Urinary system module- lec 7

By
Dr. Saeed Jebor Hemza

Regulation of Extracellular Fluid osmolarity and Sodium Concentration:

For the cells of the body to function properly, they must be bathed in extracellular fluid with a
relatively constant concentration of electrolytes and other solutes. The total concentration of
solutes in the extracellular fluid—and therefore the osmolarity—is determined by the amount of
solute divided by the volume of the extracellular fluid. Thus, extracellular fluid sodium
concentration and osmolarity are regulated by the amount of extracellular water. The body water
in turn is controlled by (1) fluid intake, which is regulated by factors that determine thirst, and
(2) renal excretion of water, which is controlled by multiple factors that influence glomerular
filtration and tubular reabsorption.

The Role of Kidneys in Formation of Diluted Urine

The normal kidney has tremendous capability to vary the relative proportions of solutes and
water in the urine in response to various challenges. When there is excess water in the body and
body fluid osmolarity is reduced, the kidney can excrete urine with an osmolarity as low as 50
mOsm/L, a concentration that is only about one sixth the osmolarity of normal extracellular fluid.
Conversely, when there is a deficit of water and extracellular fluid osmolarity is high, the kidney
can excrete urine with a concentration of 1200 to 1400 mOsm/L. Equally important, the kidney
can excrete a large volume of dilute urine or a small volume of concentrated urine without major
changes in rates of excretion of solutes such as sodium and potassium. This ability to regulate
water excretion independently of solute excretion is necessary for survival, especially when fluid
intake is limited.

Antidiuretic Hormone Controls Urine Concentration

There is a powerful feedback system for regulating plasma osmolarity and sodium concentration
that operates by altering renal excretion of water independently of the rate of solute excretion. A
primary effector of this feedback is antidiuretic hormone (ADH), also called vasopressin. When
osmolarity of the body fluids increases above normal, the posterior pituitary gland secretes more
ADH, which increases the permeability of the distal tubules and collecting ducts to water. This
allows large amounts of water to be reabsorbed and decreases urine volume but does not
markedly alter the rate of renal excretion of the solutes. When there is excess water in the body
and extracellular fluid osmolarity is reduced, the secretion of ADH by the posterior pituitary
decreases, thereby reducing the permeability of the distal tubule and collecting ducts to water,
which causes large amounts of dilute urine to be excreted. Thus, the rate of ADH secretion
determines, to a large extent, whether the kidney excretes a dilute or a concentrated urine.

Renal Mechanisms for Excreting a Dilute Urine

When there is a large excess of water in the body, the kidney can excrete as much as 20 L/day of
dilute urine, with a concentration as low as 50 mOsm/L. The kidney performs by continuing to
reabsorb solutes while failing to reabsorb large amounts of water in the distal parts of the
nephron, including the late distal tubule and the collecting ducts. Figure 28–1 shows the
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 approximate renal responses in a human after ingestion of 1 liter of water. Note that urine
volume increases to about six times normal within 45 minutes after the water has been drunk.
However, the total amount of solute excreted remains relatively constant because the urine
formed becomes very dilute and urine osmolarity decreases from 600 to about 100 mOsm/L.
Thus, after ingestion of excess water, the kidney rids the body of the excess water but does not
excrete excess amounts of solutes. When the glomerular filtrate is initially formed, its osmolarity
is about the same as that of plasma (300 mOsm/L). To excrete excess water, it is necessary to
dilute the filtrate as it passes along the tubule. This is achieved by reabsorbing solutes to a
greater extent than water, as shown in Figure 28– 2 below.

Steps of urine dilution

1. As fluid flows through the proximal tubule, solutes and water are reabsorbed in equal
proportions, so that little change in osmolarity occurs with an osmolarity of about 300 mOsm/L.

2. As fluid passes down the descending loop of Henle, water is reabsorbed by osmosis and the
tubular fluid reaches equilibrium with the surrounding interstitial fluid of the renal medulla,
which is very hypertonic.
3. In the ascending limb of the loop of Henle, especially in the thick segment, sodium, potassium,
and chloride are avidly reabsorbed. However, this portion of the tubular segment is impermeable
to water, even in the presence of large amounts of ADH Therefore, the tubular fluid becomes
more dilute to about 100 mOsm/L by the time the fluid enters the early distal tubular segment.

4. As the dilute fluid passes into the late distal convoluted tubule, cortical collecting duct, and
collecting duct, there is additional reabsorption of sodium chloride. In the absence of ADH, this
portion of the tubule is also impermeable to water, and the additional reabsorption of solutes
causes the tubular fluid to become even more dilute (50 mOsm/L).

