the capillaries. According to the Gibbs–Donnan equilibrium, the product of diffusible cations and diffusible anions in the fluid on either side of a semipermeable membrane must be the same. Therefore, the intravascular space ultimately has a slightly larger total concentration of ionic species than the interstitial space. Although this difference in the sum of the concentrations of ions is small in quantitative terms (∼0.4 mmol/L), it is appreciable relative to the concentration of protein in plasma (∼0.8 mmol/L); hence, it makes an appreciable contribution to the colloid osmotic pressure. In quantitative terms, according to the Van’t Hoff factor, 1 mmol of a solute in a solution generates an osmotic pressure of 19.3 mm Hg. The plasma oncotic pressure with a normal plasma protein concentration is ∼24 mm Hg. Hence, approximately one-third of the plasma oncotic pressure (7.7 mm Hg) is attributed to the Gibbs–Donnan effect.

It was suggested that changes in intravascular volume may lead, via a yet unknown mechanism, to conformational changes in albumin that lead to a change in its negative valence and hence the Gibbs–Donnan effect. A decrease in the effective arterial blood volume (EABV) is associated with an increase in the net negative valence on albumin (detected by a rise in the anion gap in plasma (P Anion gap ) that is not accounted for by changes in the concentration of albumin in plasma (P Albumin ), an increase in the negative valence on albumin due to a rise in plasma pH, or the gain of new anions). This increase in negative net valence on plasma albumin may help defend the intravascular volume by increasing the plasma oncotic pressure via the Gibbs–Donnan effect, which may cause fluid to move from the interstitial space to the intravascular volume.

Questions

  • 9-1

    Hypertonic saline is the treatment of choice to shrink brain cell size in a patient with acute hyponatremia. What is the major effect of hypertonic saline that reduces the risk of brain herniation?

  • 9-2

    What would happen acutely to the ICF volume if the permeability of capillary membranes to albumin were to increase?

  • 9-3

    What is the volume of distribution if 1 L of each of the following intravenous fluids is retained in the body: isotonic saline, half-isotonic saline, 300 mmol of NaCl/L, or 1 L of D 5 W? What would the change in the P Na be in a normal 50-kg subject who has 30 L of total body water before the infusion of each of these solutions?

Part B

Physiology of Sodium

Overview

Although there is some evidence for stimulation of salt intake in humans when the ECF volume is low (salt craving), this is not an important element in the control of Na + ion homeostasis. Rather, Na + ion balance is regulated primarily by adjusting the rate of excretion of Na + ions in response to signals related to the degree of expansion of the EABV.

Our current understanding of Na + ion homeostasis is based on short-term balance studies in humans, in which there were large changes in salt intake. These studies suggested that a new steady state is achieved within a few days, in which Na + ion excretion matches its intake, with little change in total body Na + ion content. A number of studies, however, have challenged this accepted dogma. In two very long-term studies (105 and 520 days), Na + ion balance in healthy humans on a fixed Na + ion intake was examined, with daily urine collections for the entire duration of the study. The studies were meticulously conducted because they were done in the setting of a simulated flight to Mars; hence, subjects were confined to an enclosed, restricted environment. While these subjects remained in Na + ion balance, with the cumulative urinary excretion of Na + ions very closely matching the cumulative intake of Na + ions, there was considerable day-to-day variability in 24-hour Na + ion excretion. The subjects seem to accumulate or release Na + ions with regular periodicity of approximately 1 month independent of daily salt intake. These findings are in clear contradiction to the widely held view that the total body Na + ion content is maintained within a narrow limit. It also calls into question the validity of the 24-hour urine collection as a measure of Na + ion intake. In these studies, large amounts of Na + ions were retained or excreted without changes in body weight, indicating that Na + ions seemed to be stored in the body in an osmotically inactive form, without water retention. In fact, Na MRI measurements of Na + ion content suggested that large amounts of Na + ions are stored in the skin interstitium and in skeletal muscles bound to the highly sulfated, negatively charged glycosaminoglycans.

Control System for Sodium Balance

Normal ECF Volume

To define what a normal ECF volume is, we start by emphasizing that control mechanisms were developed in Paleolithic times. There are no survival-related pressures in modern times that have enough control strength to negate this regulation. The diet of our ancient ancestors consisted mainly of fruit and berries and contained very little NaCl. Hence, control mechanisms were set for the kidneys to preferentially retain NaCl. Because the diet in modern times is rich in salt (subjects who consume a typical Western diet have an intake of NaCl that is in excess of 150 mmol/day), it is “physiologically not correct” to think of our ECF volume as being “normal.” In fact, an expanded ECF volume is needed to provide the kidneys with a signal to prevent it from reabsorbing virtually all the filtered Na + ions. Hence, from a physiologic perspective, a “normal” ECF volume should be defined based on measurements of ECF volume in subjects who have a low intake of NaCl, because this represents the conditions in Paleolithic times, when important control mechanisms developed.

