Renal 2 MTC PDF

Renal Physiology
Part 2
Na+ Handling
Sodium Handling and Diuretics
Learning objectives
1. Describe the normal whole-body daily sodium balance.

2. Describe the contribution of the major nephron segments to the reabsorption of filtered
salt and water.
3. Outline the mechanisms for NaCl absorption along the proximal tubule and describe the
changes that occur along the length of this segment.
4. Describe the mechanism of NaCl absorption in the thick ascending limb of Henles loop,
the distal convoluted tubule and in renal principal cells.
5. Describe the molecular biology of the major sodium transport proteins in the nephron.
6. Summarize the main neurohumoral factors which regulate NaCl reabsorption along the
nephron.
This diagram shows how sodium is distributed in the body. Note the important
role of the kidney in filtering and subsequently reabsorbing that sodium. (Note:
Although not listed in the diagram above there can also be significant losses of sodium
from the gastrointestinal system (vomiting and diarrhea) and from the skin following
burns and from the cardiovascular system following haemorrhage.
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Na+ Handling
Overview of Renal Sodium Handling
Understanding mechanisms of renal sodium transport is important for several reasons. First,
NaCl and water are filtered at the highest rates and the quantities of reabsorption necessary are
enormous. Second, transport of sodium is linked to essential tubular reabsorptive and secretory
processes for many other substances. Third, mechanisms of NaCl reabsorption are modified
clinically by diuretics. Treatment with diuretics aims to reduce ECF volume by increasing renal
excretion of NaCl and water. Diuretics are commonly used medications in the treatment of
pulmonary edema and high blood pressure. An easy way to remember the importance of sodium
and water movement is that water will follow sodium in the nephron. Increase sodium
reabosrption will lead to increased water reabsorption while inhibition of sodium reabsorption
will lead to a diuresis.
The filtered load of sodium is far greater than the daily requirement for sodium excretion.
Typically the fractional excretion for sodium is about 1-2%. Filtration and reabsorption are the
only significant processes affecting NaCl and water excretion. Thus, regulation of excretion is
achieved largely by varying the amount that escapes tubular reabsorption.
The slide illustrates

segmental handling of
sodium (FE values for
chloride are similar). The
slide shows the proportion
of filtered sodium
reabsorbed in the nephron
at the different segments.
For example, the proximal
tubule extracts ~70% of
the filtered load of sodium,
so that the fractional
excretion at the end of this
segment is 30%. The loop
of Henle typically
reabsorbs another ~20% of
the filtered load, so that
around 10% of filtered
NaCl enters the distal
tubule. The % of filtered
NaCl delivered to the distal
nephron does not change
much across a wide range
of NaCl intakes. This
design allows for fine
regulation of NaCl
excretion in the distal
tubule and collecting duct,
particularly by aldosterone.
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Na+ Handling
Mechanisms Of Sodium Reabsorption
Active sodium reabsorption is the key driving force behind NaCl and water reabsorption along
the nephron. Chloride absorption is passive or occurs via secondary active transport coupled to
the movement of sodium. Water reabsorption is coupled to the reabsorption of NaCl and occurs
by osmosis.
The Na+/K+-ATPase Drives Na+ Reabsorption

All Along The Renal Tubule
Lumen Blood
Na+ ATP
3Na+
ADP
2K+
Na+
The slide describes the basic process of transcellular sodium absorption, which is a two-step
process involving passive uptake across the apical membrane (through co-transporters,
antiporters or channels) and active extrusion across the basolateral membrane. The latter is
driven by the sodium/potassium-ATPase, which in renal epithelial cells keeps intracellular
sodium at a concentration of around 30 mEq/L. The energy in the large inward sodium gradient
at the luminal membrane is coupled to the uptake of many other substrates. The sodium entry
step is the target of inhibition by the diuretics in most common clinical use.
Proximal Tubule
The mechanism for nutrient uptake in

In early proximal tubule Na+ absorption early proximal tubule is shown. Its key
is linked to nutrient transport.. feature is the presence of sodium linked
Lumen Blood cotransport at the apical membrane. This
3Na+ concentrates the nutrient molecule in the
Na+
ATP
ADP
cell and allows it to diffuse out of the cell
2K+ into the blood via facilitated diffusion.
nutrient
Depending on the nutrient molecule
nutrient
there are different cotransporters
involved. For glucose the main
Familial renal glycosuria SGLT2 mutations transporter is called SGLT2 (sodium-
Cystinuria dibasic amino acid carrier glucose transporter 2) See the Figure
Hartnups disease neutral amino acids
on the next page. This is the saturable
transporter that is overwhelmed in
hyperglycemic patients when the filtered
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Na+ Handling
glucose load exceeds reabsorptive capacity, resulting in glucose in the urine. Mutations in SGLT2
also account for an inherited condition in which there is large amounts of glucose in the urine
unrelated to diabetes mellitus. In the case of amino acids, there are several sodium linked
cotransporters involved, each with different substrate specificity for particular classes of amino
acid (e.g. acidic amino acids). In some cases genetic disorders of amino acid wasting can be traced
to a failure of amino acid uptake in the kidney and GI tract due to defective cotransporters.
Tubular lumen Proximal Tubule Cell Interstitial Fluid
Na+
K+
HIGH
Na+
Glu
LOW
Glu
Na+
Glucose
This figure shows the example of Na+ glucose cotransport in the proximal tubule. The
electrochemical gradient favoring Na+ entry into the proximal tubule cell is used to drive glucose
in against its electrochemical gradient. The relatively high concentration of glucose in the
proximal tubule cell then allows for it to move via facilitated diffusion into the interstitial fluid.
Na+ levels in the proximal tubule cell are kept low via the action of the Na+-K+ pump.
The filtered load of nutrient molecules is

But..Far More Na+ Than Nutrient Must much less than that of sodium, so that
Be Absorbed! the coupling of sodium to nutrient has
little impact on reabsorbing the sodium
Lumen Blood load. The slide summarizes the
mechanisms for sodium uptake that
Na+ 3Na+ make the biggest contribution to sodium
ATP
NHE3 reabsorption in the proximal tubule. The
ADP
H+ 2K+ most significant process is Na/H ion
exchange, via a protein called NHE3. In
Base- Na+ the early part of the proximal tubule
hydrogen ion secretion is coupled to
Cl-
3 HCO3- bicarbonate reabsorption. In the second
half of the proximal tubule sodium and
chloride absorption involves Na/H ion
4
Na+ Handling
exchange operating in parallel with chloride/base- exchange, the net result is to bring both
chloride and sodium into the cell. The base anion may be either bicarbonate, formate or oxalate.
The transport processes that result in

Absorption Mechanisms Change Along NaCl and water reabsorption in the
The Proximal Tubule proximal tubule cause the concentrations
2.0 inulin of several solutes to change along the
proximal tubule:
1.5
Cl- Q. Why does the concentration of inulin
[TFx/Px] Na+ increase?
1.0
osm
HCO3-
Q. Why does osmolality stay the same?
0.5
Glucose/amino acids
0.0 A striking feature of the graph is the fall
Length of proximal tubule in concentration of nutrient molecules
such as glucose and amino acids along
the proximal tubule. This shows that these solutes are preferentially reabsorbed from the filtrate
at a very early site. In physiological states, glucose and amino acid reabsorption is almost
complete one quarter of the way along the proximal tubule. The above slide also shows a marked
fall in bicarbonate concentration in the early part of the proximal tubule. This recovery of filtered
bicarbonate is an important feature of the renal contribution to acid-base homeostasis. In early
proximal tubule sodium absorption is mostly coupled to the uptake of nutrients and to
bicarbonate reabsorption, rather than to chloride recovery. This explains the rise in chloride
concentration in the lumen in early proximal tubule. In the mid- to late proximal tubule sodium
absorption is coupled to chloride absorption.
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Na+ Handling
Loop of Henle
In the thin limbs of Henles loop there is no active transport of NaCl. The descending and
ascending thin limbs have differences in passive permeability, which are important to the urine
concentration mechanism. The thick ascending limb is metabolically very active.
The sodium and chloride uptake into

Na+ uptake in the TALH is via a the cell are coupled via a cotransport
cotransport mechanism mechanism, which also includes uptake
of potassium. The process is electrically
Lumen Blood
Na + 3Na + neutral since it involves 1 sodium, 2
2Cl- NKCC2 chloride and 1 potassium ions. At the
K + 2K +
basolateral membrane sodium is
pumped out via the Na/K-ATPase,
ROMK Cl- CLC-Kb
whereas chloride leaves via an ion
channel. At the apical membrane the
+ cations presence of a potassium channel to
Mutations in any of NKCC2, ROMK recycle potassium that enters during
or CLC-Kb NaCl uptake is important. First, the
= BARTTERS SYNDROME concentrations of sodium chloride in
tubular fluid entering the thick
ascending limb are much higher than potassium concentration. This means that there would not
be sufficient potassium available to load the cotransporter for sodium chloride uptake, if
potassium was not recycled. The second reason the apical potassium conductance is important is
that, in conjunction with the basolateral chloride conductance a lumen positive tranepithelial
electrical potential difference is generated. This potential difference is important because the tight
junctions in this region are cation permeable, particularly to magnesium ions. The lumen positive
potential allows for a significant paracellular cation flux.
The molecular identity of all the transporters in the thick ascending limb cell model are known
(see slide). If a loss of function mutation arises in the cotransporter, the apical potassium channel
or the basolateral chloride channel, a rare inherited condition called Bartters Syndrome occurs.
This disease is associated with urinary wasting of NaCl due to the loss of reabsorption in the
thick ascending limb. Bartters Syndrome patients also lose large amounts of calcium and
magnesium, reflecting the importance of this segment in divalent cation handling.
Distal Tubule
The distal tubule is a heterogeneous segment. Early distal tubule (distal convoluted tubule) is
lined by epithelial cells with the transport proteins shown below. The late distal tubule merges
with a connecting tubule, which in turn merges with a cortical collecting duct. During this
transition the epithelial lining becomes a mixture of cell types, including those seen in the early
distal tubule and the renal principal cells, which are described in the section on collecting duct
below.
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Na+ Handling
In early distal tubule sodium and

