HUMAN
RENAL SYSTEM PHYSIOLOGY
Lecture 7,8
BY: LECT. DR. ZAINAB AL -AMILY
objectives
 Describe urea handling in the nephron
 Describe Ca handling in the nephron
 Describe regulation of body fluid osmolarity
 Describe pathophysiology of ADH secretion
 Describe renal mechanisms for excreting concentrated or
diluted Urine: The Countercurrent Mechanism:
Regulation of body sodium content by the kidney
 Because Na ion is the most abundant cation in the
ECF, and that Na+ salts accounts for over 90% of the
osmotically active solutes in the plasma and ISF.
 So, the amount of Na ions is the prime determinant
of the ECF volume.
 Na+ is filtered in large amount, but normally(96%99%) of the filtered Na is reabsorbed.
 Through the effect of regulatory mechanisms the
amount of Na excreted is adjusted to equal the
amount of ingested over a wide range of dietary
intake and the individual stays in Na+ balance.
 An increase in Na+ ingestion in the diet will result in an increase in
body fluid osmolarity, which will act through the thirst mechanism to
increase the water intake.
 The action of ADH will result in increased reabsorption of water by
the kidneys that will bring back the body fluid osmolarity towards
normal.
 These changes causing increased body fluid volume , hence
increased venous return, cardiac output and BP.
 These changes are sensed by the baroreceptors causing increased
discharge that will result in generalized vasodilatation.
 The afferent arteriolar vasodilatation will result in increased
hydrostatic pressure within the glomerular capillaries leading to
raised GFR and increased loss of Na+ and water.
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 Other regulatory mechanism by the kidneys is by
regulation of Na+ excretion through a decrease in the
level circulating aldosterone.
 Increased BP will inhibit renin secretion by
juxtaglomerular cells in the walls of afferent arterioles
resulting in a fall in the circulating level of angiotensin II
causing a decline in the circulating aldosterone level,
then a decreased reabsorption of Na+ and water by the
tubules
Urea
 is freely filtered across the glomerular capillaries, and the
concentration in the initial filtrate is identical to that in
blood (i.e., initially, there is no concentration difference
or driving force for urea reabsorption).
 as water is reabsorbed along the nephron, the urea
concentration in tubular fluid increases, creating a driving
force for passive urea reabsorption.
Therefore, urea reabsorption generally follows the same
pattern as water reabsorption— the greater the water
reabsorption, the greater the urea reabsorption and the lower
the urea excretion.
 In the proximal tubule, 50% of the filtered urea is reabsorbed
by simple diffusion. As water is reabsorbed in the proximal
tubule, urea lags slightly behind, causing the urea
concentration in the tubular lumen to become slightly higher
than the urea concentration in blood; this concentration
difference then drives passive urea reabsorption, thus 50%
remains in the lumen
 In the thin descending limb of Henle’s loop, urea is secreted
there is a high concentration of urea in the interstitial fluid
of the inner medulla.
The thin descending limb of Henle’s loop passes through the
inner medulla, and urea diffuses from high concentration
in the interstitial fluid into the lumen of the nephron.
 More urea is secreted into the thin descending limbs than
was reabsorbed in the proximal tubule; thus, at the bend of
the loop of Henle, 110% of the filtered load of urea is present.
 The thick ascending limb of Henle, distal tubule, and cortical
and outer medullary collecting ducts are impermeable to
urea, thus no urea transport occurs in these segments.
 in the presence of antidiuretic hormone (ADH), water
is reabsorbed in the late distal tubule and the cortical
and outer medullary collecting ducts—
consequently ,in these segments, urea is “left behind,” and
the urea concentration of the tubular fluid becomes quite
high.
 In the inner medullary collecting ducts, there is a specific
transporter for the facilitated diffusion of urea (urea
transporter 1, UT1), which is activated by ADH.
 Thus, in the presence of ADH, urea is reabsorbed by
UT1, moving down its concentration gradient from the
lumen into the interstitial fluid of the inner medulla.
In the presence of ADH, approximately 70% of the filtered
urea is reabsorbed by UT1, leaving 40% of the filtered urea to
be excreted in the urine.
 The urea that is reabsorbed into the inner medulla
contributes to the corticopapillary osmotic gradient in a
process called urea recycling
 Calcium (Ca2)
 most of the body’s calcium (Ca2) is contained in bone (99%).
