1. Regulation of Body Fluid Osmolality – Regulation of Water Balance (DSA) Flashcards

1
Q

Describe the permeability of the collecting duct.

A
  1. Cortical collecting duct is impermeable to water AT ALL TIMES, unless ADH is present.
  2. Medullary CD- Medullary CD actively reabsorbs NaCl is always permeable to water, despite if ADH is present or not. However, ADH makes it more permeable.
    1. ADH is controlled by osmoreceptors in the hypothlamus to plasma osmolality and volume.
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2
Q

What factors contribute to making the osmotic gradient?

A
  1. countercurrent multiplier
  2. urea recycling
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3
Q

What 2 sources created our medullary interstitial osmotic gradient?

A
  1. AQP channels and no tight junctions in the thin descending limb allow water to move to the medulla without Na+.
  2. Loop of Henle and the CD’s role in the countercurrent multiplier, which increase osmolality as the loop goes deeper into the medulla.
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4
Q

Describe the 7 step process of urine concentration

A
  1. As fluid enters the descending limb from the proximal tubule, it is isotonic with the medulla (300 mOsm).
  2. Descending LoH becomes hypertonic until is reaches 1200-1400 at the bottom of the loop.
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5
Q

___________ and the _________ always come to eqiullbrium, creating a concentration gradient that ranges from what to what?

A

Medulla and desending limb always come to equillibrium, creating a concentration gradient that ranges from 300-1200 mOsm/L.

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6
Q

Concentration in the tubular fluid ________ in the ascending limb.

Why?

A

Decreases.

NaCl is pumped out via NKCC2, but water cannot follow to offset the gradient.

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7
Q

Befores the tubular fluid leavs the ascending lumb to enter the distal tubule, what happens?

A

The tubular fluid will become even MORE hypotonic at 100mOsm/L.

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8
Q

Describe the process of urea recycling and how it contribues to creating an osmotic gradient?

A

Urea recycling is controlled by ADH and contributes to osmotic gradient.

Occurs in inner medullary CD

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9
Q

Urea is reabsorbed from the [nephron–> the medulla] at what part of the nephron?

This is accomplished via ________________

A

inner medullary collecting duct via urea transporters

[UT-A1 and UT-A3].

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10
Q

What happens to the urea the exits the nephron through UT-A1 and UT-A3 transporters in the inner medullary CD?

A

UREA RECYCLING.

Some of the urea re-enters the thin descending loop of Henle via UT-A2 transporters, to flow back through the rest of the nephron.

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11
Q

When does urea accumulation in the medulla occur most effectively?

A

When a hyperosmotic urine is excreted (antidiuresis).

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12
Q

When dilute urine is made, osmolality of medullary interstitium declines almost entirely d/t _____.

A

Urea.

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13
Q

High urea in the medulla allows what?

A

it can be excreted in small volumes in urine, limiting the amount of water we need to excrete the amount the body makes.

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14
Q

What is the purpose of the vasa recta?

A

Vasa recta are capillaries that send blood to the medulla and is highly permeable to solute and water;

It is involved in the countercurrent exchange: remove solute and water that is continuously added to the medulla to help us maintain the gradient.

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15
Q

Osmotic gradient is highest when: ___ ADH

A

High

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16
Q

Increase in blood flow in vasa recta –>

A

decreases the medullary gradient;

because removing more NaCl than is being added

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17
Q

Decrease in blood flow of vasa recta–>

A
  1. Increase the gradient of the medulla and reduces O2 delivery to the nephron –>
  2. decreases salt and solute transport by nephron segments in the medulla –>
  3. reduces ability to concentrate urine.
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18
Q

What are the main solutes in the medullary ISF?

A

1. NaCl

2. Urea

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19
Q

Because water resbsorption is driven by osmotic gradient in the medulla, urine can/can never be more concentrated than the medulla.

A

CAN NEVER

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20
Q

Can urea drive water reabsorption in the medulla?

A

No.

the inner medullary collecting duct is highly permeable to urea, especially in the presence of AVP, urea cannot drive water reabsorption across this nephron segment.

Urea in the tubular fluid and medulla equillbriate and a small amount of urine is made with a high concentration of urea.