Early distal tubule uses Na/Cl chloride are coupled directly via
cotransport for Na+ absorption a cotransporter. Uphill sodium
exit is via the usual pathway of
Lumen Blood the Na/K-ATPase, while that
3Na+ for chloride is via an ion
Na+ channel. The molecular identity
NCCT
2K+ of the cotransporter is known
and mutations in this protein are
Cl-
Cl- the basis for a rare salt wasting
disease called Gittelmans
Syndrome.
NCCT mutations cause
GITTELMANS SYNDROME
Cortical Collecting Duct
This segment has two distinct cell types. Principal cells are the most abundant cells and are
associated with NaCl reabsorption. Intercalated cells are the other cell type present and are
involved with acid-base balance.
Principal cells are the only site

Na+ entry in the collecting duct in the nephron where sodium
is via an ion channel uptake from the lumen occurs
via simple diffusion through an
Lumen Blood ion channel. The presence of
potassium channels in the
Na+ apical membrane is important
ENaC
3Na+
to the overall function of this
ROMK K+ cell. Aldosterone signals to the
2K+
kidney to conserve sodium and
excrete more potassium.
Principal cells are the major
target for aldosterone, which
ENaC gain of function = LIDDLES SYNDROME increases the activity of all the
ENaC loss of function = transporters shown.
PSEUDOHYPOALDOSTERONISM (PHA)
The sodium channel in the apical membrane of renal principal cells is ENaC. In Liddles
syndrome ENaC is mutated so that it becomes more active than it should be. Liddles Syndrome
is associated with salt-sensitive hypertension because patients reabsorb too much salt in the late
distal tubule and cortical collecting duct. This leads to expansion of the ECF volume and to
increased blood pressure. ENaC channels can also be mutated so that function is lost. This
causes a syndrome that appears to be the same as having no aldosterone production. These
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Na+ Handling
patients have salt wasting, leading to hypovolemia and also have a reduced ability to excrete
potassium.
Regulation Of NaCl Reabsorption

The regulation of NaCl reabsorption may be controlled by two separate mechanisms.
Regulation by glomerulotubular balance

This term means there is a balance between the glomerular filtration of Na+ and its tubular
reabsorption. This balance is that for whatever amount of Na+ is filtered at the glomerulus a
certain fraction will always be reabsorbed at a proximal tubule. The diagram below shows the
relationship between the filtered load of Na+ and the amount reabsorbed in the proximal tubule.
It can be seen from this graph that the fraction of the filtered load of Na+ reabsorbed remains
constant throughout ie. as filtered load increase so does the reabsorbtion. Although this seems to
be stating the obvious, it means that the proximal tubule has the ability to increase the amount of
Na+ it reabsorbs when the filtered load increases. However, the mechanism by which this occurs
are not completely obvious. We will cover these in the next few diagrams.
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Na+ Handling
GFR regulation of Na+ reabsorption
This diagram shows how the change in filtration fraction changes Na+ reabsorption. This looks
difficult at first but really it is not too bad. With a normal GFR Na + is actively transported into
the lateral intercellular space by the Na+-K+ pump. As has been discussed early Na+ reabsorption
is coupled to that of water. As not all water is reabsorbed and some moves back into the tubule
Na+ ions follow. This is called passive back leak. Now look at the increased filtration fraction
diagram, for example if we increase GFR. An increase in GFR will mean decreased volume of
blood in the peritubular capillary (assuming renal blood flow remains constant) which in turn will
decrease capillary hydrostatic pressure. Secondly the decreased volume will increase plasma
protein oncotic pressure, both of these will favor greater reabsorption of fluid into the capillary.
As stated above the Na+ will follow and so you will have greater Na+ reabsorption.
9
Na+ Handling
So why is this important ? In the following table we can see the importance of coupling GFR
with sodium reabsorption. An increase in GFR by one third leads to an increased reabsorption
of sodium (Period 1 to Period 2). Without an increase in sodium reabsorption subsequent to an
increase in GFR there is a rapid loss of sodium from the ECF.
Table 23.5 Glomerulotubular Balancea
Period Filtered (mEq/min) Reabsorbed (mEq/min) = Excreted (mEq/min)
1 6.00 5.95 0.05
Increase GFR by one third
2 8.00 7.90 0.10
a
Results from an experiment performed on a 10-kg dog. In response to an increase in
glomerular filtration rate (GFR) (produced by infusing a drug that dilated afferent
arterioles), tubular reabsorption of Na+ also increased, so that only a modest increase
in Na+ excretion occurred. If there had been no glomerulotubular balance and if
tubular Na+ reabsorption had stayed at 5.95 mEq/min, the kidneys would have
excreted 2.05 mEq/min in period 2. If we assume that the extracellular fluid (ECF)
volume in the dog is 2 L (20% of body weight) and if plasma [Na+] is 140 mEq/L, an
excretion rate of 2.05 mEq/min would result in excretion of the entire ECF Na+ (280
mEq) in a little over 2 hours. The dog would have been dead long before this could
happen, which underscores the importance of glomerulotubular balance.
10
Na+ Handling
Neurohormal regulation of Na+ reabsorptoin (Ang II, NE, ADH Aldosterone & ANP)
Maintenance of arterial blood

Neurohumoral regulation of Na+ pressure involves interaction
reabsorption: between control of cardiac output,
systemic vascular resistance and
Angiotensin II
Norepinephrine NO also the circulatory volume. The
Dopamine latter is governed by renal NaCl
excretion. One way of altering
excretion of NaCl is to vary the
aldosterone rate of reabsorption by the renal
ADH PGE2 tubule. The slide shows that
control over renal NaCl excretion
ANP includes neural, hormonal and local
factors and also involves every
nephron segment. There is a
Stimulate Na+ reabsorption Inhibit Na+ reabsorption balance between factors that
promote sodium retention and
those that promote sodium excretion. The next group of slides looks at the mechanism of
actions of some of these regulators
Angiotensin II Major effect at the

proximal tubule
Lumen Blood
Na+ ATP
3Na+
NHE3
ADP
H+ 2K+
Na+
Base- Na+
? ? 3 HCO3-
Cl-
The diagram above shows the direct mechanism of action of angiotensin II (AII) on the proximal
tubule. AII increases the number and activity of the NHE3 transporter and Na+-K+ pump
found on the luminal and basolateral side of the proximal tubule respectively. This favors the
movement of Na+ from the nephron lumen to the interstitial fluid.
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Na+ Handling
Norepinephrine Via 1 receptors
Lumen Blood
Na+ ATP
3Na+
NHE3
ADP
H+ 2K+
Na+
Base- Na+
? ? 3 HCO3-
Cl-
Norepinephrine has a similar effect on the proximal tubule cell as AII. It does this by binding to
1-receptors.
Makes interstitial fluid more
Has an effect in
hypertonic. Important for ADH TALH
concentrating urine
Lumen Blood
Na+ 3Na+
2Cl- NKCC2
2K+
K+
ROMK Cl- CLC-Kb
Na+
+ cations
ADH has a direct action on Na+ reabsorption in the thick ascending limb of the Loop of Henle.
It acts by increasing the number and activity of the NKCC2 transporter and of ROMK. This
also stimulates reabsorption of important cations. This reabsorption of Na+ helps to maintain
the osmolarity difference that is important for the renal countercurrent multiplication system (See
next Chapter)
12
Na+ Handling
Aldosterone
Lumen Blood
Na+ ENaC
3Na+
ROMK K+
2K+
Na+
Principal Cell
Aldosterone acts by increasing the number and activity of ENaC transporters, Na+-K+ pumps
and ROMK channels in the principal cells of the collecting duct. This elevates Na+
reabsorption.
13
Na+ Handling
Atrial Natriuretic Peptide

Lumen Blood
Na+ ENaC 3Na+
ROMK K+ 2K+
Some question over is it ANP

or Urodilatin involved in this
response
ANP acts by decreasing the activity of the ENaC channel of the principal cell of the collecting
duct. This decreases the amount of sodium that can leave the lumen via the collecting duct.
14
Urine Concentration and Dilution
Learning objectives.
1. Identify the major routes of water loss from the body.