In order to understand the mechanisms regulating the ECF volume, it is important to appreciate that what is sensed is the EABV. EABV can be defined as the part of the ECF volume that is located in the arterial blood system and that effectively perfuses tissues. Changes in the EABV are sensed by baroreceptors located in the large arterial blood vessels (the carotid sinus and the aortic arch) and glomerular afferent arterioles. These are stretch receptors that detect changes in the pressure inside or the “filling” of these vessels.

The EABV is often, although not always, correlated with the ECF volume and is proportional to total body Na + ion content. Na + ion loading generally leads to EABV expansion, whereas Na + ion loss leads to EABV depletion. Hence, regulation of both Na + ion balance and the EABV are related functions. Nevertheless, there are several situations in which this correlation is lost. An example is the patient with congestive heart failure. A decrease in cardiac output leads to a decrease in the perfusion pressure of the baroreceptors (i.e., a reduced EABV is sensed). This leads to renal Na + ion retention and ECF volume expansion. The net result is a state of increased total ECF volume, but a reduced EABV. The increase in plasma volume is partially appropriate in that intraventricular filling pressure rises and, by increasing myocardial stretching, leads to improved ventricular contractility, thereby raising cardiac output and restoring blood pressure and the stretch of the baroreceptors toward normal. However, Na + ion retention and ECF volume expansion may lead to both peripheral and pulmonary edema.

Control of the Excretion of Sodium Ions

The regulation of Na + ion excretion is the most important factor that maintains the EABV. The major renal work that requires energy expenditure is the reabsorption of filtered Na + ions. With a glomerular filtration rate (GFR) of 180 L/day and P Na of 150 mmol/L of plasma water, the load of Na + ions that is filtered daily is enormous (27,000 mmol). In an adult who consumes a typical Western diet that contains 150 mmol of NaCl each day, only 150 mmol of NaCl need to be excreted to achieve balance for these electrolytes. The kidneys use a large amount of fuel to provide the ATP needed to reabsorb close to 99.5% of the filtered load of Na + ions (26,850 mmol/day). Depending on the properties of the nephron site where reabsorption of Na + ions occurs, the kidneys utilize this energy to reabsorb other valuable compounds or ions (e.g., glucose and
HCO 3 − ions in the proximal convoluted tubule [PCT]) or to secrete others (e.g., K + ions in the late cortical distal nephron [CDN]). Nevertheless, filtering and reabsorbing such a large quantity of Na + ions may be thought of as a “waste of energy” at first glance. Filtering this large amount of Na + ions is dictated by the high GFR. Although there are several hypotheses to explain why there is such a high GFR, the one favored by the authors is to think of the high GFR in energy or O 2 consumption terms. In more detail, to make the kidneys the ideal site for the production of erythropoietin, a central requirement is that the PO 2 at the site of release of erythropoietin should be influenced solely by the concentration of hemoglobin in blood. Because the kidney has a large blood flow, only a small amount of O 2 is extracted from each liter of blood. When the same amount of O 2 is extracted from blood that has a lower content of O 2 because of a lower hemoglobin concentration, the drop in PO 2 would be larger because one is operating on the flat part of the sigmoid-shaped oxygen-hemoglobin dissociation curve. In addition, because there is little variation in P Na , renal work, which is largely the reabsorption of filtered Na + ions (O 2 consumption) is directly related to the GFR. Because the ratio between the GFR (O 2 consumption) to renal plasma flow (O 2 delivery)—that is, the filtration fraction does not vary appreciably—the sensor for PO 2 should be exposed to near constant PO 2 unless hemoglobin concentration in blood falls (see margin note).

Another Benefit for the High GFR

  • Having a high GFR permits more fuel oxidation because more work is being done (reabsorbing a larger filtered load of Na + ions).

  • During metabolic acidosis, one of the fuels that is consumed by the kidneys to provide the energy to reabsorb Na + ions is glutamine. Thus, the kidneys can have a higher rate of production of ammonium ions (
    NH 4 +     ) and hence a higher rate of addition of new
    HCO 3 −     ions to the body (see Chapter 1 ).

Before dealing with a detailed description of reabsorption of Na + ions in individual nephron segments, the overall strategy for the reabsorption of Na + ions will be considered. There are two elements: a driving force (a low concentration of Na + ions and a negative voltage inside tubular cells) and a means (transporters or channels) to permit Na + ions to cross the luminal membrane in each nephron segment. A diagrammatic illustration of the nephron segments is shown in Figure 9-4 , and a quantitative estimate of the amount of Na + ion reabsorbed in the different nephron segments is provided in Table 9-2 . In the next several sections, we provide a detailed explanation for our estimates of the amount of Na + ions that is reabsorbed in each segment of the renal tubule. Although a bit complex at times, we believe it provides the reader with a more clear picture of the role of each tubule segment in Na + ion handling.

Figure 9-4, Tubular Segments of Juxtamedullary Nephrons.