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21
Q

Cortex: _____ salt; ____ water

Medulla: _____ salt; ____ water

A

Cortex: low salt; high water

Medulla: high salt; low water

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22
Q

In the countercurrent multiplier, as fluid moves around the hairpin loop and goes to the ascending limb, what maintains the ion concentration as they are pumped out?

A

Na/K ATPases.

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23
Q

When water intake is low or water losses increase, how to the kidneys respond?

A

conserve water by producing a small volume of urine that is hyperosmotic with respect to plasma.

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24
Q

When water intake is high, how to the kidneys respond?

A

A large volume of hypoosmotic urine is produced.

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25
Q

If our water balance is fucked up, it is due to changes in ______________

A

Plasma osmolality.

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26
Q

What is the major determinant of plasma osmolality?

A

Na+ (with its anions Cl- and HCO3-).

these disorders also result in alterations in the plasma [Na+]

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27
Q

When plasma osmolality is reduced (hypoosmolality)–>

A

water moves from ECF–> cells, causing them to swell.

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28
Q

When plasma osmolality is increased (hyperosmolality)–>

A

water is lost from cells, causing them the shrink

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29
Q

Whether or not the kidney maintains water balance by excreting hypoosmotic (dilute) or hyperosmotic (concentrated) urine is determined by _____

A

ADH (vasopressin).

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30
Q

What is ADH?

A

Acts on the kidneys to regulate the volume and osmolality of the urine.

Increasse the permeability (reabsorption) of the collecting duct to water by adding AQP 2 channels on the DCT and CD–> decreasing urine volume.

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31
Q

High and low concentrations of ADH.

A
  • Low levels of ADH–> CD is made impermeable to water–> large volume of dilute urine is excreted (diuresis).
  • High levels of ADH–> insertion of AQP channels –> increasing water reabsorption in the small volume of concentrated urine is excreted (antidiuresis).
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32
Q

Where is ADH made?

A

Supraoptic and PVN neurons in the hypothalamus.

The hormone is then stored in the neurohyophysis, located in the posterior pituitary.

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33
Q

Secretion of ADH is influenced by what 2 primary mechanisms?

A

1. Osmolality of the plasma*

2. BP/BV

3. Nausea (+), Angiotensin II (+) and ANP (-), to a smaller degree

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34
Q

What regulates ADH’s response to plasma osmolality?

A

Osmoreceptors:

  • detect changes small changes in plasma osmolality RAPIDLY and regulate the activity of ADH-secreting neurons by either shrinking or swelling and
  • causing thirst.
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35
Q

Increase in effective osmolality of plasma–>

A

[pic]

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36
Q

Decrease in effective plasma osmolality–>

A

[Pic]

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37
Q

As we have said: activation of osmoreceptors cause the activates ADH pathway and thirst. What occurs first?

A

Activation of ADH pathway occurs rapidly. Thirst occurs later.

This allows us to not always have to search for water.

38
Q

When does ADH secretion occur?

A

The set point is the plasma osmolality value at which ADH secretion begins to increase.

  • 275-290 mOsm/kh H2O.
  • However, it will shift in response to BV, BP, pregnancy.
39
Q

How does BP and BV affect ADH secretion?

A

[pic]

Decrease in BP/BV–> + ADH secretion.

Increase in BP/BV–> - ADH secretion

40
Q

How do changes in BP/BV change plasma osmolality?

A
  • Decrease in BV/BP–> set point is shifted to lower osmolality values. Thus, when circulatory collapse, the kidneys continue to conserve water, even though by doing so, they reduce the osmolality of the body fluids.
  • Increase in BV/BP–> set point is shifterd to higher osmolality values (thus, a higher osmolality will trigger ADH release).
41
Q

What are the actions of ADH? 4

A
  1. Primary action: increase the permeability (reabsorption) of the collecting duct to water by adding aquaporin 2 channels on the DCT and CD–> decreasing urine volume.
  2. Increase the permeability of the medullary collecting duct to urea.
  3. Stimulate NaCl reabsorption at the thick ascending LoH, distal tubule and CD via V2 receptors.
  • This helps to maintain a hyperosmotic medullary interstitium when, at the same time, ADH is increasing collecting duct water reabsorption
    4. Vasoconstriction of vascular SM via V1 receptors–> increasing

BP–> increasing Na+ excretion (HENCE; VASOPRESSIN)

42
Q

As a result of these competing effects, ADH may either increase or decrease NaCl excretion. What determines which response predominates ____________.