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 Concentration of Urine
Every day 180 L of glomerular filtrate is formed with large quantity of water. If this much of
water is excreted in urine, body will face serious threats. So, the concentration of urine is very
essential. Osmolarity of glomerular filtrate is same as that of plasma and it is 300 mOsm/L. But
normally urine is concentrated and its osmolarity is four times more than that of plasma, i.e.
1,200 mOsm/L. The basic requirements for forming a concentrated urine are :
1- A high level of ADH, which increases the permeability of the distal tubules and collecting
ducts to water, thereby allowing these tubular segments to avidly reabsorb water.

2- A high osmolarity of the renal medullary interstitial fluid, which provides the osmotic
gradient necessary for water reabsorption to occur in the presence of high levels of ADH.
Medulary hyperosmolarity
Cortical interstitial fluid is isotonic to plasma with the osmolarity of 300 mOsm/L.
Osmolarity of medullary interstitial fluid near the cortex is also 300 mOsm/L. However,
while proceeding from outer part towards the inner part of medulla, the osmolarity
increases gradually and reaches the maximum at the inner most part of medulla near renal
sinus. Here, the interstitial fluid is hypertonic with osmolarity of 1,200 mOsm/L. This means
that the renal medullary interstitium has accumulated solutes in great excess of water. This
type of gradual increase in the osmolarity of the medullary interstitial fluid is called the
medullary gradient. It plays an important role in the concentration of urine. The major
factors that contribute to the buildup of solute concentration into the renal medulla are as
follows:
1. Active transport of sodium ions and co-transport of potassium, chloride, and other ions
out of the thick portion of the ascending limb of the loop of Henle into the medullary
interstitium.
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2. Active transport of ions from the collecting ducts into the medullary interstitium.
3. Facilitated diffusion of large amounts of urea from the inner medullary collecting ducts
into the medullary interstitium.
4. Diffusion of only small amounts of water from the medullary tubules into the medullary
interstitium, far less than the reabsorption of solutes into the medullary interstitium.

Development and maintenance of medullary gradient

Kidney has some unique mechanism called countercurrent mechanism, which is responsible for
the development and maintenance of medullary gradient and hyper- osmolarity of interstitial
fluid in the inner medulla. The countercurrent mechanism depends on the special anatomical
arrangement of the loops of Henle and the vasa recta, the specialized peritubular capillaries of the
renal medulla.

Counter current mechanism

A countercurrent system is a system of ‘U-shaped tubules (tubes) in which, the flow of fluid is in
opposite direction in two limbs of the ‘‘U-shaped tubules. countercurrent system has two
divisions:
1. Countercurrent multiplier formed by loop of Henle.
2. Countercurrent exchanger formed by vasa recta.

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Countercurrent multiplier
Loop of Henle:
Loop of Henle functions as countercurrent multiplier. It is responsible for development of
hyperosmolarity of medullary interstitial fluid and medullary gradient.
Special Characteristics of Loop of Henle That Cause Solutes to Be Trapped in
the Renal Medulla.
The most important cause of the high medullary osmolarity is active transport of sodium and
co-transport of potassium, chloride, and other ions from the thick ascending loop of Henle into
the interstitium. This pump is capable of establishing about a 200-milliosmole
concentration gradient between the tubular lumen and the interstitial fluid. Because the thick
ascending limb is virtually impermeable to water, the solutes pumped out are not followed by
osmotic flow of water into the interstitium. Thus, the active transport of sodium and other ions
out of the thick ascending loop adds solutes in excess of water to the renal medullary
interstitium. There is some passive reabsorption of sodium chloride from the thin
ascending limb of Henle’s loop, which is also impermeable to water, adding further to the
high solute concentration of the renal medullary interstitium. The descending limb of Henle’s
loop, in contrast to the ascending limb, is very permeable to water, and the tubular fluid
osmolarity quickly becomes equal to the renal medullary osmolarity. Therefore, water diffuses
out of the descending limb of Henle’s loop into the interstitium, and the tubular fluid osmolarity
gradually rises as it flows toward the tip of the loop of Henle.