TABLE 9-2
Amount of Na + Reabsorbed in Different Segments of the Nephron
Nephron Segment Amount of Na + Reabsorbed/Day

  • Proximal convoluted tubule

22,650

  • Thin ascending limb of the loop of Henle of juxtamedullary nephrons

360

  • Medullary thick ascending limb of the loop of Henle

750

  • Cortical thick ascending limb of the loop of Henle

1890

  • Distal convoluted tubule and cortical distal nephron

1200

  • Medullary collecting duct

0
The numbers in the table are approximations based on a filtered load of Na + ions of 27,000 mmol/day (GFR 180 L/day × P Na 150 mmol/L) in a subject who consumes a typical Western diet and excretes 150 mmol of Na + ions in his/her urine per day. A large amount of Na + ions are reabsorbed in the medullary thick ascending limb of loop of Henle (about 3135 mmol/day), but only 750 mmol represent net reabsorption of Na + ions. The remainder does not represent net reabsorption but rather recycling of Na + ions because it is added back to the thin descending limbs of the loop of Henle of superficial nephrons. GFR , Glomerular filtration rate.

Driving force

A low concentration of Na + ions and a negative voltage in renal tubular cells are created by the electrogenic pumping of Na + ions out of cells by the Na-K-ATPase in their basolateral membranes. This ion pump is electrogenic because it exports 3 Na + ions out of the cell and imports only 2 K + ions into the cell.

Transport mechanism

The Na-K-ATPase generates an electrochemical gradient that favors the movement of Na + ions into cells, but cell membranes are not permeable to Na + ions. Therefore, specific transporters (cotransporters or antiporters) that bind Na + ions and another ligand, or specific Na + ion channels in the luminal membrane of cells, are required for the transport of Na + ions in different nephron segments.

Proximal convoluted tubule

The function of the PCT is to reabsorb most of the filtered Na + ions in order to deliver only a small quantity of Na + ions to downstream sites; these latter sites can then adjust their rate of reabsorption of Na + ions to achieve balance for this cation in the steady state.

The mechanism for the reabsorption of Na + ions in the PCT is active and is driven by the basolateral Na-K-ATPase. Virtually all the valuable water-soluble compounds and some ions (e.g., glucose, amino acids,
HCO 3 − ) that are filtered have transport systems in PCT that are linked directly to the reabsorption of Na + ions.

Quantitative analysis

It was formerly thought that about 66% of the GFR is reabsorbed along the entire PCT. This is based on the measured ratio of the concentration of inulin in fluid samples obtained from the lumen of the PCT (TF), and its concentration in plasma (P) – (TF/P) inulin in micropuncture studies in rats in which inulin was infused. Because inulin is freely filtered at the glomerulus and is not reabsorbed or secreted in the tubules, a (TF/P) inulin value of around 3 suggests that approximately two-thirds (66%) of the filtrate was reabsorbed in the PCT. However, these measurements underestimate the actual volume of fluid reabsorbed in the PCT because in micropuncture studies, measurements are made at the last visible portion of the PCT that reaches the surface of the renal cortex and hence do not take into account additional volume that may be reabsorbed in the deeper part of the PCT, including its pars recta portion. An important recent observation is that AQP1 water channels are not present in the descending thin limbs (DtL) of the loop of Henle of superficial nephrons. Because superficial nephrons constitute about 85% of the total number of nephrons, the entire loop of Henle of the large majority of the nephrons is likely impermeable to water. Therefore, the volume of filtrate that enters their loops of Henle can be deduced using of the value for the (TF/P) inulin obtained from micropuncture studies in the early distal convoluted tubule (DCT) in rats. Because the minimum measured value is around 6, a reasonable estimate of the proportion of filtrate that is reabsorbed in the entire PCT of superficial nephrons is close to five-sixths (83%). This value is close to the estimate of fractional reabsorption in the PCT obtained with measurement of lithium clearance (which is thought to be a marker for fractional reabsorption in the PCT) in human subjects. Hence, a larger proportion of the filtered load of Na + ions is subject to regulation by mechanisms that influence the rate of Na + ion reabsorption in the PCT.

Based on this, with a GFR of 180 L/day and if five-sixths of the GFR is reabsorbed in the PCT, the volume of filtrate that exits the PCT into the loop of Henle is about 30 L/day ( Table 9-3 ). If the concentration of Na + ions in this fluid is close to 145 mmol/L (see margin note), then 4350 mmol of Na + ions/day are delivered to the loop of Henle. Because 27,000 mmol of Na + ions are filtered per day, 22,650 mmol of Na + ions are reabsorbed in PCT per day.

Concentration of Na + Ions in Luminal Fluid Entering the Loop of Henle

  • The osmolality of the fluid entering the loop of Henle is about 300 mosmol/kg H 2 O.

  • Because the amount of urea filtered is about 900 mmol/day (GFR 180 mmol/day × plasma urea 5 mmol/L), and because about 500 mmol of urea are reabsorbed in the PCT, 400 mmol of urea/day are delivered to the loop of Henle. Because 30 L of fluid are delivered to the loop of Henle, the concentration of urea in this fluid will be close to 13 mmol/L.