2. Identify the two most potent stimuli for ADH release and the negative feedback
mechanism for each.
3. Describe the role of the ascending limb of the loop of Henle in producing high medullary
interstitial fluid osmolality and dilute distal tubular fluid.
4. Describe the mechanisms of countercurrent multiplication and exchange.
5. Explain the importance of urea in formation of concentrated urine.
6. Explain the mechanisms by which ADH causes formation of concentrated urine.
7. Distinguish between central and nephrogenic Diabetes Insipidus based on the plasma
ADH level and the response to injected ADH.
8. Define free water clearance. Given the urine and plasma osmolalities and urine flow rate,
calculate osmolar and free water clearance. Identify expected free water clearance for an
individual producing either a dilute or a concentrated urine.
15
Overview of Water Balance
Maintenance of near constant body fluid osmolality despite fluctuations in water intake is due to
the kidneys ability to regulate water excretion independently of solute excretion. A major goal of
this lecture is to understand the mechanisms within the kidney that allow for excretion of either
excess solute free water, or for the retention of water without equivalent solute retention.
The slide shows the routes and

Typical Daily Water Balance typical amounts of water loss per day
from the body. Insensible water
losses cannot be prevented, such as
Average Daily Water Losses (ml): via breathing and also some
Insensible loss 900
evaporative loss from the skin.
WATER BALANCE Water losses can be highly variable.
Feces 100
For instance, it is possible to
Urine 1500 (loss = intake) produce 10-12L of sweat per day.
TOTAL = 2500 Secretory diarrhea can produce
several liters of fluid loss per day. In
diabetes insipidus, large volumes of
Plasma osmolarity water are lost from the kidney. For
= 285 mOsm/L steady-state to exist, the total
amount of water lost must equal that
ingested. The ability of the renal
system to vary water excretion over a wide range in response to fluctuations in plasma osmolality
is the main reason that water balance exists.
Something that is not entirely obvious is the role of the bodies metabolism in water balance. As
can be seen from Table 23.3 from your text book the water created by oxidation accounts for a
significant contribution to the total body water input.
Input Output
Source Amount Source Amount
Water in 1,000 mL Skin and lungs 900 mL
beverages
Water in food 1,200 mL Gastrointestinal 100 mL
tract (feces)
Water of 300 mL Kidneys (urine) 1,500 mL
oxidation
Total 2,500 mL Total 2,500 mL
16
Anti-diuretic Hormone (alias Arginine Vasopressin ; AVP)
Coupling between changes in plasma osmolality and renal water excretion is mediated by changes
in circulating ADH. There is a close correlation between plasma osmolality and plasma ADH
concentration (see Figure on this page and Figure 23.4 from your text). When plasma osmolality
is at a typical set point of 287 mosM, plasma ADH concentration is 2-3 pg/ml. This means that
ADH secretion is able to fall in the event of excess water intake. However, the range over which
ADH secretion can be increased is much wider.
The two major physiological activities of ADH are vasoconstriction and renal water retention. I
have probably already mentioned this in lectures but ADH and arginine vasopressin (AVP) are
exactly the same compound. Historically this endocrine peptide was described as a powerful
vasoconstricor hence its name vasopressin (the human version has an arginine residue at position
8 hence its name arginine vasopressin). Subsequently the anti diuretic activity of this compound
was described and it is more commonly called Anti Diuretic Hormone (ADH). This gives rise to
some confusing nomenclature as the vasoconstrictor actions of ADH are mediated through V1
receptors (ie Vasopressin subtype 1) while the water retention actions are mediated through the
V2 receptor subtype. Its vasoconstrictor function, which is mediated via V1 receptors on
arteriolar smooth muscle cells. This effect of ADH is part of an overall response to reduced
vascular volume, which is another stimulus for ADH secretion. The second action, renal water
retention, gives rise to the name anti-diuretic hormone. This effect is mediated through V2
receptors, which are found mainly in the renal collecting duct.
Osmoreception is coupled to anti-

diuretic hormone (ADH) secretion
Thirst
12
Plasma ADH (pg/ml)
8
Vasopressin - V1 receptor
Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly
4
ADH - V2 receptor
0
270 280 290 300 310
Plasma osmolality (mOsM)
17
Synthesis of ADH occurs in the supraoptic (SON) and paraventricular (PVN) nuclei of the
hypothalamus. It moves by axonal transport to nerve terminals located in the posterior pituitary
gland. The most sensitive mechanism for ADH release is a change in plasma osmolality, detected
by neuronal osmoreceptors, in the hypothalamus. Osmoreceptors respond to changes in cell
volume that occur when ECF tonicity changes. They signal to neighboring cell bodies in the
SON and PVN to bring about a change in ADH secretion and also signal directly within the CNS
to elicit thirst. Osmoreception is able to respond to changes of less than 1% in plasma tonicity.
Altered plasma tonicity is the primary physiologic mechanism controlling ADH release.
Additional factors have been identified that affect ADH secretion. Reductions in plasma volume
of more than 10% cause ADH secretion. This stimulus is important during hemorrhage. There
are several sensors measuring plasma volume that influence ADH release. First, arterial
baroreceptors responding to a fall in arterial blood pressure cause increased ADH release. The
rise in ADH secretion caused by decreased plasma volume is also sensed by low pressure
baroreceptors in the atria, lungs and liver. In addition to these neuronal pathways, a fall in
effective circulating volume is detected by the juxtaglomerular apparatus. The consequent
increase in plasma angiotensin II levels also causes an indirect increase in ADH secretion.
This is summarized simply in the diagram on the next page.
Hypothalamus Via baroreceptors
Via osmoreceptors
ECF ECF
osmolarity volume
MOST
IMPORTANT
Posterior
Pituitary
ADH
Clinical Correlate: A variety of other inputs increase ADH secretion. These include pain and
general stress responses. Pharmacological agents including opiates and some anesthetics increase
ADH secretion, which together with post-operative pain often results in a syndrome of
inappropriate ADH secretion following major surgery. This results in water retention and a
temporary hyponatremia, until the physiologic control of ADH secretion is restored. Commonly
ingested agents that affect ADH are nicotine, which increases secretion and ethanol, which
inhibits secretion.
18
Elaboration of Dilute or Concentrated Urine
If a large volume of water is ingested, plasma hypotonicity develops. Urine flow rate starts to
increase in about 15-20min and the urine produced is dilute. This occurs in the absence of a
significant increase in solute excretion and without a rise in glomerular filtration rate. So how
does the kidney do it?
The slide shows the osmolality of

Making a dilute urine - free tubular fluid along the renal
tubule during water diuresis.
water excretion Proximal tubule luminal fluid
Low ADH remains isotonic to plasma. In
1200 The medullary the descending limb of the loop
interstitium is
hypertonic of Henle there is an increase in
Isosmotic The ascending limb of osmolality of tubular fluid.
reabsorption Henles loop is the
Hypertonicity in the medullary
mOsmM
diluting segment
600 interstitium (and thus in the very
water permeable descending
limb) is a feature of the
anatomical arrangement of the
0
PT DL AL DCT CCD MCD loop of Henle and is described in
detail below. There is almost
always some degree of
hypertonicity in the medulla,
even during maximal water diuresis. The key to production of dilute urine is NaCl reabsorption
in the ascending limb of the loop of Henle, which occurs without water reabsorption. By the time
fluid leaves the loop of Henle it is hypotonic relative to plasma. Thus, the ascending limb is called
the diluting segment.
During water diuresis when ADH levels approach zero, the water permeability of the distal
nephron and collecting duct is also very low, so that salt reabsorption continues to reduce the
osmolality of tubular fluid. This ability to separate salt and water reabsorption, particularly in the
ascending limb of Henles loop is the reason why a dilute fluid can be produced by the nephron.
The maximal diluting capacity is about 5-10 fold (i.e. urine osmolality of 30-60 mosM).
19
The slide superimposes the

How do we make a profile of tubular fluid
concentrated urine? osmolality observed during
maximal antidiuresis. In the
High ADH case where a subject is
1200
The cortico- dehydrated (excess water loss)
medullary
osmolality or ingests salt in excess of
gradient is water, plasma osmolality rises
much bigger
mOsmM
600 and plasma ADH levels

Osmotic
equilibration increase. The effect of high
is occurring ADH on segmental osmolality
in the
collecting is shown. As before proximal
0 duct tubule reabsorbs isosmotically
PT DL AL DCT CCD MCD and does not contribute
directly to the urine
concentrating mechanism. The
degree of hypertonicity in the
medullary interstitium is much increased. Note that the ascending limb again reabsorbs salt
without water, generating a dilute luminal fluid entering the distal tubule. A major difference
between the curves is seen in the collecting duct, where there is now equilibration between
luminal fluid and the hypertonic medullary interstitium. This results in a large amount of water
reabsorption in the collecting ducts, and formation of a concentrated urine.
In summary, a dilute urine is formed by reabsorbing salt without water from the ascending limb
of Henles loop and the distal tubule. Even though the salt reabsorbed by the loop is deposited in
the medullary interstitium, making it hypertonic, there is low water permeability in the remainder
of the renal tubule, so that little water is reabsorbed in the collecting duct and the urine remains
dilute. Formation of concentrated urine involves the same basic process of salt reabsorption in
the loop of Henle (albeit strongly stimulated), making the medullary interstitium hypertonic. In
this case the presence of ADH makes the collecting duct water permeable and water is
reabsorbed, leaving the urine concentrated.
20
Counter-current Multiplication
The slide describes the two processes

How does the medullary that underlie generation of medullary
interstitium get so concentrated? hypertonicity. The first is the ability to
produce a gradient of osmolality
290 90 horizontally between the limbs of the
loop of Henle, called the single osmotic
effect. This is a gradient of about 200
390 190
mOsM, which cannot be increased, since
it is limited by the maximum
electrochemical gradient that the
1400
epithelial cells can transport against. The
single osmotic effect is then multiplied
Single osmotic effect Counter-current multiplication longitudinally in the axis of the cortex-
medulla-papilla. This effect is called
countercurrent multiplication and is a
consequence of having flow in opposite directions (i.e. counter-current) in the two limbs of
Henles loop. In summary, transport of solute dilutes the ascending limb and concentrates the
descending limb. The shift of fluid due to inflow from proximal tubule pushes the concentrated
fluid to the tip of the loop. In the kidney the two limbs are separated by the medullary
interstitium, the osmolality of which rises along with the descending limb. If the size of the single
osmotic effect is fixed, then the only way to increase the final osmolality at the tip of the loop is
to have longer loops. In humans the length of the loops determines the maximum urine
osmolarity at approx. 1400 mOsm/L. Mammals that need to concentrate urine to conserve
water have very long loops of Henle. The kangaroo rat can survive in an almost waterless
environment partly through the production of hyperosmotic urine of up to 5870 mOsm/L.
21
How Does The Counter-current Multiplier