A

Plasma levels of ADH.

  • Low-moderate ADH levels; V2 mediated response predominates and NaCl excretion is decreased
  • High ADH levels: V1 mediated response predominates and NaCl excreteion is increased.
    • Even when NaCl excretion is increased w/ high AVP levels, NaCl reabsorption by the thick ascending limb of Henle’s loop, the distal tubule, and the collecting duct is still stimulated. However, the resorptive capacity of these segments is overwhelmed by the NaCl delivered to these segments from the proximal tubule, and as result, NaCl excretion is increased.
43
Q

Late distal tubule and CD have what 2 cell types that do what?

A
  1. Principal cells: reabsorb Na+, Cl- and H20 and secrete K+
  2. Intercalated cells, which reabsorb K+ and secrete H+
44
Q

How does ADH act on principal cells of the late DCT and CD?

What happens to K and Na+?

A
  1. High ADH/restriction of water–> inserts AQP2 channels apical membrane of the late DCT and CD–> + permeability to water–> + reabsorption of water –> creating a more concentrated urine.
  2. No ADH/ingestion of large amount of water–> no AQP2 channels inserted –> DCT and CD are impermeable to water –> little H2O is reabsorbed–> creating a more dilute urine.
    - Na is reabsorbed via Na/K ATPases. K enters the cell from the BL membrane via Na/K ATPase and diffuses down concentration gradient –> apical membrane–> tubular fluid.
45
Q

Number of AQP channels–> affects the volume of water reabsorbed or secreted.

Which affects what?

A

1. Plasma osmolarity

2. Urine osmolarity

3. BP

46
Q

SIMPLE RULES FOR ADH

Overhydrated –> _____ ADH

Dehydrated –> _____ ADH

A

Overhydrated –> low ADH

Dehydrated –> high ADH

47
Q

Why are intercalated cells important?

A

Intercalated cells are important for acid-base balance.

+ Aldosterone–> + H+ secretion via H+-ATPase

48
Q

Aldosterone is often called ____________.

Where is it made and how is it released.

A

Aldosterone aka “salt-retaining hormone”.

Released from the adrenal CTX d/t

  1. Indirectly via angiotensin II
  2. Directly via increased plasma K+ levels.
49
Q

Aldosterone mechanism.

A

[pic]

50
Q

Decrease in plasma K+–> _____ aldosteroen

A

reduction in aldosterone secretion

51
Q

Plasma osmolality of a hydrated person–>

Plasma osmolality if a dehydrated person–>

A

Plasma osmolality of a hydrated person–> 275-295 mOsm/kg

Plasma osmolality if a dehydrated person–> >300 mOsm/kg

52
Q

Central Neurogenic Diabetes Insipidus occurs after

A

head trauma

brain neoplasma

infections

53
Q

Central Neurogenic Diabetes Insipidus effect:

A

Low ADH levels d/t abnormal synthesis and secretion of ADH

54
Q

Characteristcs of Central Neurogenic Diabetes Insipidus (3) and treatment

A

1. Poluria–> inadequate release of ADH from the posterior pituitary causes an excretion of a large volume of dilute urine. Leads to increased thirst, to compensate for too much water loss.

2. Dilute urine

3. Polydipsia–> Increase thirst leads to an increase in water consumption.

  • Thus, a person with CDI must ingest a shit ton of water to maintain a constant body fluid osmolality.

-Thus: production of a large volume of dilute urine that can exceed 15 L/day.

Tx: exogenous ADH (desmopressin).

55
Q

Patients with Central Neurogenic Diabetes Insipidus exhibit polydipsia, an increase in thirst and consumption of what. What happens if water intake is restricted or the patient is unconscious because of a head injury?

A

Body fluids become serverely hyperosmotic and severe dehydration occurs.

56
Q

Nephrogenic Diabetes Insipidus effect

A

Effect: ADH levels are norma or elevated, however collecting ducts do not respond to ADH. Thus, cannot maximally concentrate urine.

  • Thought to be d/t a failure of the countercurrent mechanism to create a hyperosmotic medulla or the distal and CD to respond to ADH.
57
Q

Nephrogenic Diabetes Insipidus characteristics (2) and tx.

A
  1. Polyuria
  2. Dilute urine
  3. Polydipsia

Large volumes of dilute urine are made, causing dehydration unless fluid intake is increased by the same amount as urine volume is increased.