  • Therefore, the concentration of Na + ions in the luminal fluid entering the loop of Henle is close to 145 mmol/L ([300 − 13]/2).

TABLE 9-3
Comparison Between Superficial Nephrons and Juxtamedullary Nephrons
Superficial Nephrons Juxtamedullary Nephrons

  • % total

85% 15%

  • GFR (L/day)

153 27

  • Volume reabsorbed in the PCT (L/day)

127 22.5

  • Volume exit from the PCT (L/day)

26 4.5

  • Volume reabsorbed in the outer medulla (L/day)

0 3.0

  • Volume reabsorbed in the inner medulla (L/day)

0 0.2

  • Volume delivered to the DCT (L/day)

26 1.3
The numbers are approximations. In contrast to juxtamedullary nephrons, thin descending limbs of superficial nephrons (the large majority of nephrons) lack aquaporin 1 (AQP1) in their luminal membranes and hence are largely water impermeable. Out of the 4.5 L of filtrate that are delivered to the descending thin limbs of the loop of Henle of the juxtamedullary nephron per day, 3 L/day are reabsorbed in the outer medulla as the osmolality in the medullary interstitial compartment rises from 300 to 900 mosmol/kg H 2 O. The volume of water reabsorbed from the descending thin limbs of the juxtamedullary nephrons in the inner medulla was calculated at a medullary interstitial osmolality of 1050 mosmol/kg H 2 O (i.e., the midpoint between 900 and 1200 mosmol/kg H 2 O) because descending thin limbs have their bends at different levels in the inner medulla. GFR , Glomerular filtration rate; PCT , proximal convoluted tubule; DCT , distal convoluted tubule.

Process

AQP1 are constitutively present in the PCT. Hence, when Na + and Cl − ions are reabsorbed, water follows. Accordingly, the fluid reabsorbed is isotonic to plasma.

In the early PCT, the Na + /H + exchanger-3 (NHE-3) is the main transporter for the entry of Na + ions into cells. This transporter mediates the indirect reabsorption of NaHCO 3 in the PCT. The reabsorption of Na + and
HCO 3 − ions in the early PCT results in the transport of water and thereby causes a rise in the concentration of Cl − ions in the remaining tubular fluid. The electrochemical gradient for Na + ions provides the driving force for the reabsorption of Na + ions with glucose and other filtered solutes (e.g., amino acids, phosphate, and organic anions) via Na + ion-dependent transporters. This electrogenic transport of Na + creates a small, lumen-negative, transepithelial potential difference of approximately −2 mV. The rise in luminal fluid Cl − ion concentration and the small lumen-negative transepithelial voltage provide the driving force for the reabsorption of Cl − ions via the paracellular route ( Fig. 9-5 ). This paracellular flux of Cl − ions causes reversal of the transepithelial voltage to a small lumen-positive voltage (+2 mV), which drives the paracellular reabsorption of Na + .

Figure 9-5, Na + -Coupled Transport in the PCT.

Transcellular reabsorption of Cl − ions coupled to reabsorption of Na + ions also occurs in the latter part of the PCT, mediated by NHE-3 (or by an Na + -sulfate cotransporter) in tandem with a Cl − /base − exchanger (CFEX, SLC26A6) that is capable of transporting, in addition to Cl − ions, other anions such as formate,
HCO 3 − , sulfate, and oxalate ( Fig. 9-6 ).

Figure 9-6, Transepithelial NaCl Transport in the Proximal Convoluted Tubule.

Control

Precise control of the excretion of Na + ions cannot be exerted in the PCT because ∼27,000 mmol of Na + are filtered and ∼22,650 mmol are reabsorbed daily in this nephron segment. Hence, it is extremely unlikely that the PCT could adjust its rate of reabsorption of Na + ions to change the rate of excretion of Na + ions by 100 or so mmol/day. This does not mean that there is no regulation of Na + ion reabsorption in the PCT but rather that it is not the site where fine adjustment of the rate of excretion of Na + ions takes place.

Glomerulotubular balance

Glomerulotubular balance refers to the phenomenon whereby changes in the GFR are matched by equivalent changes in tubular reabsorption so that fractional reabsorption of fluid and NaCl is maintained constant. The impact of changes in the GFR on the reabsorption of Na + and Cl − ions are particularly pronounced in the PCT.

In the PCT, both peritubular and luminal factors are thought to contribute to glomerulotubular balance. With regard to peritubular factors, an increase in the GFR without a rise in renal blood flow reflects an increase in filtration fraction and hence a higher concentration of albumin in peritubular capillary blood. The higher oncotic pressure in peritubular capillary blood can increase net reabsorption in the PCT. With regard to luminal factors, an increase in the GFR increases the filtered load of
HCO 3 − ions, glucose, and other solutes, the absorption of which is coupled to the reabsorption of Na + ions by their respective Na + ion-dependent cotransporters. The resultant rise in luminal Cl − ion concentration drives its passive, paracellular reabsorption.