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Steps Involved in Causing Hyperosmotic Renal Medullary Interstitium.
Step 1: a s s u m e t h a t the loop of Henle is filled with fluid with a concentration of 300
mOsm/L, the same as that leaving the proximal tubule (Osmolarity of glomerular filtrate is same
as that of plasma).
Step 2: the active pump of the thick ascending limb on the loop of Henle is turned on, reducing
the concentration inside the tubule and raising the interstitial concentration; this pump
establishes a 200-mOsm/L concentration gradient between the tubular fluid and the interstitial
fluid. The limit to the gradient is about 200 mOsm/L because paracellular diffusion of ions back
into the tubule eventually counterbalances transport of ions out of the lumen when the 200-
mOsm/L concentration gradient is achieved.
Step 3: the tubular fluid in the descending limb of the loop of Henle and the interstitial fluid
quickly reach osmotic equilibrium because of osmosis of water out of the descending limb. The
interstitial osmolarity is maintained at 400 mOsm/L because of continued transport of ions out of
the thick ascending loop of Henle.
Step 4 : additional flow of fluid into the loop of Henle from the proximal tubule, which causes the
hyperosmotic fluid previously formed in the descending limb to flow into the ascending limb.
Step 5: Once this fluid is in the ascending limb, additional ions are pumped into the interstitium,
with water remaining behind, until a 200-mOsm/L osmotic gradient is established, with the
interstitial fluid osmolarity rising to 500 mOsm/L.
Step 6: once again, the fluid in the descending limb reaches equilibrium with the hyperosmotic
medullary interstitial fluid, and as the hyperosmotic tubular fluid from the descending limb of the
loop of Henle flows into the ascending limb, still more solute is continuously pumped out of the
tubules and deposited into the medullary interstitium.
Step 7: These steps are repeated over and over, with the net effect of adding more and more
solute to the medulla in excess of water; with sufficient time, this process gradually traps solutes
in the medulla and multiplies the concentration gradient established by the active pumping of
ions out of the thick ascending loop of Henle, eventually raising the interstitial fluid osmolarity to
1200 to 1400 mOsm/L .
Thus, the repetitive reabsorption of sodium chloride by the thick ascending loop of Henle and
continued inflow of new sodium chloride from the proximal tubule into the loop of Henle is called
the countercurrent multiplier. The sodium chloride reabsorbed from the ascending loop of Henle
keeps adding to the newly arrived sodium chloride, thus “multiplying” its concentration in the
medullary interstitium.

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Role of Distal Tubule and Collecting Ducts in Excreting a Concentrated Urine

When the tubular flows into the distal convoluted tubule in the renal cortex, the fluid is dilute
(100 mOsm/L). The early distal tubule further dilutes the tubular fluid because this segment
actively transports sodium chloride out of the tubule but is relatively impermeable to water. As
fluid flows into the cortical collecting tubule, the amount of water reabsorbed is critically
dependent on the plasma concentration of ADH. In the absence of ADH, this segment is almost
impermeable to water but continues to reabsorb solutes and further dilutes the urine. When
there is a high concentration of ADH, the cortical collecting tubule becomes highly permeable to
water, so that large amounts of water are now reabsorbed from the tubule into the cortex
interstitium, where it is swept away by the rapidly flowing peritubular capillaries. As the tubular
fluid flows along the medullary collecting ducts, there is further water reabsorption from the
tubular fluid into the interstitium. The reabsorbed water is quickly carried away by the vasa
recta into the venous blood. When high levels of ADH are present, the collecting ducts become
permeable to water, so that the fluid at the end of the collecting ducts has essentially the same
osmolarity as the interstitial fluid of the renal medulla—about 1200 mOsm/L. Thus, by
reabsorbing as much water as possible, the kidneys form a highly concentrated urine, excreting
normal amounts of solutes in the urine while adding water back to the extracellular fluid and
compensating for deficits of body water.

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Other Factors Responsible for Hyperosmolarityof Medullary Interstitial Fluid
Recirculation of urea
Urea contributes about 40% to 50% of the osmolarity (500–600 mOsm/L) of the renal medullary
interstitium when the kidney is forming a maximally concentrated urine. Unlike sodium chloride,
urea is passively reabsorbed from the tubule. When there is a water deficit and blood
concentration of ADH is high, large amounts of urea are passively reabsorbed from the inner
medullary collecting ducts into the interstitium. The mechanism for reabsorption of urea into the
renal medulla is as follows. As water flows up the ascending loop of Henle and into the distal and
cortical collecting tubules, little urea is reabsorbed because these segments are impermeable to
urea. In the presence of high concentrations of ADH, water is reabsorbed rapidly from the cortical
collecting tubule, and the urea concentration increases rapidly because urea is not very permeant
in this part of the tubule. As the tubular fluid flows into the inner medullary collecting ducts, still
more water reabsorption takes place, resulting in an even higher concentration of urea in the
fluid. This high concentration of urea in the tubular fluid of the inner medullary collecting duct
causes urea to diffuse out of the tubule into the renal interstitial fluid. This diffusion is greatly
facilitated by specific urea transporters, UT-A1 and UT-A3. These urea transporters are activated
by ADH, increasing transport of urea out of the inner medullary collecting duct even more when
ADH levels are elevated. The simultaneous movement of water and urea out of the inner
medullary collecting ducts maintains a high concentration of urea in the tubular fluid and,
eventually, in the urine, even though urea is being reabsorbed.