Work?
mTALH mCD
NaCl
H2O
NaCl
[ NaCl]
The slide shows a model of countercurrent multiplication. In the medullary thick ascending limb,
there is active NaCl reabsorption. This occurs in a water impermeable epithelium, so that salt is
deposited in the outer medullary interstitium. The high water permeability of the descending limb
means that osmotic equilibration occurs and fluid in the descending limb becomes hypertonic.
The hard part to explain is how the inner medulla gets so concentrated when there is no active
salt transport in the thin limbs. This is where urea comes in. About 40% of total osmolality in the
inner medulla is due to the presence of urea. In the renal medulla urea is an effective osmolyte
and draws water out of the descending limb of Henles loop. This means that NaCl inside the
descending limb is concentrated above that in the medullary interstitium. When the luminal fluid
turns the hairpin to enter the ascending limb, it contains a high NaCl concentration. The
ascending limb is highly NaCl permeable, but water impermeable, so that NaCl diffuses out to
further increase medullary interstitial osmolality and also makes the fluid in ascending limb
hypotonic.
The next few diagrams on the next page are taken from your text (Chapter 22) and are used in
the lecture to explain the renal countercurrent system in the Loop of Henle and how this helps in
the conservation of water by the kidney. I would suggest either coming to the lecture to hear my
explanation or watching it on sonic foundry to understand these diagrams.
22
23
The figure above is a useful demonstration of the importance of urea in concentrating the
interstitial fluid in the inner medulla of the kidney. You can see that the interstitial fluid Na+
concentration reaches its maximum in the outer medulla. Any further increase in interstitial fluid
osmolarity is dependent upon urea. It is important during times of water conservation by the
kidney that the inner medulla osmolarity can be increased to cause more water reabsorption
occurring in thin descending limb.
Not surprisingly, ADH not only stimulates water reabsorption in the collecting duct but it also
increases the number of urea transporters in the collecting duct. This allows for more urea to
leave the collecting duct, to increase the osmolarity of the interstitial fluid of the inner medulla
and so also increase water reabsorption by the Loop of Henle.
24
How Does The Counter-current Multiplier

Work?
mTALH mCD
NaCl ADH
H2O
NaCl
UREA
UREA
[ NaCl]
Clinical correlate: The importance of urea is shown clinically since patients with a low protein
intake have a reduced capacity to concentrate the urine. Children under the age of 1, who use
proteins for rapid growth and do not produce much urea, also have less urine concentrating
ability. Hence maximal urine concentrating ability in the newborn is about 600 mosM, compared
to the adult value of about 1400 mosM.
25
Counter-current Exchange
Having expended a lot of energy to make a hypertonic medulla, how is it that the gradient is not
simply washed away by the blood flow to the region? This is achieved by the special features of
the blood circulation in the medulla. First, recall that the blood flow to the medulla is low, but
secondly the vasa recta capillaries have a counter-current loop configuration as well. See Figure
22.24 taken from your text and see the counter current direction of blood flow in the vasa recta
capillaries.
26
Mechanism Of ADH Action In The Collecting Duct
High levels of ADH seen during antidiuresis increase medullary hypertonicity. This has 2 major
components: active transport in the thick ascending limb and passive urea reabsorption in the
inner medullary collecting duct. The other major action of ADH is to increase water permeability
in the collecting duct.
During water diuresis the collecting duct

How does ADH control water has a low water permeabiliy, which
reabsorption in the collecting duct? changes to a very large water
Lumen Principal cell Blood permeability during antidiuresis. The
Aquaporin 2 - reason for this is that renal principal cells
containing express large numbers of aquaporin 2
vesicles AQP3 Low ADH
(AQP2) water channels, in their apical
H 2O membranes in the presence of ADH
(antidiuresis), which are rapidly
High internalized into sub-membrane vesicles
V2
AQP2 ADH in the absence of ADH (diuresis). ADH
H2 O acts via V2 receptors to increase cAMP,
AQP3
AQP2 causing insertion of AQP2-containing
vesicles into the apical membrane (see
Figure on the next page). Water is then
able to flow into the cell. At the basolateral membrane water flows out through other aquaporins
which are expressed all the time.
At the kidney (collecting duct)
ADH
cAMP
V2
Vesicles
s AQP2
Nephron containing Interstitial
production
lumen AQP2 Space
27
Diabetes Insipidus
Water reabsorption under the control of ADH is called facultative whereas that occurring in
more proximal nephron segments and not under ADH control is called obligatory.
Facultative water reabsorption (can be reabsorbed or excreted) is about 23L per day. People who
lack proper control by ADH have Diabetes Insipidus (DI). At its worst a patient may excrete 23L
per day and an equivalent water intake is needed to maintain water homeostasis. DI is caused
either by the inability to secrete ADH properly from the posterior pituitary (Central DI), or due
to failure of the kidney to respond to ADH correctly (Nephrogenic DI). In other cases, some
mentally ill patients compulsively drink water (psychogenic polydipsia), though there is nothing
wrong with the ADH system per se. Central and Nephrogenic forms of DI may be congenital, or
much more commonly are said to be acquired. For example severe head injury involving the
pituitary is a relatively common cause of Central DI, and lithium therapy (used widely in some
psychiatric disorders), interferes with AQP2 expression, causing acquired Nephrogenic DI.
3 patients are subjected to a diagnostic test with water

restriction for six hours followed by administration of a
non-pressor ADH analogue. One suffers from
psychogenic polydipsia, one from central diabetes
insipidus and one from nephrogenic diabetes insipidus.
1200
No water to drink
Urine osmolality (mOsM)
600
0
0 2 4 6 8
hours
Give ADH here
28
Free Water Clearance
Urine may be thought of as being composed of an isosmotic volume containing excreted solutes
and a volume of water added to or subtracted from this volume to give dilute or concentrated
urine respectively. When body fluids are hypertonic (e.g. dehydration) the kidneys job is to
reabsorb osmotically free water, thereby diluting the blood plasma. In this case concentrated
urine is produced. Conversely, if excess water has been ingested, the role of the kidney is to
excrete osmotically free water so that a dilute urine is produced. The terms concentrated and
dilute urine are relative to plasma osmolality.
Suppose that the kidney was producing urine that was isotonic to plasma. In this case all the
osmotically active constituents are being excreted in a volume of water that is just sufficient to
keep the urine at the same osmolality as plasma. In other words, this urine volume is the same as
the volume of plasma cleared of osmolytes i.e. the osmolar clearance
Osmolar clearance = Cosm = (Uosm V) Posm

(units = ml/min)
Where Posm = plasma osmolality; Uosm = urine osmolality; V = urine flow rate
In our example of urine being isosmotic to plasma we can write:
Uosm = Posm so that Uosm/Posm = 1
Inserting this into the formula for osmolar clearance, in this case it reduces to:
Cosm = V
When a dilute urine is produced, it must be made up of an additional volume of free water as
well as isosmotic fluid (Cosm), so that we end up with the formula:
V = Cosm + CH20
Where CH20 is known as the free water clearance. Generation of free water depends on the
removal of salt without water in the ascending limb of Henles loop AND on the excretion of
this free water because collecting duct water permeability is low (i.e. LOW ADH).
When the urine is concentrated, Uosm/Posm > 1, V must be less than Cosm. In other words some
water is taken away from the isotonic urine and free water clearance (CH2O) is a negative
number. (ie HIGH ADH)
29
Regulation of Extracellular Fluid volume
1. Explain what the effective circulating volume is, how it relates to the extracellular fluid
volume and the importance of body sodium in determination of both.
2. Describe the receptors involved in monitoring the effective circulating volume.
3. Outline how the renin-angiotensin-aldosterone axis is stimulated when effective
circulating volume falls.
4. Identify the actions of angiotensin II which operate to conserve/increase effective
circulating volume
5. Describe the stimuli for aldosterone release and the actions which operate to
conserve/increase effective circulating volume.
6. Describe the actions of the sympathetic nervous system on the kidney which operate to
conserve/increase effective circulating volume.
7. Describe the regulation of proximal tubule reabsorption by changes in Starlings forces.
8. Discuss the role of the cardiac atria as volume sensors and in the release of atrial
natriuretic peptide (ANP).
9. Describe how the actions of ANP bring about a reduction in ECF volume.
Principles Of Salt And Water Homeostasis
Total body content of sodium is the primary determinant of extracellular fluid volume, which in
turn is the main determinant of plasma volume and therefore the adequacy of circulation. The
amount of sodium in the body is determined by the balance between intake and excretion, and is
regulated primarily by renal excretion. Signals which reflect the adequacy of circulation are the
main controllers of renal sodium excretion. It is important to understand that the concentration
of NaCl (osmolality) is not reflective of total body sodium. NaCl concentration is a function of
water balance and is regulated mainly by signals that affect osmolality.
Body Na+ Determines ECF Volume And Therefore