Changes in the EABV seem to alter this relationship between the GFR and fractional reabsorption in the PCT. For example, a decrease in the EABV leads to a fall in the GFR but an increase in fractional reabsorption in the PCT. This is likely mediated by activation of the sympathetic nervous system and the release of angiotensin II, both of which are known to enhance the reabsorption of NaCl in the PCT.

Neurohumoral effects

NaCl reabsorption by the PCT is affected by a number of hormones and neurotransmitters. NaCl reabsorption in PCT is stimulated by renal sympathetic activation and angiotensin II, and inhibited by dopamine.

Epinephrine and norepinephrine stimulate proximal NaCl reabsorption via binding to α-adrenergic receptors at the basolateral membrane. Angiotensin II has a potent effect on NaCl reabsorption in the PCT. In addition to circulating angiotensin II, angiotensin II is also synthesized and secreted by the PCT; its effect is mediated via the AT1 receptor, both at the luminal and basolateral membrane. Dopamine is synthesized in the PCT and inhibits NaCl reabsorption via binding to its D 1 receptor.

NHE-3 is the primary target for these stimulatory and inhibitory effects. NHE-3 is regulated by the combined effects of its direct phosphorylation and interaction with scaffolding proteins, which affect its trafficking to the luminal membrane.

In addition to a direct effect on NHE-3, these effects on NaCl reabsorption may also be mediated by changes in glomerular hemodynamics. For example, angiotensin II is a potent vasoconstrictor, especially of the renal efferent arterioles (and to a lesser degree the afferent arterioles). Efferent arteriolar constriction increases the filtration fraction and hence the peritubular capillary plasma oncotic pressure. The latter promotes the uptake of fluid into capillaries and, as a result, an increase in the net reabsorption of NaCl in PCT.

Disorders involving the PCT

The presence of excessive excretion of glucose, phosphate, organic anions,
HCO 3 − , and/or urate in the presence of low values for their concentrations in plasma indicates a defect in PCT function. These defects may occur in isolation or as part of generalized proximal tubular dysfunction (Fanconi syndrome). The clinical diagnosis of proximal renal tubular acidosis can be confirmed by detecting a high fractional excretion of
HCO 3 − ions during NaHCO 3 loading and by the presence of a high rate of excretion of citrate anions in the urine in the presence of metabolic acidosis (see Chapter 4 for more discussion).

The only important pharmacologic diuretic that acts on the PCT is acetazolamide, which inhibits the luminal carbonic anhydrase, carbonic anhydrase IV, and hence diminishes the reabsorption of NaHCO 3 and thus of NaCl in PCT.

Descending thin limb of the loop of Henle

The traditional view of the physiology of this nephron segment is that it has AQP1 and is therefore permeable to water. This means that, for example, when the interstitial osmolality doubles, half of the volume of water reaching the descending thin limb is reabsorbed. An important finding is that AQP1 are not present in the descending thin limbs of the loop of Henle of superficial nephrons, which constitute ∼85% of all nephrons. Hence, in contradiction to the traditional view, with the exception of descending thin limbs of juxtamedullary nephrons (∼15% of all nephrons), the vast majority of the descending thin limbs of the loop of Henle are likely to be largely impermeable to water.

Of note, the concentration of Na + ions rises progressively in the luminal fluid in the descending thin limb of the loop of Henle of superficial nephrons as they descend down into the medulla. It is necessary to have a high concentration of Na + ions in the luminal fluid that reaches the medullary thick ascending limb (mTAL) of the loop of Henle to allow for the voltage-driven, paracellular Na + ion reabsorption (which represents 50% of Na + ion reabsorption in this nephron segment) to occur in the face of a high medullary interstitial concentration of Na + ions. Because AQP1 are not present in the descending thin limb of the loop of Henle of the majority of the nephrons, and hence they are likely to be largely impermeable to water, the rise in Na + ion concentration in their luminal fluid is unlikely to be caused by water exit. Accordingly, entry of Na + ions (via Na + ion channels) and Cl − ions (via Cl − ion channels) is likely to be the mechanism responsible for the bulk of this rise in the luminal concentrations of Na + and Cl − ions. The quantitative implications of this process of addition of Na + and Cl − ions to the luminal fluid in the descending thin limbs of the loop of Henle of the superficial nephrons are further discussed when events in the mTAL of the loop of Henle are considered.