Tx:

58
Q

How can we distinguish Nephrogenic Diabetes Insipidus from Central Diabetes Insipidus?

A

-Administration of Desmopressin-

If the patient does not decrease urine volune and increase urine osmolarity within 2 hours after the injection–> nephrogenic DI.

59
Q

Nephrogenic Diabetes insipidus is also assx with what?

A
  1. Hypernatremia (can be decreased with a low-Na+ diet and thiazide diuretic, with increases Na+ secretion)
  2. Hypokalemia
  3. Hypocalcemia
  4. Low protein diet
  5. Uretal obstruction
60
Q

SIADH is caused by what?

A
  1. Infections and neoplasms of the brain,
  2. drugs
  3. pulmonary diseases
  4. lung cancer.
61
Q

Effects of SIADH

A

Elevated plasma ADH levels above what would be expected for ones plasma osmolarity, BP and BV.

62
Q

Characteristic of SIADH (mechanism)

A
  1. If plasma osmolality has dropped and ADH continues to be released–>
  2. Increased aquaporin 2 channels on DCT and CD–>
  3. Increase water reabsorption in blood (increasing ECF)–>
    1. Diluting blood (hypoosmotic) –>
    2. Dilutes Na+ and [takes up more space in blood vessels]–>
    3. Decrease in aldosterone, causing a decrease in plasma Na+ as Na+ is secreted –>
    4. Increases GFR
  4. Creates a concentration gradient–>
  5. Increased Na+ excretion and a shifting fluid into cells and causing them to swell to balance the concentration of fluid (water intoxication).
  6. Normalizing fluid volume in blood

Thus, we are retaining water and removing Na+ from our body, which already has low Na+

Tx: non-peptide vasopressin antagonists.

63
Q

A patient with SIADH will develop what?

A

Thirst, dyspnea on exertion, vommiting, abdominal cramps, confusion, lethargy and hypnotremia.

64
Q

Diabetes Insipidus

____ urinary output

____ levels of ADH

____natremia

Overhydrated/dehydrated

Loses/retains too much fluid

_____ thirst

A

High urinary output

Low levels of ADH

Hypernatremia

Dehydrated

Loses too much fluid

Excessive thirst

65
Q

SIADH

____ urinary output

____ levels of ADH

____natremia

Overhydrated/dehydrated

Loses/retains too much fluid

_____ thirst

A

SIADH

Low urinary output

High levels of ADH

Hyponatremia

Overhydrated

Retains too much fluid

Excessive thirst

66
Q

Excreting Dilute Urine (Water diuresis) when ADH levels are low.

Steps:

A
  1. Fluid entering the descending thin limb of the LoH is isosmotic with the plasma, reflecting the isosmotic nature in the proximal tubule.
  2. Thin Descending LoH: water is reabsorbed (mostly in the outer medulla) via AQP1.
    1. This limits the amount of the amount of water added the deepest part of the inner medullary interstitial space, preserving the hyperosmolarity of this part of the medulla
  3. Inner medulla of the terminal descending thin limb and the thin ascending limb is impermeable to water.
    1. However, they have CLCK1 Cl- channels, allowing Cl- to be reabsorbed and Na+ to be reabsorbed paracellular. This begins the dilution of the tubular fluid.
  4. Thick ascending LoH: reabsorbs NaCl & impermeable to water, diluting the tubular fluid and creating a hypoosmotic setting.
    1. NaCl accumulates in the medullary interstitium and is necessary to make urine hyperosmotic to plasma because it creates an osmotic gradient for water reabsorption in the medullar collecting duct.
  5. DCT and cortical portion of CD: actively reabsorb NaCl.
      • ADH–> not permeable to water–> osmolality of the tubular fluid is further reduced because NaCl is reabsorbed without water.
    1. Fluid in the cortical portion of the collective duct is hypoosmotic with the plasma.
  6. Medullary CD: actively reabsorbs NaCl. Even without ADH, it is slightly permeable to water and some is reabsorbed.
  7. Urine osmolality is as low as 50 mOsm/kg H2O and has low concentrations of NaCl.
    1. Volume can be as much as 18 L/day.
67
Q

Pt Johnny consumes a large amount of water. Excess H20 must be removed from the body without losing solutes that are critical for homeostasis.