Adequacy Of Circulation If there is a conflict of signals (e.g. low
volume and low osmolality), preservation
of an adequate circulation comes first.
Amount of body Na+
ECF volume
Renal Na+ excretion (and plasma volume)
Effective circulating
volume (EfCV)
Effective Circulating Volume
The concept of effective circulating volume is key to understanding the regulation of salt
excretion. There is no one definition of effective circulating volume. It can be thought of as the
component of blood that is perfusing the tissues, or more specifically, the sum of all parts of the
circulation that are perfusing areas in which volume sensors are located. Effective circulating
volume is therefore related to the fullness of the circulation and the pressure within specific
parts of the circulation. These include the high pressure sensors (carotid sinus, aortic arch,
juxtaglomerular apparatus) and low pressure baroreceptors in the pulmonary system and cardiac
atria.
Effective circulating volume is
the controlled variable Viewed as a negative feedback loop, the
controlled variable is effective circulating
Effective circulating volume. The slide shows the basic scheme
Congestive heart
volume (ECV)
failure whereby a change in ECV is sensed by
several volume receptors; effector
Volume sensors pathways alter renal sodium excretion to
Nephrotic
syndrome bring about a change in total body sodium,
KIDNEY which in turn corrects the ECV. Coupling
between changes in sodium excretion and
Liver cirrhosis changes in ECV comes about due to
Renal Na+ excretion
31
altered plasma osmolality, ADH secretion, and altered water excretion. The slide mentions
congestive heart failure, nephrotic syndrome and liver cirrhosis. These are sometimes referred to
as the great sodium retaining states. Towards the end stage of these disorders, there is
accumulation of extracellular fluid and often edema, with renal sodium retention. This arises
because effective circulating volume is low, so that in the context of the physiological negative
feedback loop shown, sodium retention is the appropriate response to restore ECV. Due to the
pathologies, the additional extracellular fluid volume does not improve ECV and the cycle of
sodium retention continues. This illustrates that the absolute volume of plasma or ECF is not the
controlled variable it is the adequacy of the circulation as judged by volume sensors that
matters.
There are several overlapping sensor-

Where/what are the volume effector loops that accomplish sodium
sensors? balance. The main signals that provide
Blood volume information on ECV arise from altered
systemic arterial perfusion. Receptors
baroreceptors MAP respond to the fullness of the circulation
through changes in distending pressure.
Renal perfusion GFR The dominant sensor for ECV is the
Renal nerves
juxtaglomerular apparatus. The JGA
JUXTAGLOMERULAR
APPARATUS Macula measures changes in afferent arteriolar
densa wall tension as an index of renal arterial
RENIN
perfusion pressure. The JGA functions
RELEASE without the need for a comparitor from
the central nervous system and is able to
secrete renin at a rate appropriate to the initiating stimulus. Thus the JGA triggers the renin-
angiotensin-aldosterone axis directly in response to altered renal perfusion. Renin secretion is
modulated by other inputs. These are the baroreceptor reflex, which in the case of a fall in arterial
blood pressure triggers a rise in sympathetic nerve activity to the kidney. Efferent sympathetic
nerves (or circulating catecholamines) stimulate granular cells in the afferent arteriole to release
renin. Vasoconstriction mediated by sympathetic nerves also reduces perfusion through the
afferent arteriole, stimulating renin release. The other modulator of renin release is the
tubuloglomerular feedback mechanism. A fall in ECV reduces tubular fluid flow rate past the
macula densa due to avid reabsorption of fluid in the proximal tubule (see physical forces
below). The macula densa then signals to the renin secreting cells to increase renin production.
Responses To Low ECV
A fall in ECV is counteracted in three main ways. First, by activation of the renin-angiotensin-
aldosterone axis, second via the baroreceptor reflex and third through alterations in Starlings
forces acting in the proximal tubule.
32
Renin acts on the circulating globulin
brain
ADH angiotensinogen, which is secreted by the
R.A.S liver. Renin is a proteolytic enzyme that
cleaves angiotensinogen to form the
Angiotensin II decapeptide angiotensin I. This inactive
A.C.E
lung product is converted to the bioactive
Angiotensin I adrenal
octapeptide angiotensin II by the action of
angiotensinogen Angiotensin Converting Enzyme (ACE), the
liver
Aldosterone activity of which is high in the lungs.
kidney
RENIN
(Kidney also has a local RAS)
Angiotensin II is particularly potent as an

Angiotensin II defends the effective agent to increase ECV and should be
circulating volume in several ways regarded as the primary hormone in sodium
regulation. The actions of angiotensin II
ADH release
Angiotensin II Water retention promote renal sodium conservation. It also
causes increased water intake and
Thirst
generalized vasoconstriction to combat
Vasoconstriction hypovolemia. Some actions are direct, for
Aldosterone example vasoconstriction and increased
systemic
Proximal active sodium reabsorption in the proximal
tubule Na+ intrarenal
reabsorption tubule. Important indirect actions of
Angiotensin II include stimulation of ADH
Distal tubule Na reabsorption
+ secretion from the posterior pituitary, to
induce water retention, and also stimulation
of aldosterone secretion from the adrenal cortex. There is a local renin-angiotensin system in
the kidney, so that tissue levels of angiotensin II may be significantly higher in renal tissue than in
the general circulation.
33
Two independent stimuli, plasma
Aldosterone is important for angiotensin II and high plasma potassium
concentration cause increased
Na+ conservation aldosterone production. The cellular
Ang II action of aldosterone is on cells of the
plasma
Adrenal distal nephron and cortical collecting
[K ]
+
aldosterone duct, where it increases sodium
reabsorption and potassium secretion.
With respect to sodium reabsorption,
Na
+ ENaC
aldosterone increases both Na/K-
Blood
ATPase activity at the basolateral
Lumen
3Na
ROMK+ K
+
membrane and also sodium entry at the
+ 2K apical membrane. Aldosterone has
Renal principal cell (DT and CCD)/large bowel
surface membrane receptors that mediate
these effects within minutes and also a
cytoplasmic steriod receptor, which activates epithelial cells over hours to days. The aldosterone-
steroid receptor complex is a DNA binding protein that increases expression of several genes.
Aldosterone-induced proteins activate ENaC in the apical membrane, increase mitochondrial
ATP production and increase the number of Na/K-ATPase transporters.
It should be noted that there are additional molecular targets for aldosterone in the distal
nephron and collecting duct. One is an increase in NCCT transport activity in distal tubule.
However that the major effect of aldosterone is at the level of the ENaC / ROMK / Na;K
ATPase on principal cells in the which are mainly found in the collecting duct.
In addition, Na/H ion exchangers present in the luminal cell membrane throughout the distal
tubule are stimulated by aldosterone, resulting in more sodium absorption and greater urinary
hydrogen ion loss. This effect becomes significant when considering the physiological response
to a change ECF Volume and its effect on the Acid Base Balance. This will be discussed later in
Part 3; Acid Base Physiology.
The mineralocorticoid receptor has equal affinity for glucocorticoids, which circulate at around
1000 times the concentration of aldosterone. In order for aldosterone to selectively control
sodium absorption in the distal nephron, these cells convert glucocorticoids to inactive
metabolites using the enzyme 11-hydroxysteriod dehydrogenase.
Q. Licorice (thats real licorice not the fake stuff !) inhibits the enzyme 11-hydroxysteriod
dehydrogenase. Why would a person with excessive licorice consumption get hypertension?
34
Sodium conservation mediated through the renin-angiotensin-aldosterone system is augmented
by renal sympathetic nerves. A fall in
ECV sufficient to reduce arterial blood
.and dont forget the pressure stimulates the baroreceptor
baroreceptor reflex! reflex and increases sympathetic
outflow, which promotes sodium
Blood Baroreceptor Sympathetic conservation. Effects include
pressure firing tone vasoconstriction and a fall in GFR,
which reduces the filtered sodium load.
Systemic vascular resistance Renal Na excretion
+ There is redistribution of some blood
flow within the kidney to
juxtamedullary nephrons, which are
afferent arteriole resistance
inherently sodium conserving. Renal
renin release
nerves innervate the JGA to promote
proximal tubule Na+ reabsorption renin release as discussed above and
also directly innervate proximal tubule
cells to increase sodium reabsorption.
Starlings Forces Directly Influence

Renal Na+ Excretion Remember
ECF volume: 2nd capillary bed
Peritubular
Proximal tubule cell capillary
Lateral P
Intercellular flux Flux ( P- )
Space
Proximal tubule cell