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The remaining 1% is present in ICF (mostly in bound form)
and in ECF.
The total Ca2 concentration in plasma is 5 mEq/L or 10 mg/
dL. Of the total plasma Ca2 , 40% is bound to plasma
proteins, 10% is bound to other anions such as phosphate
and citrate, and 50% is in the free, ionized form.
The plasma Ca2 concentration is regulated by PTH
Filtration of Ca2 differs from Na at the filtration step.
Any Ca2 bound to plasma proteins (i.e., 40% of the
total Ca2) cannot be filtered across glomerular capillaries;
therefore, only 60% is ultrafilterable
 The pattern of Ca2 reabsorption along the nephron is quite
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similar to the pattern for Na reabsorption
Like Na, over 99% of the filtered Ca2 is reabsorbed, leaving
less than 1% to be excreted.
Ca2 reabsorption is tightly coupled to Na reabsorption in the
proximal tubule and loop of Henle, and only in the distal
tubule is the reabsorption of the two ions dissociated.
the distal tubule is the site of regulation of Ca2 reabsorption.
The following three points concerning regulation in the
distal tubule are :
(1) The distal tubule is the only nephron segment in which
Ca2 reabsorption is not coupled directly to Na reabsorption.
 (2) In the distal tubule, PTH(parathyroid hormone)secreted
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from parathyroid gland increases Ca2 reabsorption via a
basolateral receptor, activation of adenylyl cyclase,
This action of PTH on the distal tubules called its
hypocalciuric action.
Thus, PTH has two effects on the nephron, both of which are
mediated by cAMP: a phosphaturic action in the proximal
tubule, and a hypocalciuric action in the distal tubule.
(3) Because of the uncoupling of distal Ca2 and Na
reabsorption, the effect of thiazide diuretics on Ca2
reabsorption differs entirely from the effects of diuretics
that act in the proximal tubule or thick ascending limb.
Thiazide diuretics increase Ca2 reabsorption, while the other
classes of diuretics decrease it.
Mg2+ competes with Ca2+ for reabsorption in the thick
ascending limb, hypermagnesemia will cause hypercalciuric
action
 Which of the following would produce an increase in the
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reabsorption of isosmotic fluid in the proximal tubule?
(A) Increased filtration fraction
(B) Extracellular fluid (ECF) volume expansion
(C) Decreased peritubular capillary protein
concentration
(D) Increased peritubular capillary hydrostatic pressure
(E) Oxygen deprivation
REGULATION OF BODY FLUID OSMOLARITY
 The regulation of body fluid osmolarity is best illustrated
by two commonplace examples.
 The first example is the body’s response to water deprivation;
 The second is the body’s response to drinking water.
 Response to Water Deprivation
1. Water is continuously lost from the body in sweat and
in water vapor from the mouth and nose (called insensible
water loss).
If this water is not replaced by drinking water, then plasma
osmolarity increases
 2.The increase in osmolarity stimulates osmoreceptors
in the anterior hypothalamus, which are exquisitely
sensitive and are stimulated by increases in osmolarity of less
than 1 mOsm/L.
3. Stimulation of the hypothalamic osmoreceptors has
two effects. It stimulates thirst, which drives drinking
behavior. It also stimulates secretion of ADH from the
posterior pituitary gland.
4. The posterior pituitary gland secretes ADH.
ADH circulates in the blood to the kidneys, where it
produces an increase in water permeability of the principal
cells of the late distal tubule and collecting duct.
5. The increase in water permeability results in increased
water reabsorption (5a) in the late distal tubule and
collecting ducts. As more water is reabsorbed by these
segments, urine osmolarity increases and urine volume
decreases (5b).
6. Increased water reabsorption means that more water is
returned to the body fluids.
 Coupled with increased thirst and drinking behavior, plasma
osmolarity is decreased, back toward the normal value.
Response to Water Drinking
 When a person drinks water, the ingested water is distributed
throughout the body fluids.
 Since the amount of solute in the body is unchanged, the
added water will dilute the body fluids and cause a decrease
in plasma osmolarity.
2. The decrease in plasma osmolarity inhibits osmoreceptors
in the anterior hypothalamus.
3. Inhibition of the osmoreceptors has two effects.
It decreases thirst and suppresses water drinking behavior.
It also inhibits secretion of ADH from the posterior pituitary
gland.