Ascending thin limb of the loop of Henle

Reabsorption of Na + ions in the ascending thin limb of the loop of Henle of the juxtamedullary nephrons in the inner medulla is a passive process, occurring down a concentration difference for Na + ions between the tubular fluid (higher) and the interstitial compartment (lower). In more detail, actions of vasopressin cause the insertion of both AQP2 and urea transporters in the luminal membrane of cells in the inner MCD. The addition of water (with urea) into the interstitial compartment lowers the concentration of Na + and Cl − ions in the interstitial compartment in the inner medulla. This creates a driving force for the passive movement of Na + and Cl − ions from the luminal fluid in the water impermeable, ascending thin limbs of the loop of Henle into the interstitial compartment in the inner medulla. As the osmolality in the interstitial compartment in the inner medulla rises (because of the addition of urea and NaCl), water will be reabsorbed from the thin descending limbs of the loop of Henle because they possess AQP1, and therefore are water permeable. This movement of water raises the concentration of Na + and Cl − ions in the luminal fluid in the descending thin limbs of the loop of Henle, and therefore in the ascending limbs, which will further facilitate the diffusion of Na + and Cl − ions into the medullary interstitial compartment.

Quantitative analysis

If juxtamedullary nephrons represent ∼15% of the total number of nephrons and hence receive 27 L of GFR/day (180 L/day × 15%), and because about five-sixths of the filtrate is reabsorbed in the PCT, ∼4.5 L/day will enter the loop of Henle of these nephrons. Because the concentration of Na + ions in the luminal fluid is about 145 mmol/L, ∼650 mmol of Na + per day (4.5 L × 145 mmol/L) will be delivered to their loops of Henle. Our best estimate of the amount of Na + ions reabsorbed in the thin ascending limbs of the loop of Henle of the juxtamedullary nephrons is approximately 360 mmol/day (see Part D for details of our calculation).

Medullary thick ascending limb of the loop of Henle

Quantitative analysis

There are four important issues to consider to estimate the amount of Na + ions that are reabsorbed in the loop of Henle ( Table 9-4 ). First, the volume of fluid delivered to the loops of Henle, of both superficial and juxtamedullary nephrons, is close to one-sixth of the GFR, or 30 L/day (⅙ × 180 L/day = 30 L/day). Second, the concentration of Na + ions in the fluid delivered to the loop of Henle is about 145 mmol/L. Therefore, approximately 4350 mmol of Na + ions are delivered to the loop of Henle each day (145 mmol/L × 30 L/day). Third, the volume of filtrate delivered to the early DCT is about 27 L/day (see Table 9-3 ). Fourth, to estimate how many Na + ions are reabsorbed in the loop of Henle, one needs to know the concentration of Na + ions in the fluid that is delivered to the DCT. The Na + ion concentration measured in fluid obtained from the early accessible part of the DCT in micropuncture studies in rats is close to 50 mmol/L. If applicable to humans, then 1350 mmol of Na + ions/day exit the loop of Henle (27 L × 50 mmol/L). Because ∼4350 mmol/day of Na + ions entered the loop of Henle and 360 mmol/day are reabsorbed in the ascending thin limbs (see Part D ), we estimate that close to 2640 mmol of Na + ions are reabsorbed daily in both the medullary and cortical segments of the thick ascending limb of the loop of Henle.

TABLE 9-4
Calculation of the Amount of Na + IONS That ARE Reabsorbed in the Medullary and Cortical Segments of the Thick Ascending Limb of the Loop of Henle

  • Volume of filtrate that enters the loop of Henle (L/day)

30

  • Na + concentration in luminal fluid that enters the loop of Henle (mmol/L)

145

  • Amount of Na + delivered to the loop of Henle (mmol/day)

4350 (30 × 145)

  • Amount of Na + reabsorbed in the ascending thin limbs of the loop of Henle of juxta medullary nephrons (mmol/day)

360

  • Amount of Na + delivered to the mTAL of the loop of Henle (mmol/day)

3990 (4350 − 360)

  • Volume of filtrate delivered to the early DCT (L/day)

27

  • Na + concentration in luminal fluid in the early DCT (mmol/L)

50

  • Amount of Na + delivered to the early DCT (mmol/day)

1350 (27 × 50)

  • Amount of Na + reabsorbed in the mTAL and cTAL of the loop of Henle (mmol/day)

2640 (3990 − 1350)
For details, see text. mTAL , Medullary thick ascending limb; cTAL , cortical thick ascending limb; DCT , distal convoluted tubule.

There are two functions of the process of reabsorption of Na + and Cl − ions into the mTALs of the loop of Henle.

  • 1.

    Add Na + ions to water reabsorbed in the renal medulla to make it into an isotonic solution.

    The volume of water that is reabsorbed in the medulla and added to the blood that exits the medulla via the ascending vasa recta is approximately 7.4 L per day. This includes 3.3 L of water/day that are reabsorbed from the MCD in the outer medulla ( Table 9-5 ), 3 L of water/day that are reabsorbed from the descending thin limbs of the loop of Henle of juxtamedullary nephrons (those with AQP1) in the outer medulla, and 1.1 L of water/day that are reabsorbed in the inner medulla from the inner MCD and from the descending thin limbs of the loops of Henle (see Table 9-6 and Part D for a detailed analysis). Because every liter of this water must exit the renal medulla via the as cending vasa recta with the same Na + ion/H 2 O ratio as the fluid that entered the medulla via the descending vasa recta (∼150 mmol/kg H 2 O), about 1110 mmol of Na + ions are required to be added to these 7.4 L of water. We estimated that 360 mmol of Na + ions are reabsorbed from the ascending thin limbs of the loop of Henle of juxtamedullary nephrons; hence, about 750 mmol of Na + ions need to be reabsorbed from the mTAL of the loop of Henle to serve this function. This is the only component of Na + ion reabsorption in the mTAL of the loop of Henle that represents a net reabsorption of filtered Na + ions.