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Countercurrent exchanger Vasa Recta:
Vasa recta functions as countercurrent exchanger. It is responsible for the maintenance of
medullary gradient, which is developed by countercurrent multiplier . Vasa recta acts like
countercurrent exchanger because of its position. It is also ‘U’ shaped tubule with a descending
limb, hairpin bend and an ascending limb. Vasa recta runs parallel to loop of Henle. Its descending
limb runs along the ascending limb of Henle loop and its ascending limb runs along with
descending limb of Henle loop.

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Role of Vasa Recta in the Maintenance of Medullary Gradient
The sodium chloride reabsorbed from ascending limb of Henle loop enters the medullary
interstitium. From here it enters the descending limb of vasa recta. Simultaneously water diffuses
from descending limb of vasa recta into medullary interstitium. The blood flows very slowly
through vasa recta. So, a large quantity of sodium chloride accumulates in descending limb of
vasa recta and flows slowly towards ascending limb. By the time the blood reaches the ascending
limb of vasa recta, the concentration of sodium chloride increases very much. This causes
diffusion of sodium chloride into the medullary interstitium. Simultaneously, water from
medullary interstitium enters the ascending limb of vasa recta. And the cycle is repeated. If the
vasa recta would be a straight vessel without hairpin arrangement, blood would leave the kidney
quickly at renal papillary level. In that case, the blood would remove all the sodium chloride from
medullary interstitium and thereby the hyperosmolarity will be decreased. Therefore, when
blood passes through the ascending limb of vasa recta, sodium chloride diffuses out of blood
and enters the interstitial fluid of medulla and, water diffuses into the blood. Thus, vasa recta
retain sodium chloride in the medullary interstitium and removes water from it. So, the
hyperosmolarity of medullary interstitium is maintained. The blood passing through the
ascending limb of vasa recta may carry very little amount of sodium chloride from the medulla.
Recycling of urea also occurs through vasa recta. From medullary interstitium, along with sodium
chloride, urea also enters the descending limb of vasa recta. When blood passes through
ascending limb of vasa recta, urea diffuses back into the medullary interstitium along with
sodium chloride. Thus, sodium chloride and urea are exchanged for water between the ascending
and descending limbs of vasa recta, hence this system is called countercurrent exchanger.

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Role of ADH
Final concentration of urine is achieved by the action of ADH. Normally, the distal convoluted
tubule and collecting duct are not permeable to water. But the presence of ADH makes them
permeable, resulting in water reabsorption. Water reabsorption induced by ADH is called
facultative reabsorption of water. A large quantity of water is removed from the fluid while
passing through distal convoluted tubule and collecting duct. So, the urine becomes hypertonic
with an osmolarity of 1,200 mOsm/L (Fig. 53.3 below).

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 Applied Physiology
1. Osmotic Diuresis
Diuresis is the excretion of large quantity of water through urine. Osmotic diuresis is the diuresis
induced by the osmotic effects of solutes like glucose. It is common in diabetes mellitus

2. Nephrogenic Diabetes Insipidus

Sometimes, ADH secretion is normal but the renal tubules fail to give response to ADH resulting
in polyuria. This condition is called nephrogenic diabetes insipidus.