Steps:

A
  1. No ADH is secreted, so the DT and the CT are impermeable to water.
  2. Tubular fluid entering the DT hypotonic (100 mOsm), having lost NaCl without H20 in the thick ascending LoH.
  3. As it goes through the distal tubule and is CT, the medullary osmotic gradient does not effect tubular fluid because the late tubule because it is impermeable to H20.
  4. Without ADH, 20% of the filtered fluid that reaches the distal tubule is not reabsorbed. However, excretion of wastes and other solutes is constant.
  5. When we have excess water, urine flow rate increases and the concentration of the urea in the inner medullary CD is reduced, causing less diffusion of urea in the medulla
  6. RESULT: large volume of dilute urine, which helps ride the body of excess H20.
68
Q

What happens when we have a H20 deficit? (* look at slide)

A
  1. H20 deficit–> Increases ADH levels.
  2. ADH stimulates NaCl reabsorption in the thick ascending LoH, which maintains the medullary gradient as water is being added from the medullary collecting duct, which would decrease the gradient.
  3. Fluid reaching CD is hypoostmotic, compared to interstitialàcreates a concentration gradient. ADH inserts AQP2 channels into late DCT and CD–> water is reabsorbedàfluid osmolarity increases, concentrating the urine
  4. As tubular fluid descends deeper into the medulla, water continues to be reabsorbed from the CDàincreasing tubular fluid osmolality to 1200 mOsm/kg H2O.
  5. Urine made when ADH levels are high has an osmolality of 1200 mOsm/kg H20 and has a high concentration of urea + other solutes.
    1. Urine volune can be as low as 0.5 L/day.
69
Q

In the presence of ADH, recall that the intra-tubular fluid of the distal tubule can only reach, ____ mOsm / kg H20. Why?

A

300 mOsm/kg H20.

This is because the interstitial fluid of the cortex is isotonic.

70
Q

In situations where we have no ADH and high ADH levels, how much fluid is delivered to the late DT and CD?

A

In both situations, a constant volume of dilute tubular fluid is delivered to the ADH-late DT and CD. ADH levels will then determine the amount of water that we reabsorb.

  • Low ADH–> small volume is reabsorbed and hypoosmotic urine is excreted.
  • High ADH–> high volume is reabsorbed and a small volume of hyperosmotic urine is excreted.

Most H20 is reabsorbed in the distal tubular and cortical and outer medullary portions of the CD. Thus, only a small amount of urine will reach the inner medullar CD, where it is then reabsorbed.

71
Q

What is hyponatremia?

A

Hyponatremia–> high water, low Na+ in the plasma.

It usually occurs d/t high ADH decreasing water excretion.

72
Q

Very rarely is hyponatremia a consequence of what two things?

A
  1. Insufficient solute consumption
  2. Polydipsia.
73
Q

What is hypernatremia?

A

Hypernatremia–> High Na+, compared to water.

Often d/t

  1. impaired thirst
  2. decreased water consumption
74
Q

in diabetes insipidus, even in situations of hypernatremia, the urine is _____

A

dilute

75
Q

in salt intoxication, the concentration of sodium in the urine will be ______– as would be expected.

A

very high

76
Q

Values for

Polyuria

Oliguria

Anuria

A
  1. Polyuria: >2.5L/day
  2. Oliguria (output below minimum): 300-500 mL/day
  3. Anuria (virtually no pee): <50mL/day
77
Q

Polyuria is usually associated with __________

A

polydipsia (water intake >100 mL/kg/day)

78
Q

4 mechanisms can cause polyuria

A
  1. Increased intake of fluids.
  2. Increased GFR (hyperthyroidism, fever, hyper metabolic states.)
  3. Increased output of solutes (diabetes mellitus, hyperthyroidism, hyperparathyroidism, diuretic use)
  4. Inability of the kidney to reabsorb water in the distal convoluted tubule (diabetes insipidus, drug use, chronic renal failure.)
79
Q

What is water diuresis?

A

An increase in water excretion, without an increase in Na+ excretion.

  • Primary cause: increased intake in water (as in polydipsia and diabetes insipidus).
80
Q

What is solute (osmotic) diuresis?

A

Increased water excretion + increased NaCl excretion due to increase salt in fluid.

Examples include: IV, hyperglycemia, high protein intake, recovery from AKI.