    TABLE 9-5
    Volume of Water Reabsorbed in the Cortical and Medullary Collecting Ducts

    • Volume delivered to collecting ducts (L/day)

    		27

    • Volume reabsorbed in the CCD (L/day)

    		22

    • Volume delivered to the MCD (L/day)

    		5

    • Volume reabsorbed in the outer medulla (L/day)

    		3.3

    • Volume reabsorbed in the inner medulla (L/day)

    		0.4
    We estimated that 5 L exit the terminal CCD based on: (1) when vasopressin acts, the osmolality in the terminal CCD is equal to the plasma osmolality (300 mosmol/kg H 2 O), and (2) the number of osmoles in the terminal CCD is 1500 mosmol (1000 mosmol of urea and 500 mosmol of electrolytes [Na + + K + ions with their accompanying anions]). In the outer medulla, the osmolality in the interstitial compartment rises from 300 to 900 mosmol/kg H 2 O, hence two-thirds of the volume of water delivered will be reabsorbed (i.e., 3.3 L out of 5 L). In the inner medulla, the osmolality in the interstitial compartment rises from 900 to 1200 mosmol/kg H 2 O; hence, one-quarter of the volume of water delivered will be reabsorbed (i.e., 0.4 L out of 1.7 L). CCD , Cortical collecting duct; MCD , medullary collecting duct.

    TABLE 9-6
    Calculation of Volume of Water Reabsorbed in the Inner Medulla

    • Volume of water reabsorbed from the inner MCD with 600 mmol of urea (L/day)

    		0.5

    • Volume of water reabsorbed from the inner MCD as interstitial osmolality rises from 900 to 1200 mosmol/kg H 2 O (L/day)

    		0.4

    • Volume of water reabsorbed from the descending thin limbs of juxtamedullary nephrons (L/day)

    		0.2

    • Total volume of water reabsorbed in the inner medulla (L/day)

    		1.1
    About 600 mmol/day of urea are reabsorbed in the inner MCD and added to the interstitial compartment at an osmolality of 1200 mosmol/kg H 2 O (see Figure 9-21 ). Therefore, 0.5 L of water is reaborbed in the inner MCD with this amount of urea. As medullary interstitial osmolality rises from 900 to 1200 mosmol/kg H 2 O, one-quarter of the volume of water in the MCD (1.7 L) will be reabsorbed (0.4 L). The volume of water in the descending thin limbs of juxtamedullary nephrons as they enter the inner medulla is 1.5 L (see Table 9-3 ). Because the descending thin limbs of the loop of Henle have their bends at different levels in the inner medulla, the volume of water reabsorbed from the descending thin limbs of the juxtamedullary nephrons was calculated at medullary interstitial osmolality of 1050 mosmol/L (i.e., the midpoint between 900 and 1200 mosmol/kg H 2 O). Therefore, if 1.5 L of fluid with osmolality of 900 mosmol/L enter the inner medulla in the descending thin limbs of the loop of Henle, because the interstitial osmolality in the inner medulla rises to 1050 mosmol/kg H 2 O, 0.2 L of water will be reabsorbed. MCD , Medullary collecting duct.

  • 2.

    Replace Na + ions that entered the descending thin limbs of the loop of Henle of superficial nephrons from the medullary interstitial compartment.

    As mentioned earlier, the descending thin limbs of the loop of Henle of the majority of the nephrons do not have AQP1, and therefore are likely water impermeable. Therefore, the rise in Na + ion concentration in their luminal fluid is likely to be because of entry of Na + ions from the medullary interstitial compartment. This component of Na + reabsorption from the mTAL simply restores the interstitial concentration of Na + ions to its original hypertonic value. We estimate that about 2530 mmol of Na + ions per day are reabsorbed from the mTAL of loop of Henle for this purpose (for a detailed calculation, see Part D ). Notwithstanding, this considerable amount of Na + ion reabsorption does not represent a net reabsorption of Na + ions, but rather a recycling of Na + ions. This is because these Na + ions are reabsorbed from the mTAL of the loop of Henle and are added back to the thin descending limb of the loop of Henle.

    Therefore, out of a total amount of ∼3990 mmol of Na + ions that are delivered to the mTAL of the loop of Henle per day (see Table 9-4 ), there is net reabsorption of 750 mmol of Na + ions, and 3240 mmol of Na + ions are delivered to the cortical thick ascending limb (cTAL) of the loop of Henle.