4.When ADH secretion is inhibited, circulating levels of ADH are
reduced, and less ADH is delivered to the kidneys.
As a result of the lower ADH levels, there is a decrease in water
permeability of the principal cells of the late distal tubule and
collecting ducts.
5. The decrease in water permeability results in decreased water
reabsorption by the late distal tubule and collecting ducts (5a).
The water that is not reabsorbed by these segments is excreted,
decreasing urine osmolarity and increasing urine volume (5b).
6. Since less water is reabsorbed, less water is returned to the
circulation.
Coupled with the inhibition of thirst and the suppression of water
drinking, plasma osmolarity increases back toward the normal
value.
 Decreased plasma osmolality and hypovolaemia. Would you
see: (T or F)
A. Decreased urine output
B. Increased urine output
C. Decreased ADH secretion
D. Increased Renin –Angiotensin- Aldosterone secretion
E. No change in urine output
Diabetes insipidus (DI)
 Caused by a deficiency of or a decreased response to ADH.
 Two types of DI
 Central “neurogenic” DI
 Defect in the synthesis or release of ADH
 Nephrogenic DI
 Kidneys do not respond to ADH.
SIADH (syndrome inapproperiate antidiuretic hormone
secretion): the body secretes ADH when it shouldn't. Thus,
water is retained when it should be excreted. This often leads to
electrolyte disturbances (such as sodium levels).
Causes: include head injury/trauma, meningitis, cancer
(especially lung cancer), some infections and some drugs.
 Choose the appropriate nephron site
in the diagram
In a patient with severe central
diabetes insipidus caused by a lack of
antidiuretic hormone
secretion, which part of the tubule
would have the lowest tubular fluid
osmolarity?
In a person on a very low potassium
diet, which part of the nephron would
be expected to reabsorb
the most potassium?
Which part of the nephron normally
reabsorbs the most water?
In a normally functioning kidney,
which part of the tubule has the lowest
permeability to water during
antidiuresis?
Hyponatremia
Na+ concentration below 135 mEq/L (135 mmol/L).
1) 1) Hypertonic (translocational):
i. results from an osmotic shift of water from
ICF to ECF, such as occurs with
hyperglycemia  Na+ becomes diluted.
2) Hypotonic (dilutional):
I. most common form
II. caused by water retention and characterized
by a decrease in serum osmolality.
Hypernatremia
Serum Na+ level above 145 mEq/L
Serum osmolality greater than 295 mOsm/kg.
Na+ is functionally an impermeable solute  contributes to the
tonicity and movement of water across cell membranes.
Hypernatremia is characterized by hypertonicity of the ECF
and almost always causes cellular dehydration.
Hypernatremia represents a deficit of water in relation to the
body’s Na+ levels.
Hypokalemia
Refers to a serum K+ level below 3.5 mEq/L.
Causes:
i.
ii.
iii.
iv.
v.
vi.
vii.
viii.
ix.
 Shift of K+ from ECF into ICF (insulin & β-adrenergic agonist
drugs).
Metabolic alkalosis
Mg2+ depletion (ICF )
Trauma and stress
Hyperaldosteronism
Vomiting
Heavy perspiration
Diuretics like thiazide and loop diuretics.
Burns
Extracellular-Intracellular Shifts
Movement of K+ between the ECF and ICF  K+ to move into
body cells when serum levels are high and move out when
serum levels are low.
Factors that alter K+ distribution between the ECF and ICF are:
A.Insulin increases cellular uptake of K+ after a
meal.
B. β-adrenergic (e.g., epinephrine) stimulation
facilitate K+ movement into muscle tissue during
periods of physiologic stress.
Extracellular-Intracellular Shifts
C. Serum osmolality: When increased because of the
presence of impermeable solutes such as glucose
(without insulin), water leaves the cell 
produces an increase in intracellular K+, causing
it to move out of the cell into the ECF.
D. Acid-base disorders.
In metabolic acidosis, H+ move into body cells for buffering 
causes K+ to leave the cells and move into the ECF.
Metabolic alkalosis has the opposite effect.
Extracellular-Intracellular Shifts
Exercise can also produce compartmental shifts in K+.
Repeated muscle contraction releases K+ into the ECF.
Although the increase usually is small with modest
exercise, it can be considerable during exhaustive
exercise.
Hyperkalemia
An increase in serum levels of K+ > 5.0 mEq/L.