81
Q

What is the obligatory urine volume (minimum amount of urine one must excrete in day)?

How many mOsm of solutes/day must a bedridden and active person excrete?

A

Obligatory urine volume –> minimum amount of urine one must excrete in day.

Bedridden: 700 mOsm

Active: 1000 mOsm.

—the kidney can concentrate up to 1200 mOsm/L a day—.

82
Q

How can we calculate obligatory urine volume?

A

(mOsm of solutes/day an individual of a certain weight must excrete)/ 1200 mOsm/L

An individual must excrete at least 600 mOsm of solutes per day, and the kidneys are capable of concentrating urine to a maximum of 1200 mOsm per liter. This means an individual must excrete at least .5 L/day of urine. We call this “Obligatory Urine Volume.”

83
Q

What is free water clearance?

A

Free water clearance–> rate at which solute free water is excreted from the kidney.

Free water clearance (CH2O )= [urine flow rate - osmolar clearance]

if +, excess water is being excreted from the kidneys.

If -, excess solutes are being removed from the blood by the kidneys and water is being conserved.

84
Q

How to calculate osmolar clearance

A

Cosm= Uosm*V/Posm

=urine osmolarity * urine flow rate/ plasma osmolarity

85
Q

Why is the ratio of urine osmolarity (Uosm) to plasma osmolality (Posm) useful?

A

It can tell us the ability of the kidney to concetrate or dilute urine.

86
Q

Uosm:Posm > 1

tells us what?

A

The kidney can concentrate urine.

87
Q

Uosm:Posm = 1

tells us what?

A

Water and solute are being excreted in a state that is iso-osmotic with plasma.

88
Q

Uosm:Posm < 1

tells us what?

A

Kidneys are able to dilute urine.

89
Q

Look at last slides in the ppt

A
90
Q

State tubular fluid osmolalities during diuresis and antidiuresis at the distal end of each of the following tubular segments of juxtamedullary nephrons: the proximal convoluted tubule, descending limb of Henle’s loop, thick ascending limb of Henle’s loop, distal convoluted tubule, cortical collecting duct, and inner medullary collecting duct.

A

Proximal convoluted tubule:

“Reabsorption of solute in the proximal tubule results in the reabsorption of a proportional amount of water.” Therefore, the proximal tubule cannot be said to produce dilute or concentrated tubular fluid. Furthermore, fluid that enters the proximal convoluted tubule is isosmotic. Therefore, fluid that exits the proximal convoluted tubule must also be iso-osmotic.

Descending limb of the loop of Henle:

Isosmotic fluid enters the descending limb of the loop of Henle, and is rapidly concentrated. 1200 milliosmolar in the presence of ADH, 600 milliosmolar in the absence of ADH. The difference here is due to the increased amount of urea in the medullary interstitial space, increasing the osmotic pressure.

Ascending limb of the loop of Henle:

The ascending limb of the loop of Henle is not permeable to water, but it is permeable to solutes. Sodium chloride, for example, is pumped out very quickly. I like to think that the speed of this transporter is why we see an osmolality of 140 whether we are in the presence of ADH or not.

Distal convoluted tubule / Cortical collecting duct:

The distal tubule and cortical collecting duct reabsorb sodium chloride (NaCl goes into the interstitium). These sections are only permeable to water in the presence of ADH. Therefore, in the absence of ADH, the intertubular fluid here becomes even more hypoosmotic, because sodium chloride is reabsorb without water.

Inner medullary collecting duct:

The inner medullary collecting duct actively reabsorbs NaCl. Even in the absence of ADH, some water will leave the medullary collecting duct. This is when the difference between concentrated and un-concentrated urine is the most significant, and we see and osmolality of 1200 in the presence of ADH, and and osmolality of 50 in the absence of ADH.

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Q
  1. Describe the actions of diuretics on the ability of the kidneys to maximally concentrate and dilute urine.
A

Diuretics decrease the ability of the kidneys to maximally concentrate urine by inhibiting the sodium / potassium / chloride transporters that the nephron would use to establish an increase of osmolality of the medullary interstitium.

However, diuretics would increase the ability of the kidneys to dilute urine, as the activity of the solute transporters would be diminished, but the activity of ADH would be unaffected. This would be useful in cases where the patient needs to release water in greater amounts than the kidney is normally capable of, such as in cases of edema.