So H2O absorption into
the capillary stimulates
further Na+ reabsorption
When ECV changes there is adjustment in renal sodium excretion that occurs due to a change in
hemodynamic physical forces. The slide shows the lateral intercellular space between two
proximal tubule epithelial cells. Active fluid absorption by epithelial cells delivers fluid into this
space. The final step of absorption from here into peritubular capillaries is another example of
exchange between interstitial fluid and plasma and as such is governed by Starlings forces.
Note this situation is different to the net formation of interstitial fluid that occurs in typical
35
systemic capillaries. Capillary hydrostatic pressure is low and capillary oncotic pressure is high
since this blood is coming from the efferent arteriole after glomerular filtration has occurred. The
balance of Starlings forces here favors entry of fluid into to the plasma.
A fall in ECV due to loss of NaCl and water affects both the capillary hydrostatic pressure and
the capillary oncotic pressure. A fall in ECV, through a generalized fall in venous pressure causes
a fall in capillary hydrostatic pressure. At the same time, the smaller volume of fluid in which
plasma colloids are suspended, causes a rise in capillary oncotic pressure. Both these effects cause
a rise in net absorption of fluid into the capillary. This in turn increases the reabsorption of
filtrate in the proximal tubule, so that the sodium load in distal nephron is reduced.
Responses To High ECV
Responses to high ECV are not the simple mirror image of those to low ECV. Levels of plasma
renin, angiotensin and aldosterone are low during states of moderate sodium intake and
excretion. When ECV rises, there is only a small reduction in activity of the renin-angiotensin
system possible, such that removal of an acute volume load is not mediated to a great extent by
inhibition of the renin-angiotensin system.
Since a volume load is located largely in the venous system, volume receptors within the venous
system become relatively more important in the case of high ECV. The right atrium couples
cardiac preload to the secretion of atrial natriuretic peptide (ANP). Atrial mycocytes contain
granules that store a prohormone for ANP. Distension of the right atrial wall is the physiological
stimulus for ANP release. ANP promotes loss of sodium at the kidney. Inhibition of ADH, renin
and aldosterone secretion can be demonstrated, but these hormones are likely to be at fairly low
levels during states of high ECV. An increase in GFR occurs, increasing filtered sodium load and
promoting sodium loss. Direct inhibition of sodium absorption in the terminal collecting duct by
ANP also occurs. Collectively these effects produce natriuresis.
36
The Right Atrium Is A Volume Sensor
-ve feedback
Effective circulating Na+ excretion
volume
Preload HEART
KIDNEY
ANP
Starlings Forces Can Change Renal Na+

Excretion In Both Directions
ECF volume:
Peritubular
Proximal tubule cell capillary
Lateral P
Intercellular flux flux ( P- )
Space
Proximal tubule cell Less H2O absorption into

the capillary is favored
Decreasing Na+ reabsorption
Disposal of an acute volume load involves a significant contribution from altered Starling forces.
The slide shows the opposite effects to those described for low ECV. In this case the high
venous blood volume causes an increased venous pressure that increases the peritubular capillary
hydrostatic pressure. Additional volume dilutes plasma proteins and reduces capillary oncotic
pressure. Both effects reduce the driving force for fluid uptake from the interspace and inhibit
fluid absorption from the tubule. The sodium load arriving in the distal nephron can be greatly
increased by this process and distal nephron does not recover all of the additional sodium and
fluid delivery, so that natriuresis and diuresis occur.
37
Renal Handling Of Magnesium, Urea, Calcium & Phosphate
1. Outline the role of magnesium in the body and contrast its renal handling with that of
sodium and calcium.
2. Describe the segmental handling of urea and explain why urea excretion is dependent on
urine flow rate.
3. Identify the typical dietary intake of calcium, its major storage pools and major routes of
loss from the body.
4. Describe the chemical forms of calcium and phosphate in the blood plasma.
5. Identify the tubular sites of absorption for calcium and phosphate.
6. Describe the regulation of renal calcium and phosphate reabsorption by parathyroid
hormone and vitamin D3.
38
Overview of Magnesium Homeostasis
Total body magnesium is about 1 mole. More than 50% is in bone, with only 1% in ECF.
Magnesium is the second most abundant intracellular cation after potassium. It is an essential
cofactor in many enzymatic reactions. Cellular phosphorylation reactions require MgATP. Mg
also interacts with many ion channels. Magnesium deficiency affects neuromuscular,
cardiovascular and gastrointestinal function. It also reduces the effectiveness of PTH, leading to
hypocalcemia. Total plasma magnesium concentration is 0.8-1.1 mM, or 1.8-2.4mg/dL. About
25% is bound to plasma protein, 15 % is complexed to anions such as phosphate and 60% is in
the free ionized form. Dietary magnesium intake is about 300mg per day. Intestinal absorption
occurs in the ileum (not duodenum as for calcium) .
Renal Magnesium Handling
Magnesium has an unusual profile of

segmental handling. Of the filterable
Segmental fraction about 25% is reabsorbed in the
Mg2+ handling proximal tubule. The main site of
differs from magnesium absorption is in the loop of
Henle, where around 65% of the filtered
Na+ and Ca2+ load is reabsorbed. The principal driving
force is the positive transepithelial
no single
hormone regulates
potential difference in the thick
remaining
Mg excretion
2+ ascending limb discussed previously. The
% Mg2+
intrinsic
reason that there is such a high fraction
regulation of renal of magnesium reabsorption at this site is
Mg2+ excretion that the paracellular pathway has a
G PT LOH DT CD U channel called paracellin with
particularly high magnesium
permeability. The distal tubule reabsorbs a small amount of magnesium and is the last site of
regulated uptake. Luminal magnesium enters distal tubule cells via a magnesium ion channel and
exits via sodium/magnesium exchange.
39
Mg2+ reabsorption is linked to the
transepithelial voltage gradient in TALH
Lumen Blood
Na+ 3Na+
2Cl- NKCC2
K+ 2K+
ROMK Cl- CLC-Kb
+ Mg2+
Via Paracellin channel
Magnesium homeostasis depends on a balance between intestinal absorption and renal excretion.
Hormonal regulation of magnesium is poorly defined. The key sites of regulation are small
intestine, thick ascending limb and distal tubule.
Renal Urea Handling
Normal plasma urea concentration (blood

Sites of tubular urea transport urea nitrogen, BUN) is in the range 8-
25mg/dL. Urea is the end product of
nitrogen metabolism. It is very water soluble
and has a low toxicity. Hence urea
concentration is not the subject of
homeostatic regulation. Nevertheless, urea
must be excreted and this is most effectively
achieved when antidiuretic hormone levels
are low and the urine flow rate is high.
(ADH - dependent) Fractional urea excretion varies from around
30-60% depending on urine flow rate. The
Diagram after C Lote
FEurea = 30-60%
sites of urea reabsorption in the nephron are
the proximal tubule and medullary collecting
duct. At both sites urea reabsorption is passive. The thin ascending limb of Henles loop is a site
of urea secretion. This mechanism recycles some urea from the medullary interstitium to the
medullary collecting duct, which further supports the counter current multiplier (see previous
notes).
40
Urea reabsorption occurs by diffusion.
Urea excretion is dependent on Water reabsorption causes luminal urea
urine flow rate concentration to rise, creating a diffusion
Anti-diuresis (high ADH)
gradient for urea absorption. Recall that in
PH2O > Purea
the medullary collecting duct high levels of
ADH stimulate facilitated urea
H 2O reabsorption, due to increased expression
Urea output mg/min
of urea uniporters. At the same time, high

urea
levels of water reabsorption occur from the
collecting duct when ADH levels are high,
so that luminal urea is concentrated and a
large diffusion gradient for its reabsorption
Medullary
Urine flow rate ml/min
collecting duct
is developed. Thus, antidiuresis causes urea
retention, whereas diuresis increases urea
excretion.
Urea recycling
This diagram (Fig 22.28 from your text book) and included in your lectures shows how the urea
is recycled by being reabsorbed in the IMCD before being secreted into the thin ascending LofH.
The fact that ADH increases urea reabsorption makes sense because in times of antidiuresis the
urea concentration of the IMCD will be greater favoring reabsorption to maintain the high
osmolarity of the inner medulla to further water reabsorption at the Loop of Henle.
41
Overview of Calcium Homeostasis
Calcium is the most abundant element in

Only a small proportion of body calcium the body (25-30 moles), though most of
exists in an exchangeable pool it is in the skeleton, with only about 1%
Diet
in ECF. The slide summarizes typical
1000mg
daily calcium balance. Note that net
calcium reabsorption in the GI tract only
300mg
200mg Calcium pool takes in about 20% of daily ingested
Gut Bone
300mg calcium. Intestinal absorption occurs in
10 000mg
the duodenum. There is dynamic
exchange of calcium between the bones
Feces Kidneys
and ECF due to osteoblast and osteoclast
800mg
activity. Of the large filtered load of
Urine calcium at the kidney, only 1-2% is
200mg
typically excreted. Plasma calcium is
finely regulated, with a normal range of
4.2-5.6 mg/dL.
The slide illustrates the chemical forms

What is normal plasma [Ca2+]? in which calcium exists in plasma. The
mM mg/100ml value of plasma calcium frequently given
2.5 10 is total calcium. Physiologically the
relevant concentration is free ionized
2.0 8 Non-diffusible 40% Ca-protein calcium. 40% of total calcium is bound
40%
to plasma proteins, mainly albumin. This
1.5
15%
6 fraction is not filterable at the kidney.
Ca-complex
The protein bound fraction is affected by
1.0 4
plasma pH. Acidemia displaces bound
Diffusible 60%
45% calcium and may result in a rise in free
0.5 2
Free ionized Ca2+ calcium concentration, whilst alkalosis
0 0
has the opposite effect. Of the remaining
filterable fraction, a further 10-15% is
complexed with a variety of anions such
as citrate, oxalate, bicarbonate, phosphate, sulfate etc. About 45% of total plasma calcium is in
the free ionized form. Note that interstitial calcium concentration approximates the diffusable
portion of plasma calcium, since there is little interstitial albumin to bind calcium.
42
Hormonal control of plasma calcium is primarily via parathyroid hormone. A fall in free ionized
calcium is sensed by the extracellular calcium sensing receptor (CaR). CaR is a G-protein coupled
receptor, directly linking extracellular calcium to intracellular second messengers. PTH
concentration increases as plasma calcium falls. The most important direct effect of PTH is
increased release of calcium from bone, though it also increases renal calcium reabsorption. PTH
has an important secondary effect acting through renal activation of vitamin D3. The primary
effect of 1,25 (OH2)D3 is to increase intestinal calcium reabsorption, though it has a small effect
to increase renal calcium reabsorption.
Parathyroid Hormone And Vitamin D3 Are