Causes:
i. Hypoaldosteronism
ii. Renal failure & hyperkalemia
iii. Excessive IV fluid administration
iv. Excessive hemolysis  large amount of K+ release from the
RBCs
v. Drugs like K+ -sparing diuretics and ACEI
At which nephron site is the
tubular fluid/plasma (TF/P)
osmolarity lowest
in a person who has been deprived
of water?
(A) Site A
(B) Site B
(C) Site C
(D) Site D
(E) Site E
At which nephron site is the
tubular fluid inulin concentration
highest during antidiures is?
(A) Site A
(B) Site B
(C) Site C
(D) Site D
(E) Site E
Renal Mechanisms for Excreting Concentrated or Diluted
Urine: The Countercurrent Mechanism:
 The ability of the kidneys to excrete concentrated urine
(than plasma) is essential for survival of mammals living
on land.
 It depends upon the maintenance of a gradient of
increasing osmolarity along the medullary pyramids.
 This gradient is produced by the operation of the loops
of Henle as “countercurrent multipliers” and is
maintained by the operation of vasa recta as
“countercurrent exchangers”.
 There are important facts about the countercurrent system within
the kidneys:
1. A countercurrent system is a system, in which the inflow runs
parallel to, in close proximity to and in opposite direction to the
outflow; which is the case for both the loop of Henle and vasa
recta in the renal medulla.
2. There is an osmotic pressure gradient from the cortico-medullary
junction to the tips of the medullary pyramids (which is made
up of Na+, Cl¯ and urea),
The longer the medullary depth, the greater the length of the
loops of Henle, the higher the osmotic pressure gradient that can
be reached at the tip of the pyramid; which means more chances
to excrete a concentrated urine.
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3..a high level of ADH is another basic requirement for forming
concentrated urine.
 The operation of each loop of Henle as a countercurrent multiplier
depends on the active transport of Na+ and, Cl¯ out of its thick
ascending limb, due to the presence of (Na+–K+–2Cl¯) exchanger
proteins.
 This creates an osmotic pressure gradient between the fluid in the
ascending limb and the medullary interstitium.
 Urea Recycling
 Urea recycling from the inner medullary collecting ducts is
the second process that contributes to the establishment of
the corticopapillary osmotic gradient.
 1. In the cortical and outer medullary collecting ducts,
ADH increases water permeability, but it does not
increase urea permeability.
As a result, water is reabsorbed from the cortical and outer
medullary collecting ducts, but urea remains behind in the
tubular fluid.
 2. This differential effect of ADH on water and urea
permeability in cortical and outer medullary collecting
ducts causes the urea concentration of tubular fluid to
increase.
 3. In the inner medullary collecting ducts, ADH increases
water permeability and it increases the transporter for
facilitated diffusion of urea, UT1 (in contrast to its effect on
only water permeability in cortical and outer medullary
collecting ducts).
 4. Since the urea concentration of tubular fluid has been
elevated by reabsorption of water in the cortical and outer
medullary collecting ducts, a large concentration gradient
has been created for urea.
 In the presence of ADH, the inner medullary collecting
ducts can transport urea, and urea diffuses down its
concentration gradient into the interstitial fluid.
 Urea that would have otherwise been excreted is recycled
into the inner medulla, where it is added to the
corticopapillary osmotic gradient.
 Two factors allows the movement of water out into
the osmotically high medullary interstitium by
osmosis:
The high permeability to water of the thin descending limb
of the loop of Henle,
2. The continuous inflow of tubular fluid from the proximal
tubule
1.
CORTICOPAPILLARY OSMOTIC
GRADIENT
 it is a gradient of osmolarity in the interstitial fluid of the
kidney from the cortex to the papilla
 The osmolarity of the cortex is approximately 300 mOsm/L,
similar to the osmolarity of other body fluids.
 Moving from the cortex to the outer medulla, inner medulla,
and papilla, the interstitial fluid osmolarity progressively
increases.
 At the tip of the papilla, the osmolarity can be as high as
1200 mOsm/L.
countercurrent multipliers
 The process is best understood hypothetically for a cortical
nephron as follows (see the diagram below):
 Assuming that the osmolality throughout the descending and
ascending limbs and the medullary interstitium is (300
mosm/kg H2O) (1).