Process

Because of the action of Na-K-ATPase at the basolateral membrane, Na + ions enter cells in the mTAL from the lumen down its concentration gradient on the electroneutral Na + , K + , 2 Cl − cotransporter-2 (NKCC-2). This transporter requires the presence of all three ions and hence is limited by the quantity of K + ions in the lumen of this nephron segment. Hence, K + ions must re-enter the lumen via the renal outer medullary K + (ROMK) ion channel. Cl − ions exit from the cell in an electrogenic fashion via the Cl − ion channel (ClC-Kb) at the basolateral membrane. This entry of K + ions into the lumen and the electrogenic exit of Cl − ions at the basolateral membrane generate a transepithelial, lumen-positive voltage ( Fig. 9-7 ). The transepithelial, lumen-positive voltage drives the electrogenic reabsorption of Na + ions, as well as of ionized calcium (Ca 2+ ) and ionized magnesium (Mg 2+ ), through the paracellular pathway, which expresses the tight junction proteins, claudin 16 (paracellin-1) and claudin 19. About 50% of the amount of Na + ion reabsorbed by the mTAL occurs via the paracellular pathway.

Figure 9-7, Transport of Na + and Cl − Ions in the mTAL of the Loop of Henle.

Control

Because regulation of NaCl reabsorption is likely to be mediated by inhibitory control (see Part C ), this process is not likely to be regulated by activation of NKCC-2 or the quantity of NKCC-2 in the luminal membrane.

The signal to increase the reabsorption of Na + ions in the mTAL of the loop of Henle is likely to be mediated by a fall in the concentration of an inhibitor in the medullary interstitial compartment. This fall in concentration of the inhibitor may begin with the addition of water from the water-permeable nephron segments that traverse the medullary interstitial compartment. One possible candidate that seems to have ideal properties for this function is the activity of ionized Ca 2+ ions in the medullary interstitial compartment. In more detail, when the concentration of ionized calcium rises, it binds to the calcium-sensing receptor (Ca-SR) at the basolateral membrane of cells of the mTAL of the loop of Henle. This generates a signal (an arachidonic acid metabolite, 20-hydroxyeicosatetraenoic acid) that leads to inhibition of the ROMK. This latter step is critical for the process of NaCl reabsorption in the mTAL of the loop of Henle because it supplies the K + ions for the function of NKCC-2 and also generates the lumen-positive voltage required for the passive reabsorption of Na + ions via the paracellular pathway ( Fig. 9-8 ). Hence, a fall in the concentration of ionized Ca 2+ in the medullary interstitial compartment will lead to increased NaCl reabsorption in the mTAL of the loop of Henle.

Figure 9-8, Control of NaCl Reabsorption in the mTAL by Interstitial Ionized Calcium.

Role of hormones

A number of hormones, which increase cyclic adenosine monophoshate (cAMP) in cells of the mTAL of the loop of Henle (e.g., vasopressin, parathyroid hormone, glucagon, calcitonin, β 2 adrenergic activation), are thought to activate NKCC-2 and increase the reabsorption of NaCl. These probably act to facilitate faster rates of transport once the interstitial concentration of the inhibitor of the ROMK in the luminal membrane has decreased.

Inhibitors

Loop diuretics (furosemide, bumetanide, ethacrynic acid) inhibit the reabsorption of Na + and Cl − ions in the thick ascending limb of the loop of Henle by competing with luminal Cl − ions for binding to NKCC-2.

Disorders involving this nephron segment

Inhibition of NaCl reabsorption in the mTAL of the loop of Henle leads to a clinical picture of Bartter’s syndrome with urinary wasting of Na + , K + , and Cl − ions: a contracted EABV, hypokalemia, metabolic alkalosis, a renal concentrating defect, hypercalciuria, and less commonly renal Mg 2+ wasting with hypomagnesemia (for more discussion, see Chapter 14 ). Mutations that cause Bartter’s syndrome have been identified in five separate genes (see Fig. 14-1 ). The first two abnormalities lead to antenatal Bartter’s syndrome and include mutations in the gene encoding NKCC-2 and the gene encoding the ROMK channel. A third lesion involves the basolateral Cl − channel (ClC-Kb); this may also affect the functions of the DCT. Mutations in the gene that encodes for an essential β-subunit of this Cl − channel, called Barttin, have been reported in patients with Bartter’s syndrome and sensorineural deafness, which suggests that Barttin is involved in the function of the Cl − channels in the inner ear. Patients with Bartter’s syndrome and hypocalcemia have been reported; the basis of this disorder is an activating mutation in the gene encoding the Ca-SR.

There are also acquired disorders that lead to loop diuretic-like effects and hence a Bartter’s-like clinical picture. Examples include hypercalcemia and cationic drugs that bind to the Ca-SR (e.g., gentamicin, cisplatin). It is also possible that cationic proteins may bind to Ca-SR and lead to a Bartter’s-like clinical picture, as may be the case in some patients with multiple myeloma or autoimmune disorders.

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