Central To Calcium Homeostasis
Intestinal
absorption GUT
1,25(OH)2D
Low plasma Ca2+o

KIDNEY
Parathyroid Gland
Bone resorption Renal excretion

PTH
Renal Calcium Handling
The filtered load of calcium is the product of GFR and diffusable plasma calcium. Reabsorption
of filtered calcium is almost complete, with a typical fractional excretion of 1.5%. The pattern of
segmental calcium reabsorption is similar to that of sodium. One significant difference is the
absence of calcium reabsorption in the collecting duct. This means that the last site of hormonal
regulation is the distal tubule.
43
Segmental Ca2+
Handling Is Similar
To That Of Na+
% Ca2+
remaining
G PT LOH DT CD U
As you can see most Ca2+ is reabsorbed in the proximal tubule. The diagram below shows how.
Ca2+ enters the tubule cell down its concentration gradient via a channel, this concentration
gradient is kept large by calcium-binding proteins in the cytoplasm. Ca2+ must be actively
extruded out of the cell into the interstitial fluid, this may be via a Ca 2+ pump or Na+-Ca2+
exchange.
Calcium and the Proximal Tubule

Interstitial
lumen Proximal Tubule Cell
fluid
H+
Ca2+
Ca2+
Calcium
Na+
binding
proteins Ca2+
Ca2+
44
The thick ascending limb of Henles loop is
CaR regulates TALH Ca2+ an important site of regulation. A lumen
absorption positive transepithelial potential difference
drives paracellular calcium reabsorption.
Lumen Blood Thick ascending limb cells express an
Na+ 3Na+
extracellular calcium sensing receptor in the
2Cl- NKCC2 basolateral membrane. A fall in plasma free
2K+
K+
Cl-
calcium concentration causes direct
CLC-Kb
stimulation of the transport mechanism in
ROMK
these cells, so that transepithelial potential
+ Ca2+
difference increases and net calcium
+ cations
reabsorption rises. This provides a direct
sensor-effector mechanism to conserve
calcium when plasma free calcium levels
fall.
Calcium and the TALH (1)

Interstitial
lumen Thick Ascending LofH Tubule Cell
fluid
PTH
H+
Ca2+
Ca2+
Calcium
Na+
binding
proteins Ca2+
Ca2+
It should not be forgotten that Ca2+ may also move through the TALH tubule cell via the
mechanism described above. The amount of Ca2+ reabsorbed is under the influence of
parathyroid hormone (PTH).
45
Calcium and the DCT
Interstitial
lumen Distal Convoluted Tubule Cell fluid
PTH
H+
Ca2+
Ca2+
Calcium
Na+
binding
proteins Ca2+
Ca2+
The slide shows a cell from the late distal tubule. Cells throughout the distal tubule express the
epithelial calcum channel ECaC. Calcium flows into the cell down its electrochemical gradient, is
then bound in the cell by binding proteins called calbindins, and is extruded at the basolateral
membrane by active transport. This mechanism is the site of action of PTH, and vitamin D 3, to
enhance renal calcium reabsorption. Further clinical importance of this mechanism is the effect
thiazide diuretics have on calcium reabsorption. Thiazide therapy is among the most common
causes of hypercalcemia, due to stimulation of calcium reabsorption in the distal tubule.
Phosphate Homeostasis
Most body phosphate exists in bone (0.6 kg). A smaller amount (0.1 kg) exists in soft tissue as
organic phosphate molecules. ECF contains only 500 mg of inorganic phosphate, which exists in
two forms. Alkaline phosphate (HPO42-) is about 80% of the total inorganic phosphate at pH =
7.4, and is in equilibrium with acid phosphate (H2PO4-). Steady state plasma inorganic phosphate
concentration is in the range 2.5-4.5 mg/dL, though it is not as rigidly controlled as calcium and
acute fluctuations occur, for instance after a meal. Like calcium, plasma phosphate levels are
influenced by intestinal uptake, exchanges with bone and renal excretion. Intestinal uptake is
about 900 mg per day and occurs in the small intestine via Na/phosphate co-transport.
Exchanges with bone occur in parallel with calcium (e.g. resorption of bone liberates both
calcium and phosphate).
Renal Phosphate Handling
About 90% of plasma phosphate is ultrafilterable. About 80% of filtered phosphate is

reabsorbed in the proximal tubule via cotransport with sodium (see next two figures), with very
46
little absorbed in later nephron segments. Parathyroid hormone is the major hormone that
regulates phosphate excretion. A rise in plasma phosphate stimulates parathyroid hormone
secretion, which in turn inhibits phosphate reabsorption in the proximal tubule. Phosphate
excretion is thus increased, completing the feedback loop.
Renal Phosphate
Handling
PCT
% phosphate remaining
reabsorption
is via Na/Pi
cotransport
PTH reduces
phosphate
reabsorption
G PT LOH DT CD U
Phosphate and the Proximal Tubule

Interstitial
lumen Proximal Tubule Cell fluid
Na+
PO4 ?
PO4
PO4
The diagram above shows the known mechanisms for phosphate reabsorption by the proximal
tubule. The energy derived from Na+ moving down its concentration gradient is used to move
phosphate into cell. It is believed to enter the interstitial fluid by some passive process.
Interaction of Calcium and Phosphate Balance
Calcium and phosphate are the principal mineral components of bone and their homeostasis is
closely related. Both are regulated by the same hormones, PTH and vitamin D3. In general the
47
actions of these hormones are opposed with respect to calcium and phosphate. For example,
high levels of PTH increase plasma calcium and reduce plasma phosphate at the same time. The
reason for this pattern of activity relates to the low solubility of calcium phosphate. Normal
plasma concentrations of calcium and phosphate in plasma are close to the solubility product for
calcium phosphate. If concentrations of both increase together they begin to precipitate.
48
K+ Balance
Renal Potassium Handling
1. Identify normal dietary potassium intake and the major routes of potassium loss from the
body. Define the role of potassium in maintaining normal nerve and muscle function.
2. Describe potassium distribution within the body, extrarenal potassium homeostasis and
the role insulin, epinephrine and aldosterone play in the movement of potassium between
intracellular and extracellular pools. Describe potassium shifts caused by acidosis and
alkalosis.
3. Calculate the filtered load of potassium and identify the tubular sites of potassium
reabsorption and secretion.
4. Describe the factors that regulate potassium secretion in the distal nephron and cortical
collecting duct (aldosterone, plasma potassium, luminal flow rate, acid-base balance,
anion delivery).
49
K+ Balance
Overview of Potassium Homeostasis

Around 98% of body potassium is present within cells. Whilst some of this is loosely bound to
cellular proteins, it is virtually all exchangeable with extracellular potassium. The 2% of total body
potassium present in extracellular fluids is tightly controlled, with a range of normal
concentration between 3.5 to 5.5 mEq/L.
In most cell membranes potassium conductance predominates, so that the resting membrane
potential is greatly influenced by EK. Since EK is a function of [potassium]o/[potassium]i and
[potassium]i is large (100-160mEq/L), small changes in [potassium]o profoundly effect the
membrane potential. Thus, regulation of [potassium]o is essential for normal function of
excitable cells. Hypokalemia is defined as a plasma [potassium] below 3.5 mEq/L. Severe
hypokalemia causes muscle weakness or paralysis and mental confusion. Hyperkalemia is defined
by a plasma [potassium] of greater than 5.5 mEq/L and is serious due to the risk of cardiac
arrhythmias.
Cells exist in a steady state where potassium uptake via the Na/K-ATPase is balanced by
potassium leak through ion channels. Regulation of exchange between intra- and extracellular
fluid is known as internal potassium homeostasis. Factors which affect internal potassium balance
are important in the regulation of plasma [potassium]. Skeletal muscle cells are the major single
pool of potassium in the body and are the most important cells in relation to internal potassium
homeostasis.
The typical Western diet contains around 80mEq of potassium per day. Maintenance of
potassium homeostasis requires that the rate of potassium excretion matches daily intake. This is
known as external potassium homeostasis. Fine regulation of renal potassium output is the major
control mechanism ensuring external balance. Losses from the GI tract in feces are generally
about 10% of dietary intake, though this can become a large source of potassium loss in diarrhea.
Factors Affecting Internal Potassium Balance
Hormonal regulation of internal potassium exchange is an important aspect of potassium

balance. Insulin, even at basal levels, affects potassium uptake by liver and skeletal muscle cells.
At high concentrations, following a meal, insulin accelerates potassium uptake. Considering that
we may eat our entire extracellular potassium content in a single meal, it is vital that ingested
potassium be quickly sequestered intracellularly to prevent hyperkalemia. Insulin is very
important to physiological potassium balance. Insulin/glucose infusions are used clinically to
control hyperkalemia.
Factors affecting internal K+
Aldosterone is secreted in direct response
exchanges to a rise in plasma potassium. Aldosterone
produces a modest increase in uptake of
K+ ingestion Exercise
potassium by skeletal muscle. Its more
insulin cell epinephrine important action is increased renal
liver, skeletal muscle
potassium excretion.
skeletal
muscle
K+ (beta2 receptors)
High plasma [K+] 50

aldosterone
(skeletal muscle)
K+ Balance
Epinephrine and other beta receptor agonists stimulate potassium uptake in skeletal muscle. Its
effects are additive with those of aldosterone and insulin. There is increased epinephrine
secretion after a potassium rich meal. Epinephrine is also important during exercise. Dynamic
exercise is associated with release of potassium from working muscle cells, which is an important
aspect of the locally controlled increase in blood flow to working muscle. During intense work,
enough potassium may be released to produce potentially dangerous levels of plasma potassium.
Trained altheletes have adaptive changes that increase the rate of potassium re-uptake. The high
levels of epinephrine associated with exercise are important for stimulating potassium re-uptake.
The final common pathway for increased cellular potassium uptake with insulin,
aldosterone and epinephrine is increased Na/K-ATPase activity.
Primary disturbances in acid base balance