Control of Extracellular Fluid Osmolarity and Sodium Concentration

Regulation of extracellular fluid osmolarity and sodium concentration are closely linked because
sodium is the most abundant ion in the extracellular compartment. Plasma sodium concentration
is normally regulated within close limits of 140 to 145 mEq/L, with an average concentration of
about 142 mEq/L. Osmolarity averages about 300 mOsm/L and seldom changes more than ± 2 to
3 percent. These variables must be precisely controlled because they determine the distribution
of fluid between the intracellular and extracellular compartments.
Osmoreceptor-ADH Feedback System
When osmolarity (plasma sodium concentration) increases above normal because of
water deficit, for example, osmoreceptor-ADH feedback system operates as follows:
1. An increase in extracellular fluid osmolarity causes the special nerve cells called osmoreceptor
cells, located in the anterior hypothalamus near the supraoptic nuclei, to shrink.
2. Shrinkage of the osmoreceptor cells causes them to fire, sending nerve signals to additional nerve
cells in the supraoptic nuclei, which then relay these signals down the stalk of the pituitary gland
to the posterior pituitary.
3. These action potentials conducted to the posterior pituitary stimulate the release of ADH, which
is stored in secretory granules (or vesicles) in the nerve endings.
4. ADH enters the blood stream and is transported to the kidneys, where it increases the water
permeability of the late distal tubules, cortical collecting tubules, and medullary collecting ducts.
5. The increased water permeability in the distal nephron segments causes increased water
reabsorption and excretion of a small volume of concentrated urine. Thus, water is conserved in
the body while sodium and other solutes continue to be excreted in the urine. This causes dilution
of the solutes in the extracellular fluid, thereby correcting the initial excessively concentrated
extracellular fluid. The opposite sequence of events occurs when the extracellular fluid becomes
too dilute (hypo-osmotic).
ADH binds to specific V2 receptors in the late distal tubules, collecting tubules, and collecting ducts,
increasing the formation of cyclic AMP and activating protein kinases. This, in turn, stimulates the
movement of an intracellular protein, called aquaporin-2 (AQP- 2), to the luminal side of the cell
membranes. The molecules of AQP-2 cluster together and fuse with the cell membrane by exocytosis to
form water channels that permit rapid diffusion of water through the cells. There are other
aquaporins,AQP-3 and AQP-4, in the basolateral side of the cell membrane that provide a path for water to
rapidly exit the cells.

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Role of Thirst in Controlling Extracellular Fluid Osmolarity and Sodium
Concentration:
The kidneys minimize fluid loss during water deficits through the osmoreceptor-ADH feedback
system. Adequate fluid intake, however, is necessary to counterbalance whatever fluid loss does
occur through sweating and breathing and through the gastrointestinal tract. Fluid intake is
regulated by the thirst mechanism, which, together with the osmoreceptor-ADH mechanism,
maintains precise control of extracellular fluid osmolarity and sodium concentration. Many of
the same factors that stimulate ADH secretion also increase thirst, which is defined as the
conscious desire for water.

Central Nervous System Centers for Thirst

The same area along the anteroventral wall of the third ventricle that promotes ADH release also
stimulates thirst. Located anterolaterally in the preoptic nucleus is another small area that, when
stimulated electrically, causes immediate drinking that continues as long as the stimulation lasts.
All these areas together are called the thirst center. These cells function as osmoreceptors to
activate the thirst mechanism, in the same way that the osmoreceptors stimulate ADH release.

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Stimuli for Thirst :

Table 28–3 summarizes some of the known stimuli for thirst.

Cardiovascular Reflex Stimulation of ADH Release

ADH release is also controlled by cardiovascular reflexes that respond to decreases in blood
pressure and/or blood volume, including (1) the arterial baroreceptor reflexes and (2) the
cardiopulmonary reflexes. These reflex pathways originate in high-pressure regions of the
circulation, such as the aortic arch and carotid sinus, and in the low-pressure regions, especially
in the cardiac atria. Afferent stimuli are carried by the vagus and glossopharyngeal nerves with
synapses in the nuclei of the tractus solitarius. Projections from these nuclei relay signals to the
hypothalamic nuclei that control ADH synthesis and secretion. Whenever blood pressure and
blood volume are reduced, such as occurs during hemorrhage, increased ADH secretion causes
increased fluid reabsorption by the kidneys, helping to restore blood pressure and blood volume
toward normal.
Atrial Natriuretic Peptide:
Specific cells of the cardiac atria, when distended because of plasma volume expansion, secrete a
peptide called atrial natriuretic peptide. Increased levels of this peptide in turn inhibit the
reabsorption of sodium and water by the renal tubules, especially in the collecting ducts. This
decreased sodium and water reabsorption increases urinary excretion, which helps to return
blood volume back toward normal.

References
1. Guyton, Arthur C. Textbook of medical physiology / Arthur C. Guyton, John E
.Hall.—11th ed .
2. Essentials of Medical Physiology- 6th ed.

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