 Assuming, also, that the pumps in the thick ascending limb
can pump 100 mosm/kg of Na+ and Cl¯ from the tubular fluid
to the interstitium, increasing the interstitial osmolality to
(400 mosm/kg H2O) (2).
 Water then moves out of the thin descending limb, and its
content equilibrates with the interstitium (3).
 However, fluid continuing (300 mosm/kg H2O) is
continuously entering this limb from the proximal
tubule, which again equilibrates with the interstitium
(4),
 so the gradient against which Na+ and Cl¯ are pumped is
reduced; and more enter the interstitium (5).
 Meanwhile, hypotonic fluid flows into the distal tubule
and isotonic and subsequently hypertonic fluid flows
into the thick ascending limb (6) and (7).
 The process keeps repeating (4) – (6) and the fluid is
progressively concentrated as it flows down the
descending limb and progressively diluted as it flows up
the ascending limb.
 The final result is a gradient of osmolarity from the top to the
bottom of the loop that is even greater at the tip of
juxtamedullary nephrons with longer loops of Henle,
causing additional passive countercurrent
multiplication
Vasa Recta
 The vasa recta are capillaries that serve the medulla and
papilla of the kidney.
 The vasa recta follow the same course as the loops of Henle
and have the same hairpin (U) shape.
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 Only 5% of the renal blood flow serves the medulla, and
blood flow through the vasa recta is especially low.
 The vasa recta participate in countercurrent exchange, which
differs from countercurrent multiplication as follows:
Countercurrent multiplication is an active process that
establishes the corticopapillary osmotic gradient
 Countercurrent exchange is a purely passive process that
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helps maintain the gradient.
The passive properties of the vasa recta are the same as for
other capillaries:
They are freely permeable to small solutes and water.
Blood flow through the vasa recta is slow, and solutes and
water can move in and out, allowing for efficient
countercurrent exchange.
Countercurrent exchange is illustrated schematically
The figure shows a single vasa recta, with its descending limb
and ascending limb.
Blood entering the descending limb has an osmolarity of 300
mOsm/L.
 As this blood flows down the descending limb, it is
exposed to interstitial fluid with increasingly higher
osmolarity (the corticopapillary osmotic gradient).
 Since the vasa recta are capillaries, small solutes, such as
NaCl and urea, diffuse into the descending limb and
water diffuses out, allowing blood in the descending limb
of the vasa recta to equilibrate osmotically with the
surrounding interstitial fluid.
 At the bend of the vasa recta, the blood has an osmolarity
equal to that of interstitial fluid at the tip of the papilla, 1200
mOsm/L.
 In the ascending limb, the opposite events occur.
 As blood flows up the ascending limb, it is exposed to
interstitial fluid with decreasing osmolarity.
 Small solutes diffuse out of the ascending limb and water
diffuses in, and the blood in the ascending limb of the vasa
recta equilibrates with the surrounding interstitial fluid.
 The blood leaving the vasa recta has an osmolarity of 325
mOsm/L, which is slightly higher than the osmolarity of the
original blood that entered it.
 Some of the solute from the corticopapillary osmotic gradient
was picked up and will be carried back to the systemic
circulation.
 With time, this process could dissipate the corticopapillary
osmotic gradient.
 The gradient normally does not dissipate, however, because
the mechanisms of countercurrent multiplication and urea
recycling continuously replace any solute that is carried away
by blood flow.
 In the presence of ADH, the hypotonic tubular fluid which passes
through the distal tubule will cause water to pass out of the tubule
into the hypertonic interstitium driven by the osmotic pressure
gradient.
 Even more water would be reabsorbed into the more hypertonic
medullary interstitium, as the fluid passes down the collecting
ducts.
 This hormone makes the tubular epithelium highly permeable to
water, by:
 causing the insertion of “aquaporin 2” water channels into the
apical membrane of the principal cells.
 It would facilitate the movement of urea into the medullary
interstitium. As a result, concentrated urine would be excreted.
 in the absence of ADH, membranes of the distal tubule and the
collecting duct would become relatively impermeable to water.
 Therefore, tubular fluid remains hypotonic, causing larger
amounts to flow into the renal pelvis, increasing water loss in
urine.
 In the absence of ADH, urea would move from the
interstitium into the hypotonic tubular fluid in the inner
collecting duct and the osmotic gradient of the pyramids is
reduced; thereby aiding in the excretion of diluted urine.