Acid-base balance and internal affect the distribution of potassium across
K+ exchange cell membranes. In states of acidosis some
of the excess acid load is buffered by
Acidosis: Alkalosis:
hydrogen ion influx into cells, thereby
minimizing changes in plasma pH. This is
H+ K+o (hypokalemia) associated with an efflux of potassium
from cells, which may be sufficient to
K+ cause hyperkalemia. The converse situation
occurs in alkalosis, where hydrogen ion
H+ leaves cells to buffer the fall in ECF
K+o H+ [hydrogen ion] and at the same time
(hyperkalemia) potassium enters, potentially causing
hypokalemia.
Potassium normally enters the ECF via the

A K+ load must be quickly GI tract, but may also be released from the
removed to protect plasma [K+] ICF for example during exercise, acidemia,
tissue damage and treatment with beta-
100
adrenergic receptor antagonists. The renal
K+ moved
response to hyperkalemia is slow, taking
% response
into cells minutes to hours to produce. Maintenance

50 of optimal serum potassium therefore
Renal K+
excretion requires a control system to temporarily
sequester potassium inside cells. These
hormonal responses, described above, occur
0
6 12 in a few minutes. Time courses for the renal
K+ load Hours and extrarenal control systems are shown in
the slide.
51
K+ Balance
Renal Potassium Handling

The rate of renal potassium excretion varies over a wide range according to changes in dietary
intake. In states of low dietary potassium intake, renal tubular reabsorption is stimulated and
almost all filtered potassium is reabsorbed. More commonly the kidney must deal with the
problem of dietary potassium excess. The renal system has a large capacity to increase potassium
excretion, with fractional excretion reaching maximally 150-200%, compared to a typical value of
10-20% of the filtered load.
At all rates of excretion the majority of filtered potassium is first reabsorbed. About 70% of the
filtered potassium load is reabsorbed in the
Renal K+ handling involves filtration, proximal tubule and a further 20% is
reabsorption and secretion usually reabsorbed in the thick ascending
limb of Henles loop.
Reabsorption: Secretion:
PCT (FE=30%), DCT & CCD In contrast to sodium, potassium is able to
TALH (FE=10%) (FE = -10 to enter the urine via secretion. This occurs in
Mechanism: 150%) the late distal tubule and cortical collecting
Paracellular Mechanism: duct. When potassium excretion is
Solvent drag ROMK K+
Diffusion increased, it is potassium secretion that
channels
increases. When potassium excretion is
reduced, secretion is inhibited and net
FE K+ =
Diagram after C Lote 0 150+%
potassium reabsorption occurs in the
collecting duct.
The slide shows the cellular mechanism of

K+ excretion is determined by K+ potassium secretion, which occurs in renal
secretion in the collecting duct principal cells. Influx of potassium via the
aldosterone basolateral Na/K-ATPase results in an
3Na + intracellular potassium activity above
+ electrochemical equilibrium (EK is more
negative than Vm). There is thus a driving
Lumen Blood force for potassium efflux, which in the
K + principal cell is via either the basolateral or
apical membrane. The presence of sodium
Principal cell
channels in the apical membrane means that
the apical membrane is depolarized due to
sodium influx. potassium efflux is thus
favored across the apical membrane, since
the electrochemical gradient (Vm EK) is larger than at the basolateral membrane. The potassium
conductance of the apical membrance is also higher than that of the basolateral membrane under
most physiological conditions.
52
K+ Balance
Factors Affecting Potassium Secretion In The Cortical Collecting Duct
The most important luminal factors affecting potassium secretion are flow rate of tubular fluid
and the rate of sodium delivery to the distal nephron. The potassium concentration of fluid
entering the distal nephron is low, thus the electrochemical gradient for potassium secretion is
increased at high flow rates. Since the apical membrane is very potassium permeable, there is time
for equilibration of potassium between cell and lumen, so that net secretion rises with increased
tubular fluid flow rate. When sodium delivery increases, there is more entry of sodium into cells
via sodium channels (ENaC). This has two effects, first the rate of sodium pumping at the
basolateral membrane is increased, so that more potassium is pumped into the cell, making more
available for secretion. The second effect, illustrated on the slide, is depolarization of the apical
membrane. The electrochemical gradient
K+ secretion increases as a function of for potassium secretion increases as a
Na+ delivery to the collecting duct function of membrane depolarization, so
that more sodium delivery translates into
Vm = -40mV ; EK = -80mV
more potassium secretion. This is the
(Vm - EK) = +40mV
Na + Principal cell explanation for the large potassium losses
that occur with most diuretics, since both
flow rate and sodium delivery are
= K secretion
+
K+ markedly increased to the potassium
secretion site. An acute increase in ECV
Vm = -60mV ; EK = -80mV
causes increased fluid outflow from the
proximal tubule, and also causes
(Vm - EK) = +20mV = secretion
Apical membrane potassium excretion to rise.
Aldosterone
Elevated plasma [K] directly increases aldosterone secretion. Aldosterone is the primary hormone
controlling renal potassium excretion. When dietary potassium intake increases, plasma
potassium increases, aldosterone levels rise and renal potassium excretion increases to complete
the feedback loop. Aldosterone stimulates all parts of the potassium secretion mechanism
described above. The increase in Na/K-ATPase activity provides more potassium for secretion.
Under maximal aldosterone stimulation, this effect can be so marked that the electrogenicity of
the pump hyperpolarizes the basolateral membrane and potassium flows into the cell through
basolateral potassium channels as well. Increased activity and expression of ENaC results in more
sodium entry at the apical membrane, membrane depolarization and more potassium efflux.
These effects on sodium transport alone have marked effect on potassium secretion, which is
further enhanced by an increase in potassium channel activity in the apical membrane.
When dietary potassium is increased over a period of 1-2 days or more there are morphological
changes in principal cells such as increased membrane area in addition to the biochemical
changes mentioned. All these changes are mediated via a rise in aldosterone. This feedback loop
has pathophysiological importance in chronic renal insufficiency, where the number of functional
nephrons is declining. These patients show a remarkable adaptive response in the remaining
53
K+ Balance
nephrons to increase potassium secretion. Derangement in potassium homeostasis only becomes

apparent when the number of functional nephrons falls to below about 10% of normal.
Potassium Depletion
States of potassium depletion require renal potassium conservation. Low plasma potassium
suppresses aldosterone release (assuming ECV is normal), so that the distal nephron potassium
secretion is inhibited. This does not account, however, for the 10% of filtered potassium arriving
from the loop of Henle that needs to be reabsorbed. Alpha-intercalated cells in the collecting
duct possess an active transport mechanism for potassium absorption (H/K-ATPase), which
reclaims luminal potassium in exchange for hydrogen ion secretion. This process is activated
during potassium depletion and contributes to enhanced acid excretion during potassium
depletion.
54

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Renal Physiology

Sodium Handling and Diuretics

1. Describe the normal whole-body daily sodium balance.

Overview of Renal Sodium Handling

The slide illustrates

Mechanisms Of Sodium Reabsorption

The Na+/K+-ATPase Drives Na+ Reabsorption

The mechanism for nutrient uptake in

Tubular lumen Proximal Tubule Cell Interstitial Fluid

The filtered load of nutrient molecules is

The transport processes that result in

The sodium and chloride uptake into

In early distal tubule sodium and

Cortical Collecting Duct

Principal cells are the only site

Regulation Of NaCl Reabsorption

Regulation by glomerulotubular balance

GFR regulation of Na+ reabsorption

Table 23.5 Glomerulotubular Balancea

Period Filtered (mEq/min) Reabsorbed (mEq/min) = Excreted (mEq/min)

1 6.00 5.95 0.05

Increase GFR by one third

2 8.00 7.90 0.10

Maintenance of arterial blood

Angiotensin II Major effect at the

Norepinephrine Via 1 receptors

ROMK Cl- CLC-Kb

Atrial Natriuretic Peptide

Na+ ENaC 3Na+

Some question over is it ANP

Urine Concentration and Dilution

1. Identify the major routes of water loss from the body.

Overview of Water Balance

The slide shows the routes and

Anti-diuretic Hormone (alias Arginine Vasopressin ; AVP)

Osmoreception is coupled to anti-

This is summarized simply in the diagram on the next page.

Hypothalamus Via baroreceptors

Elaboration of Dilute or Concentrated Urine

The slide shows the osmolality of

The slide superimposes the

600 and plasma ADH levels

The slide describes the two processes

How Does The Counter-current Multiplier

How Does The Counter-current Multiplier

Mechanism Of ADH Action In The Collecting Duct

During water diuresis the collecting duct

At the kidney (collecting duct)

3 patients are subjected to a diagnostic test with water

Free Water Clearance

Osmolar clearance = Cosm = (Uosm V) Posm

In our example of urine being isosmotic to plasma we can write:

Uosm = Posm so that Uosm/Posm = 1

Body Na+ Determines ECF Volume And Therefore

Effective Circulating Volume

There are several overlapping sensor-

Responses To Low ECV

(Kidney also has a local RAS)

Angiotensin II is particularly potent as an

Starlings Forces Directly Influence

Proximal tubule cell

Responses To High ECV

Starlings Forces Can Change Renal Na+